Investigating the dependence of SCM simulated precipitation and clouds on the spatial scale of large-scale forcing at SGP [Investigating the scale dependence of SCM simulated precipitation and cloud by using gridded forcing data at SGP

DOE PAGES

Tang, Shuaiqi; Zhang, Minghua; Xie, Shaocheng

2017-08-05

Large-scale forcing data, such as vertical velocity and advective tendencies, are required to drive single-column models (SCMs), cloud-resolving models, and large-eddy simulations. Previous studies suggest that some errors of these model simulations could be attributed to the lack of spatial variability in the specified domain-mean large-scale forcing. This study investigates the spatial variability of the forcing and explores its impact on SCM simulated precipitation and clouds. A gridded large-scale forcing data during the March 2000 Cloud Intensive Operational Period at the Atmospheric Radiation Measurement program's Southern Great Plains site is used for analysis and to drive the single-column version ofmore » the Community Atmospheric Model Version 5 (SCAM5). When the gridded forcing data show large spatial variability, such as during a frontal passage, SCAM5 with the domain-mean forcing is not able to capture the convective systems that are partly located in the domain or that only occupy part of the domain. This problem has been largely reduced by using the gridded forcing data, which allows running SCAM5 in each subcolumn and then averaging the results within the domain. This is because the subcolumns have a better chance to capture the timing of the frontal propagation and the small-scale systems. As a result, other potential uses of the gridded forcing data, such as understanding and testing scale-aware parameterizations, are also discussed.« less

Negative tail fusions can improve ruggedness of single domain antibodies.

PubMed

Goldman, Ellen R; Brozozog-Lee, P Audrey; Zabetakis, Dan; Turner, Kendrick B; Walper, Scott A; Liu, Jinny L; Anderson, George P

2014-03-01

Single-domain antibodies (sdAbs), the recombinantly expressed binding domains derived from the heavy-chain-only antibodies found in camelids and sharks, are valued for their ability to refold after heat denaturation. However, some sdAbs are prone to aggregation on extended heating at high concentration. Additionally, sdAbs prepared cytoplasmically often lack the conserved disulfide bond found in variable heavy domains, which both decreases their melting point and can decrease their ability to refold. Genetic fusions of sdAbs with the acid tail of α-synuclein (ATS) resulted in constructs that had enhanced ability to resist aggregation. In addition, almost complete refolding was observed even in the absence of the disulfide bond. These sdAb-ATS fusions expand the utility of sdAbs. They provide sdAbs that are resistant to aggregation, and enable the production of re-foldable sdAbs in the reducing environment of the cytoplasm. Published by Elsevier Inc.

Enhanced production of a single domain antibody with an engineered stabilizing extra disulfide bond.

PubMed

Liu, Jinny L; Goldman, Ellen R; Zabetakis, Dan; Walper, Scott A; Turner, Kendrick B; Shriver-Lake, Lisa C; Anderson, George P

2015-10-09

Single domain antibodies derived from the variable region of the unique heavy chain antibodies found in camelids yield high affinity and regenerable recognition elements. Adding an additional disulfide bond that bridges framework regions is a proven method to increase their melting temperature, however often at the expense of protein production. To fulfill their full potential it is essential to achieve robust protein production of these stable binding elements. In this work, we tested the hypothesis that decreasing the isoelectric point of single domain antibody extra disulfide bond mutants whose production fell due to the incorporation of the extra disulfide bond would lead to recovery of the protein yield, while maintaining the favorable melting temperature and affinity. Introduction of negative charges into a disulfide bond mutant of a single domain antibody specific for the L1 antigen of the vaccinia virus led to approximately 3.5-fold increase of protein production to 14 mg/L, while affinity and melting temperature was maintained. In addition, refolding following heat denaturation improved from 15 to 70 %. It also maintained nearly 100 % of its binding function after heating to 85 °C for an hour at 1 mg/mL. Disappointingly, the replacement of neutral or positively charged amino acids with negatively charged ones to lower the isoelectric point of two anti-toxin single domain antibodies stabilized with a second disulfide bond yielded only slight increases in protein production. Nonetheless, for one of these binders the charge change itself stabilized the structure equivalent to disulfide bond addition, thus providing an alternative route to stabilization which is not accompanied by loss in production. The ability to produce high affinity, stable single domain antibodies is critical for their utility. While the addition of a second disulfide bond is a proven method for enhancing stability of single domain antibodies, it frequently comes at the cost of reduced yields. While decreasing the isoelectric point of double disulfide mutants of single domain antibodies may improve protein production, charge addition appears to consistently improve refolding and some charge changes can also improve thermal stability, thus providing a number of benefits making the examination of such mutations worth consideration.

Data and code for the exploratory data analysis of the electrical energy demand in the time domain in Greece.

PubMed

Tyralis, Hristos; Karakatsanis, Georgios; Tzouka, Katerina; Mamassis, Nikos

2017-08-01

We present data and code for visualizing the electrical energy data and weather-, climate-related and socioeconomic variables in the time domain in Greece. The electrical energy data include hourly demand, weekly-ahead forecasted values of the demand provided by the Greek Independent Power Transmission Operator and pricing values in Greece. We also present the daily temperature in Athens and the Gross Domestic Product of Greece. The code combines the data to a single report, which includes all visualizations with combinations of all variables in multiple time scales. The data and code were used in Tyralis et al. (2017) [1].

Learning and serial effects on verbal memory in mild cognitive impairment.

PubMed

Campos-Magdaleno, María; Díaz-Bóveda, Rosalía; Juncos-Rabadán, Onésimo; Facal, David; Pereiro, Arturo X

2016-01-01

The objective of this study was to examine different patterns of learning and episodic memory in 3 mild cognitive impairment (MCI) groups and a control group by administering the California Verbal Learning Test (CVLT) and using serial position effect as a principal variable. The study sample included 3 groups of patients with MCI (n = 90) divided into single-domain amnestic, multiple-domain amnestic, and multiple-domain nonamnestic MCI and a group of healthy controls (n = 60). We compared the performance of each group on several CVLT measures used in previous research, and we included a new measure that provides specific information about the serial effect. Data showed a similar pattern of learning and memory impairment in both amnestic MCI groups (i.e., no differences between the multiple-domain and single-domain subtypes); the recency effect was significantly higher in both amnestic MCI groups than in all other groups, and the primacy effect was only lower in the multiple-domain amnestic MCI subtype. Verbal learning and memory profiles of patients with amnestic MCI were very similar, independent of the presence of deficits in cognitive domains other than episodic memory. Results are discussed in light of the unitary-store model of memory.

Studies of thermostability in Camelus bactrianus (Bactrian camel) single-domain antibody specific for the mutant epidermal-growth-factor receptor expressed by Pichia.

PubMed

Omidfar, Kobra; Rasaee, Mohhamad Javad; Kashanian, Soheila; Paknejad, Malieheh; Bathaie, Zahra

2007-01-01

Camelids have a unique immune system capable of producing heavy-chain antibodies lacking the light chains and CH1 (constant heavy-chain domain 1). It has been shown that, in contrast with conventional antibody fragments, the variable domains of these heavy-chain antibodies are functional at or after exposure to high temperatures. In the present study, the VHH (variable domain of heavy-chain antibody) camel antibody was subcloned into vector Ppiczc and expressed in Pichia pastoris. ORB1-83 VHH antibody recognizes the external domain of the mutant EGFR [EGF (epidermal growth factor) receptor], EGFR VIII. This tumour-specific antigen is ligand-independent, contains a constitutively active tyrosine kinase domain and has been shown to be present in a number of human malignancies. We report here that, although expression from P. pastoris resulted in a significantly increased level of expression of the anti-EGFR VIII VHH antibodies compared with Escherichia coli [Omidfar, Rasaee, Modjtahedi, Forouzandeh, Taghikhani, Bakhtiari, Paknejad and Kashanian (2004) Tumor Biol. 25, 179-187; Omidfar, Rasaee, Modjtahedi, Forouzandeh, Taghikhani and Golmakany (2004) Tumor Biol. 25, 296-305], this antibody selectively bound to the EGFR VIII peptide and reacted specifically with the immunoaffinity-purified antigen from non-small-cell lung cancer. Furthermore, thermal denaturation stability and CD spectra analysis of the Camelus bactrianus (Bactrian camel) VHH and heavy-chain antibodies at different temperature proved reversibility and binding activity after heat denaturation. Our results indicate that the P. pastoris expression system may be useful for the expression of camel single domain antibody and the ability of the expressed protein to reversibly melt without aggregation, allowing it to regain binding activity after heat denaturation.

Enhancement of frequency domain indices of heart rate variability by cholinergic stimulation with pyridostigmine bromide.

PubMed

Zarei, Ali Asghar; Foroutan, Seyyed Abbas; Foroutan, Seyyed Mohsen; Erfanian Omidvar, Abbas

2011-01-01

Pyridostigmine bromide (PB) is a reversible cholinesterase inhibitor. The aim of this study was to determine the effect of orally administration of single dose sustained-released tablet of pyridostigmine bromide (PBSR) on the frequency domain indices of heart rate variability (HRV). Thirty-two healthy young men were participated in this study. They were divided into 2 groups; the pyridostigmine group (n = 22) and the placebo group (n = 10). Electrocardiogram (ECG) was recorded at 10, 30, 60, 90, 120, 150, 180, 210, 240, 300 and 420 min after PBSR administration. At each time, simultaneously, a blood sample was prepared and PB plasma concentration was measured by high-performance liquid chromatography (HPLC) method. Statistical analysis showed that in different indices of HRV, there is a significant increase in low frequency (LF) band at 300 min, but no difference in high frequency band (HF). It also showed significant decreases in normalized high frequency band (Hfnu), normalized low frequency band (Lfnu) and LF/HF ratio at 120, 240 and 300 min after PBSR administration. Maximum plasma concentration of PB was 150 min after the administration. In conclusion, administration of a single dose PBSR can enhance the frequency domains indices of HRV and improvesympathovagal balance.

Combining information from 3 anatomic regions in the diagnosis of glaucoma with time-domain optical coherence tomography.

PubMed

Wang, Mingwu; Lu, Ake Tzu-Hui; Varma, Rohit; Schuman, Joel S; Greenfield, David S; Huang, David

2014-03-01

To improve the diagnosis of glaucoma by combining time-domain optical coherence tomography (TD-OCT) measurements of the optic disc, circumpapillary retinal nerve fiber layer (RNFL), and macular retinal thickness. Ninety-six age-matched normal and 96 perimetric glaucoma participants were included in this observational, cross-sectional study. Or-logic, support vector machine, relevance vector machine, and linear discrimination function were used to analyze the performances of combined TD-OCT diagnostic variables. The area under the receiver-operating curve (AROC) was used to evaluate the diagnostic accuracy and to compare the diagnostic performance of single and combined anatomic variables. The best RNFL thickness variables were the inferior (AROC=0.900), overall (AROC=0.892), and superior quadrants (AROC=0.850). The best optic disc variables were horizontal integrated rim width (AROC=0.909), vertical integrated rim area (AROC=0.908), and cup/disc vertical ratio (AROC=0.890). All macular retinal thickness variables had AROCs of 0.829 or less. Combining the top 3 RNFL and optic disc variables in optimizing glaucoma diagnosis, support vector machine had the highest AROC, 0.954, followed by or-logic (AROC=0.946), linear discrimination function (AROC=0.946), and relevance vector machine (AROC=0.943). All combination diagnostic variables had significantly larger AROCs than any single diagnostic variable. There are no significant differences among the combination diagnostic indices. With TD-OCT, RNFL and optic disc variables had better diagnostic accuracy than macular retinal variables. Combining top RNFL and optic disc variables significantly improved diagnostic performance. Clinically, or-logic classification was the most practical analytical tool with sufficient accuracy to diagnose early glaucoma.

Structural considerations for functional anti-EGFR × anti-CD3 bispecific diabodies in light of domain order and binding affinity.

PubMed

Asano, Ryutaro; Nagai, Keisuke; Makabe, Koki; Takahashi, Kento; Kumagai, Takashi; Kawaguchi, Hiroko; Ogata, Hiromi; Arai, Kyoko; Umetsu, Mitsuo; Kumagai, Izumi

2018-03-02

We previously reported a functional humanized bispecific diabody (bsDb) that targeted EGFR and CD3 (hEx3-Db) and enhancement of its cytotoxicity by rearranging the domain order in the V domain. Here, we further dissected the effect of domain order in bsDbs on their cross-linking ability and binding kinetics to elucidate general rules regarding the design of functional bsDbs. Using Ex3-Db as a model system, we first classified the four possible domain orders as anti-parallel (where both chimeric single-chain components are variable heavy domain (VH)-variable light domain (VL) or VL-VH order) and parallel types (both chimeric single-chain components are mixed with VH-VL and VL-VH order). Although anti-parallel Ex3-Dbs could cross-link the soluble target antigens, their cross-linking ability between soluble targets had no correlation with their growth inhibitory effects. In contrast, the binding affinity of one of the two constructs with a parallel-arrangement V domain was particularly low, and structural modeling supported this phenomenon. Similar results were observed with E2x3-Dbs, in which the V region of the anti-EGFR antibody clone in hEx3 was replaced with that of another anti-EGFR clone. Only anti-parallel types showed affinity-dependent cancer inhibitory effects in each molecule, and E2x3-LH (both components in VL-VH order) showed the most intense anti-tumor activity in vitro and in vivo . Our results showed that, in addition to rearranging the domain order of bsDbs, increasing their binding affinity may be an ideal strategy for enhancing the cytotoxicity of anti-parallel constructs and that E2x3-LH is particularly attractive as a candidate next-generation anti-cancer drug.

Monoclonal antibodies for the identification and purification of vNAR domains and IgNAR immunoglobulins from the horn shark Heterodontus francisci.

PubMed

Juarez, Karla; Dubberke, Gudrun; Lugo, Pavel; Koch-Nolte, Friedrich; Buck, Friedrich; Haag, Friedrich; Licea, Alexei

2011-08-01

In addition to conventional antibodies, cartilaginous fish have evolved a distinctive type of immunoglobulin, designated as IgNAR, which lacks the light polypeptide chains and is composed entirely by heavy chains. IgNAR molecules can be manipulated by molecular engineering to produce the variable domain of a single heavy chain polypeptide (vNARs). These, together with the VHH camel domains, constitute the smallest naturally occurring domains able to recognize an antigen. Their special features, such as small size, long extended finger-like CDR3, and thermal and chemical stability, make them suitable candidates for biotechnological purposes. Here we describe the generation of two mouse monoclonal antibodies (MAbs), MAb 370-12 and MAb 533-10, that both specifically react with vNAR domains of the horn shark Heterodontus francisci. While the former recognizes a broad spectrum of recombinant vNAR proteins, the latter is more restricted. MAb 370-12 precipitated a single band from whole shark serum, which was identified as IgNAR by mass spectrometry. Additionally, we used MAb 370-12 to follow the IgNAR-mediated immune response of sharks during immunization protocols with two different antigens (complete cells and a synthethic peptide), thus corroborating that MAb 370-12 recognizes both isolated vNAR domains and whole IgNAR molecules. Both MAbs represent an affordable molecular, biochemical, and biotechnological tool in the field of shark single-domain antibodies.

Production of novel recombinant single-domain antibodies against tandem repeat region of MUC1 mucin.

PubMed

Rahbarizadeh, F; Rasaee, M J; Forouzandeh Moghadam, M; Allameh, A A; Sadroddiny, E

2004-06-01

Recently, the existence of "heavy-chain" antibody in Camelidae has been described. However, as yet there is no data on the binding of this type of antibody to peptides. In addition, there was not any report of production of single-domain antibodies in two-humped camels (Camelus bactrianus). In the present study, these questions are addressed. We showed the feasibility of immunizing old world camels, cloning the repertoire of the variable domain of their heavy-chain antibodies, panning and selection, leading to the successful identification of minimum-sized antigen binders. Antigen-specific fragments of the heavy-chain IgGs (V(HH)) are of great interest in biotechnology because they are very stable, highly soluble, and react specifically and with high affinity to the antigens. In this study, we immunized two camels (Camelus dromedarius and Camelus bactrianus) with homogenized cancerous tissues, synthetic peptide, and human milk fat globule membrane (HMFG), and generated two V(HH) libraries displayed on phage particles. Some single-domain antibody fragments have been isolated that specifically recognize the tandem repeat region of MUC1. The camels' single-domain V(HH) harbor the original, intact antigen binding site and reacted specifically and with high affinity to the tandem repeat region of MUC1. Indeed soluble, specific antigen binders and good affinities (in the range of 0.2 x 10(9) M(-1) to 0.6 x 10(9) M(-1)) were identified from these libraries. This is the first example of the isolation of camel anti-peptide V(HH) domains.

Hyperspectral material identification on radiance data using single-atmosphere or multiple-atmosphere modeling

NASA Astrophysics Data System (ADS)

Mariano, Adrian V.; Grossmann, John M.

2010-11-01

Reflectance-domain methods convert hyperspectral data from radiance to reflectance using an atmospheric compensation model. Material detection and identification are performed by comparing the compensated data to target reflectance spectra. We introduce two radiance-domain approaches, Single atmosphere Adaptive Cosine Estimator (SACE) and Multiple atmosphere ACE (MACE) in which the target reflectance spectra are instead converted into sensor-reaching radiance using physics-based models. For SACE, known illumination and atmospheric conditions are incorporated in a single atmospheric model. For MACE the conditions are unknown so the algorithm uses many atmospheric models to cover the range of environmental variability, and it approximates the result using a subspace model. This approach is sometimes called the invariant method, and requires the choice of a subspace dimension for the model. We compare these two radiance-domain approaches to a Reflectance-domain ACE (RACE) approach on a HYDICE image featuring concealed materials. All three algorithms use the ACE detector, and all three techniques are able to detect most of the hidden materials in the imagery. For MACE we observe a strong dependence on the choice of the material subspace dimension. Increasing this value can lead to a decline in performance.

A Cognitive Complexity Metric Applied to Cognitive Development

ERIC Educational Resources Information Center

Andrews, Glenda; Halford, Graeme S.

2002-01-01

Two experiments tested predictions from a theory in which processing load depends on relational complexity (RC), the number of variables related in a single decision. Tasks from six domains (transitivity, hierarchical classification, class inclusion, cardinality, relative-clause sentence comprehension, and hypothesis testing) were administered to…

Impaired heart rate variability and altered cardiac sympathovagal balance after antidepressant overdose.

PubMed

Waring, W S; Rhee, J Y; Bateman, D N; Leggett, G E; Jamie, H

2008-11-01

Antidepressant overdose may be associated with significant cardiotoxicity, and recent data have shown that acute toxic effects are associated with impaired heart rate variability. This study was designed to examine the feasibility of non-invasive heart rate variability recording in patients that present to hospital after deliberate antidepressant ingestion. This was a prospective study of 72 consecutive patients attending the Emergency Department after deliberate antidepressant overdose and 72 age-matched patients that ingested paracetamol, as a control group. Single time-point continuous electrocardiographic recordings were used to allow spectral analyses of heart rate variability determined in low-frequency (LF) and high-frequency (HF) domains. The LF:HF ratio was used to represent overall sympathovagal cardiac activity. Antidepressant overdose was associated with reduced overall heart rate variability: 1329 vs. 2018 ms(2) (P = 0.0239 by Mann-Whitney test). Variability in the LF domain was higher (64.8 vs. 49.8, P = 0.0006), whereas that in the HF domain was lower (24.3 vs. 36.4, P = 0.0001), and the LF:HF ratio was higher in the antidepressant group (2.4 vs. 1.2, P = 0.0003). Antidepressant overdose is associated with impaired heart rate variability in a pattern consistent with excess cardiac sympathetic activity. Further work is required to establish the significance of these findings and to explore whether the impairment of heart rate variability may be used to predict the development of arrhythmia in this patient group.

The human TREM gene cluster at 6p21.1 encodes both activating and inhibitory single IgV domain receptors and includes NKp44.

PubMed

Allcock, Richard J N; Barrow, Alexander D; Forbes, Simon; Beck, Stephan; Trowsdale, John

2003-02-01

We have characterized a cluster of single immunoglobulin variable (IgV) domain receptors centromeric of the major histocompatibility complex (MHC) on human chromosome 6. In addition to triggering receptor expressed on myeloid cells (TREM)-1 and TREM2, the cluster contains NKp44, a triggering receptor whose expression is limited to NK cells. We identified three new related genes and two gene fragments within a cluster of approximately 200 kb. Two of the three new genes lack charged residues in their transmembrane domain tails. Further, one of the genes contains two potential immunotyrosine Inhibitory motifs in its cytoplasmic tail, suggesting that it delivers inhibitory signals. The human and mouse TREM clusters appear to have diverged such that there are unique sequences in each species. Finally, each gene in the TREM cluster was expressed in a different range of cell types.

Receiver deghosting in the t-x domain based on super-Gaussianity

NASA Astrophysics Data System (ADS)

Lu, Wenkai; Xu, Ziqiang; Fang, Zhongyu; Wang, Ruiliang; Yan, Chengzhi

2017-01-01

Deghosting methods in the time-space (t-x) domain have attracted a lot of attention because of their flexibility for various source/receiver configurations. Based on the well-known knowledge that the seismic signal has a super-Gaussian distribution, we present a Super-Gaussianity based Receiver Deghosting (SRD) method in the t-x domain. In our method, we denote the upgoing wave and its ghost (downgoing wave) as a single seismic signal, and express the relationship between the upgoing wave and its ghost using two ghost parameters: the sea surface reflection coefficient and the time-shift between the upgoing wave and its ghost. For a single seismic signal, we estimate these two parameters by maximizing the super-Gaussianity of the deghosted output, which is achieved by a 2D grid search method using an adaptively predefined discrete solution space. Since usually a large number of seismic signals are mixed together in a seismic trace, in the proposed method we divide the seismic trace into overlapping frames using a sliding time window with a step of one time sample, and consider each frame as a replacement for a single seismic signal. For a 2D seismic gather, we obtain two 2D maps of the ghost parameters. By assuming that these two parameters vary slowly in the t-x domain, we apply a 2D average filter to these maps, to improve their reliability further. Finally, these deghosted outputs are merged to form the final deghosted result. To demonstrate the flexibility of the proposed method for arbitrary variable depths of the receivers, we apply it to several synthetic and field seismic datasets acquired by variable depth streamer.

The Environmental Quality Index: associations of the land and socioeconomic domains with preterm birth in New Jersey.

EPA Science Inventory

Human health is affected by simultaneous exposure to positive and negative area-level features, but research often focuses on single exposures. To address this discontinuity, a county-level environmental quality index (EQI) is being constructed, including variables representin...

T cell-recruiting triplebody 19-3-19 mediates serial lysis of malignant B-lymphoid cells by a single T cell

PubMed Central

Roskopf, Claudia C.; Schiller, Christian B.; Braciak, Todd A.; Kobold, Sebastian; Schubert, Ingo A.; Fey, Georg H.; Hopfner, Karl-Peter; Oduncu, Fuat S.

2014-01-01

Triplebody 19-3-19, an antibody-derived protein, carries three single chain fragment variable domains in tandem in a single polypeptide chain. 19-3-19 binds CD19-bearing lymphoid cells via its two distal domains and primary T cells via its CD3-targeting central domain in an antigen-specific manner. Here, malignant B-lymphoid cell lines and primary cells from patients with B cell malignancies were used as targets in cytotoxicity tests with pre-stimulated allogeneic T cells as effectors. 19-3-19 mediated up to 95% specific lysis of CD19-positive tumor cells and, at picomolar EC50 doses, had similar cytolytic potency as the clinically successful agent BlinatumomabTM. 19-3-19 activated resting T cells from healthy unrelated donors and mediated specific lysis of both autologous and allogeneic CD19-positive cells. 19-3-19 led to the elimination of 70% of CD19-positive target cells even with resting T cells as effectors at an effector-to-target cell ratio of 1 : 10. The molecule is therefore capable of mediating serial lysis of target cells by a single T cell. These results highlight that central domains capable of engaging different immune effectors can be incorporated into the triplebody format to provide more individualized therapy tailored to a patient’s specific immune status. PMID:25115385

A canonical state-space representation for SISO systems using multipoint Jordan CFE. [Continued-Fraction Expansion

NASA Technical Reports Server (NTRS)

Hwang, Chyi; Guo, Tong-Yi; Shieh, Leang-San

1991-01-01

A canonical state-space realization based on the multipoint Jordan continued-fraction expansion (CFE) is presented for single-input-single-output (SISO) systems. The similarity transformation matrix which relates the new canonical form to the phase-variable canonical form is also derived. The presented canonical state-space representation is particularly attractive for the application of SISO system theory in which a reduced-dimensional time-domain model is necessary.

Sequence Analysis and Domain Motifs in the Porcine Skin Decorin Glycosaminoglycan Chain*

PubMed Central

Zhao, Xue; Yang, Bo; Solakylidirim, Kemal; Joo, Eun Ji; Toida, Toshihiko; Higashi, Kyohei; Linhardt, Robert J.; Li, Lingyun

2013-01-01

Decorin proteoglycan is comprised of a core protein containing a single O-linked dermatan sulfate/chondroitin sulfate glycosaminoglycan (GAG) chain. Although the sequence of the decorin core protein is determined by the gene encoding its structure, the structure of its GAG chain is determined in the Golgi. The recent application of modern MS to bikunin, a far simpler chondroitin sulfate proteoglycans, suggests that it has a single or small number of defined sequences. On this basis, a similar approach to sequence the decorin of porcine skin much larger and more structurally complex dermatan sulfate/chondroitin sulfate GAG chain was undertaken. This approach resulted in information on the consistency/variability of its linkage region at the reducing end of the GAG chain, its iduronic acid-rich domain, glucuronic acid-rich domain, and non-reducing end. A general motif for the porcine skin decorin GAG chain was established. A single small decorin GAG chain was sequenced using MS/MS analysis. The data obtained in the study suggest that the decorin GAG chain has a small or a limited number of sequences. PMID:23423381

Further developments in the controlled growth approach for optimal structural synthesis

NASA Technical Reports Server (NTRS)

Hajela, P.

1982-01-01

It is pointed out that the use of nonlinear programming methods in conjunction with finite element and other discrete analysis techniques have provided a powerful tool in the domain of optimal structural synthesis. The present investigation is concerned with new strategies which comprise an extension to the controlled growth method considered by Hajela and Sobieski-Sobieszczanski (1981). This method proposed an approach wherein the standard nonlinear programming (NLP) methodology of working with a very large number of design variables was replaced by a sequence of smaller optimization cycles, each involving a single 'dominant' variable. The current investigation outlines some new features. Attention is given to a modified cumulative constraint representation which is defined in both the feasible and infeasible domain of the design space. Other new features are related to the evaluation of the 'effectiveness measure' on which the choice of the dominant variable and the linking strategy is based.

What's My Domain?

ERIC Educational Resources Information Center

Curtis, Dan

2010-01-01

This article gives a simple method for determining the maximum interval of existence for a solution of a single, autonomous, first-order differential equation as well as the behavior of the solution as the independent variable approaches the ends of the interval. The methods used are elementary enough to be included in an introductory differential…

Enhancement of Frequency Domain Indices of Heart Rate Variability by Cholinergic Stimulation with Pyridostigmine Bromide

PubMed Central

Zarei, Ali Asghar; Foroutan, Seyyed Abbas; Foroutan, Seyyed Mohsen; Erfanian Omidvar, Abbas

2011-01-01

Pyridostigmine bromide (PB) is a reversible cholinesterase inhibitor. The aim of this study was to determine the effect of orally administration of single dose sustained-released tablet of pyridostigmine bromide (PBSR) on the frequency domain indices of heart rate variability (HRV). Thirty-two healthy young men were participated in this study. They were divided into 2 groups; the pyridostigmine group (n = 22) and the placebo group (n = 10). Electrocardiogram (ECG) was recorded at 10, 30, 60, 90, 120, 150, 180, 210, 240, 300 and 420 min after PBSR administration. At each time, simultaneously, a blood sample was prepared and PB plasma concentration was measured by high-performance liquid chromatography (HPLC) method. Statistical analysis showed that in different indices of HRV, there is a significant increase in low frequency (LF) band at 300 min, but no difference in high frequency band (HF). It also showed significant decreases in normalized high frequency band (Hfnu), normalized low frequency band (Lfnu) and LF/HF ratio at 120, 240 and 300 min after PBSR administration. Maximum plasma concentration of PB was 150 min after the administration. In conclusion, administration of a single dose PBSR can enhance the frequency domains indices of HRV and improvesympathovagal balance. PMID:24250427

The generation and selection of single-domain, v region libraries from nurse sharks.

PubMed

Flajnik, Martin F; Dooley, Helen

2009-01-01

The cartilaginous fish (sharks, skates, and rays) are the oldest phylogenetic group in which a human-type adaptive immune system and immunoglobulins (Igs) have been found. In addition to their conventional (heavy-light chain heterodimeric) isotypes, IgM and IgW, sharks produce the novel isotype, IgNAR, a heavy chain homodimer that does not associate with light chains. Instead, its variable (V) regions act as independent, soluble units in order to bind antigen. In this chapter, we detail our immunization protocol in order to raise a humoral IgNAR response in the nurse shark (Ginglymostoma cirratum) and the subsequent cloning of the single-domain V regions from this isotype in order to select antigen-specific binders by phage display.

Symmetry breaking and electrical frustration during tip-induced polarization switching in the non-polar cut of lithium niobate single crystals

DOE PAGES

Ievlev, Anton; Alikin, Denis O.; Morozovska, A. N.; ...

2014-12-15

Polarization switching in ferroelectric materials is governed by a delicate interplay between bulk polarization dynamics and screening processes at surfaces and domain walls. Here we explore the mechanism of tip-induced polarization switching in the non-polar cuts of uniaxial ferroelectrics. In this case, in-plane component of polarization vector switches, allowing for detailed observations of resultant domain morphologies. We observe surprising variability of resultant domain morphologies stemming from fundamental instability of formed charged domain wall and associated electric frustration. In particular, we demonstrate that controlling vertical tip position allows the polarity of the switching to be controlled. This represents very unusual formmore » of symmetry breaking where mechanical motion in vertical direction controls the lateral domain growth. The implication of these studies for ferroelectric devices and domain wall electronics are discussed.« less

Visualization and manipulation of magnetic domains in the quasi-two-dimensional material F e3GeT e2

NASA Astrophysics Data System (ADS)

Nguyen, Giang D.; Lee, Jinhwan; Berlijn, Tom; Zou, Qiang; Hus, Saban M.; Park, Jewook; Gai, Zheng; Lee, Changgu; Li, An-Ping

2018-01-01

The magnetic domains in two-dimensional layered material F e3GeT e2 are studied by using a variable-temperature scanning tunneling microscope with a magnetic tip after in situ cleaving of single crystals. A stripy domain structure is revealed in a zero-field-cooled sample below the ferromagnetic transition temperature of 205 K, which is replaced by separate double-walled domains and bubble domains when cooling the sample under a magnetic field of a ferromagnetic Ni tip. The Ni tip can further convert the double-walled domain to a bubble domain pattern as well as move the Neel-type chiral bubble in submicrometer distance. The temperature-dependent evolutions of both zero-field-cooled and field-cooled domain structures correlate well with the bulk magnetization from magnetometry measurements. Atomic resolution scanning tunneling images and spectroscopy are acquired to understand the atomic and electronic structures of the material, which are further corroborated by first-principles calculations.

Nanoscale magneto-structural coupling in as-deposited and freestanding single-crystalline Fe7Pd3 ferromagnetic shape memory alloy thin films

PubMed Central

Landgraf, Anja; Jakob, Alexander M; Ma, Yanhong; Mayr, Stefan G

2013-01-01

Ferromagnetic shape memory alloys are characterized by strong magneto-mechanical coupling occurring at the atomic scale causing large magnetically inducible strains at the macroscopic level. Employing combined atomic and magnetic force microscopy studies at variable temperature, we systematically explore the relation between the magnetic domain pattern and the underlying structure for as-deposited and freestanding single-crystalline Fe7Pd3 thin films across the martensite–austenite transition. We find experimental evidence that magnetic domain appearance is strongly affected by the presence and absence of nanotwinning. While the martensite–austenite transition upon temperature variation of as-deposited films is clearly reflected in topography by the presence and absence of a characteristic surface corrugation pattern, the magnetic domain pattern is hardly affected. These findings are discussed considering the impact of significant thermal stresses arising in the austenite phase. Freestanding martensitic films reveal a hierarchical structure of micro- and nanotwinning. The associated domain organization appears more complex, since the dominance of magnetic energy contributors alters within this length scale regime. PMID:27877596

Natural Language Search Interfaces: Health Data Needs Single-Field Variable Search.

PubMed

Jay, Caroline; Harper, Simon; Dunlop, Ian; Smith, Sam; Sufi, Shoaib; Goble, Carole; Buchan, Iain

2016-01-14

Data discovery, particularly the discovery of key variables and their inter-relationships, is key to secondary data analysis, and in-turn, the evolving field of data science. Interface designers have presumed that their users are domain experts, and so they have provided complex interfaces to support these "experts." Such interfaces hark back to a time when searches needed to be accurate first time as there was a high computational cost associated with each search. Our work is part of a governmental research initiative between the medical and social research funding bodies to improve the use of social data in medical research. The cross-disciplinary nature of data science can make no assumptions regarding the domain expertise of a particular scientist, whose interests may intersect multiple domains. Here we consider the common requirement for scientists to seek archived data for secondary analysis. This has more in common with search needs of the "Google generation" than with their single-domain, single-tool forebears. Our study compares a Google-like interface with traditional ways of searching for noncomplex health data in a data archive. Two user interfaces are evaluated for the same set of tasks in extracting data from surveys stored in the UK Data Archive (UKDA). One interface, Web search, is "Google-like," enabling users to browse, search for, and view metadata about study variables, whereas the other, traditional search, has standard multioption user interface. Using a comprehensive set of tasks with 20 volunteers, we found that the Web search interface met data discovery needs and expectations better than the traditional search. A task × interface repeated measures analysis showed a main effect indicating that answers found through the Web search interface were more likely to be correct (F1,19=37.3, P<.001), with a main effect of task (F3,57=6.3, P<.001). Further, participants completed the task significantly faster using the Web search interface (F1,19=18.0, P<.001). There was also a main effect of task (F2,38=4.1, P=.025, Greenhouse-Geisser correction applied). Overall, participants were asked to rate learnability, ease of use, and satisfaction. Paired mean comparisons showed that the Web search interface received significantly higher ratings than the traditional search interface for learnability (P=.002, 95% CI [0.6-2.4]), ease of use (P<.001, 95% CI [1.2-3.2]), and satisfaction (P<.001, 95% CI [1.8-3.5]). The results show superior cross-domain usability of Web search, which is consistent with its general familiarity and with enabling queries to be refined as the search proceeds, which treats serendipity as part of the refinement. The results provide clear evidence that data science should adopt single-field natural language search interfaces for variable search supporting in particular: query reformulation; data browsing; faceted search; surrogates; relevance feedback; summarization, analytics, and visual presentation.

Natural Language Search Interfaces: Health Data Needs Single-Field Variable Search

PubMed Central

Smith, Sam; Sufi, Shoaib; Goble, Carole; Buchan, Iain

2016-01-01

Background Data discovery, particularly the discovery of key variables and their inter-relationships, is key to secondary data analysis, and in-turn, the evolving field of data science. Interface designers have presumed that their users are domain experts, and so they have provided complex interfaces to support these “experts.” Such interfaces hark back to a time when searches needed to be accurate first time as there was a high computational cost associated with each search. Our work is part of a governmental research initiative between the medical and social research funding bodies to improve the use of social data in medical research. Objective The cross-disciplinary nature of data science can make no assumptions regarding the domain expertise of a particular scientist, whose interests may intersect multiple domains. Here we consider the common requirement for scientists to seek archived data for secondary analysis. This has more in common with search needs of the “Google generation” than with their single-domain, single-tool forebears. Our study compares a Google-like interface with traditional ways of searching for noncomplex health data in a data archive. Methods Two user interfaces are evaluated for the same set of tasks in extracting data from surveys stored in the UK Data Archive (UKDA). One interface, Web search, is “Google-like,” enabling users to browse, search for, and view metadata about study variables, whereas the other, traditional search, has standard multioption user interface. Results Using a comprehensive set of tasks with 20 volunteers, we found that the Web search interface met data discovery needs and expectations better than the traditional search. A task × interface repeated measures analysis showed a main effect indicating that answers found through the Web search interface were more likely to be correct (F 1,19=37.3, P<.001), with a main effect of task (F 3,57=6.3, P<.001). Further, participants completed the task significantly faster using the Web search interface (F 1,19=18.0, P<.001). There was also a main effect of task (F 2,38=4.1, P=.025, Greenhouse-Geisser correction applied). Overall, participants were asked to rate learnability, ease of use, and satisfaction. Paired mean comparisons showed that the Web search interface received significantly higher ratings than the traditional search interface for learnability (P=.002, 95% CI [0.6-2.4]), ease of use (P<.001, 95% CI [1.2-3.2]), and satisfaction (P<.001, 95% CI [1.8-3.5]). The results show superior cross-domain usability of Web search, which is consistent with its general familiarity and with enabling queries to be refined as the search proceeds, which treats serendipity as part of the refinement. Conclusions The results provide clear evidence that data science should adopt single-field natural language search interfaces for variable search supporting in particular: query reformulation; data browsing; faceted search; surrogates; relevance feedback; summarization, analytics, and visual presentation. PMID:26769334

Organizational Work and the Perceived Quality of Life: Toward a Conceptual Model.

DTIC Science & Technology

1984-08-01

portion of Figure 2, arrows from the environment (A or B) and from the person ( C ) join together and lead to domain activities (D or E ) as a way of...thereby enhancing the perceived quality of marital life, and ultimately an improved pQL overall (path B- E - C -D-F-J-L in Figure 2). A single work variable may...from the two domain-related activities (A- C , B- C , D- C , or E - C ). All arrows leading into either of the two environmental sectors (A and B) rep- V

Defensive Swarm: An Agent Based Modeling Analysis

DTIC Science & Technology

2017-12-01

INITIAL ALGORITHM (SINGLE- RUN ) TESTING .........................43  1.  Patrol Algorithm—Passive...scalability are therefore quite important to modeling in this highly variable domain. One can force the software to run the gamut of options to see...changes in operating constructs or procedures. Additionally, modelers can run thousands of iterations testing the model under different circumstances

Fast conversion of scFv to Fab antibodies using type IIs restriction enzymes.

PubMed

Sanmark, Hanna; Huovinen, Tuomas; Matikka, Tero; Pettersson, Tiina; Lahti, Maria; Lamminmäki, Urpo

2015-11-01

Single chain variable fragment (scFv) antibody libraries are widely used for developing novel bioaffinity reagents, although Fab or IgG molecules are the preferred antibody formats in many final applications. Therefore, rapid conversion methods for combining multiple DNA fragments are needed to attach constant domains to the scFv derived variable domains. In this study we describe a fast and easy cloning method for the conversion of single framework scFv fragments to Fab fragments using type IIS restriction enzymes. All cloning steps excluding plating of the Fab transformants can be done in 96 well plates and the procedure can be completed in one working day. The concept was tested by converting 69 scFv clones into Fab format on 96 well plates, which resulted in 93% success rate. The method is particularly useful as a high-throughput tool for the conversion of the chosen scFv clones into Fab molecules in order to analyze them as early as possible, as the conversion can significantly affect the binding properties of the chosen clones. Copyright © 2015 Elsevier B.V. All rights reserved.

Generation and characterization of ABT-981, a dual variable domain immunoglobulin (DVD-Ig(TM)) molecule that specifically and potently neutralizes both IL-1α and IL-1β.

PubMed

Lacy, Susan E; Wu, Chengbin; Ambrosi, Dominic J; Hsieh, Chung-Ming; Bose, Sahana; Miller, Renee; Conlon, Donna M; Tarcsa, Edit; Chari, Ravi; Ghayur, Tariq; Kamath, Rajesh V

2015-01-01

Interleukin-1 (IL-1) cytokines such as IL-1α, IL-1β, and IL-1Ra contribute to immune regulation and inflammatory processes by exerting a wide range of cellular responses, including expression of cytokines and chemokines, matrix metalloproteinases, and nitric oxide synthetase. IL-1α and IL-1β bind to IL-1R1 complexed to the IL-1 receptor accessory protein and induce similar physiological effects. Preclinical and clinical studies provide significant evidence for the role of IL-1 in the pathogenesis of osteoarthritis (OA), including cartilage degradation, bone sclerosis, and synovial proliferation. Here, we describe the generation and characterization of ABT-981, a dual variable domain immunoglobulin (DVD-Ig) of the IgG1/k subtype that specifically and potently neutralizes IL-1α and IL-1β. In ABT-981, the IL-1β variable domain resides in the outer domain of the DVD-Ig, whereas the IL-1α variable domain is located in the inner position. ABT-981 specifically binds to IL-1α and IL-1β, and is physically capable of binding 2 human IL-1α and 2 human IL-1β molecules simultaneously. Single-dose intravenous and subcutaneous pharmacokinetics studies indicate that ABT-981 has a half-life of 8.0 to 10.4 d in cynomolgus monkey and 10.0 to 20.3 d in rodents. ABT-981 exhibits suitable drug-like-properties including affinity, potency, specificity, half-life, and stability for evaluation in human clinical trials. ABT-981 offers an exciting new approach for the treatment of OA, potentially addressing both disease modification and symptom relief as a disease-modifying OA drug.

High sequence variability among hemocyte-specific Kazal-type proteinase inhibitors in decapod crustaceans.

PubMed

Cerenius, Lage; Liu, Haipeng; Zhang, Yanjiao; Rimphanitchayakit, Vichien; Tassanakajon, Anchalee; Gunnar Andersson, M; Söderhäll, Kenneth; Söderhäll, Irene

2010-01-01

Crustacean hemocytes were found to produce a large number of transcripts coding for Kazal-type proteinase inhibitors (KPIs). A detailed study performed with the crayfish Pacifastacus leniusculus and the shrimp Penaeus monodon revealed the presence of at least 26 and 20 different Kazal domains from the hemocyte KPIs, respectively. Comparisons with KPIs from other taxa indicate that the sequences of these domains evolve rapidly. A few conserved positions, e.g. six invariant cysteines were present in all domain sequences whereas the position of P1 amino acid, a determinant for substrate specificity, varied highly. A study with a single crayfish animal suggested that even at the individual level considerable sequence variability among hemocyte KPIs produced exist. Expression analysis of four crayfish KPI transcripts in hematopoietic tissue cells and different hemocyte types suggest that some of these KPIs are likely to be involved in hematopoiesis or hemocyte release as they were produced in particular hemocyte types or maturation stages only.

Resolving the Origin of Pseudo-Single Domain Magnetic Behavior

NASA Astrophysics Data System (ADS)

Roberts, Andrew P.; Almeida, Trevor P.; Church, Nathan S.; Harrison, Richard J.; Heslop, David; Li, Yiliang; Li, Jinhua; Muxworthy, Adrian R.; Williams, Wyn; Zhao, Xiang

2017-12-01

The term "pseudo-single domain" (PSD) has been used to describe the transitional state in rock magnetism that spans the particle size range between the single domain (SD) and multidomain (MD) states. The particle size range for the stable SD state in the most commonly occurring terrestrial magnetic mineral, magnetite, is so narrow ( 20-75 nm) that it is widely considered that much of the paleomagnetic record of interest is carried by PSD rather than stable SD particles. The PSD concept has, thus, become the dominant explanation for the magnetization associated with a major fraction of particles that record paleomagnetic signals throughout geological time. In this paper, we argue that in contrast to the SD and MD states, the term PSD does not describe the relevant physical processes, which have been documented extensively using three-dimensional micromagnetic modeling and by parallel research in material science and solid-state physics. We also argue that features attributed to PSD behavior can be explained by nucleation of a single magnetic vortex immediately above the maximum stable SD transition size. With increasing particle size, multiple vortices, antivortices, and domain walls can nucleate, which produce variable cancellation of magnetic moments and a gradual transition into the MD state. Thus, while the term PSD describes a well-known transitional state, it fails to describe adequately the physics of the relevant processes. We recommend that use of this term should be discontinued in favor of "vortex state," which spans a range of behaviors associated with magnetic vortices.

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

Goyal, Arti; Stawarz, Łukasz; Ostrowski, Michał

We present the results of our power spectral analysis for the BL Lac object PKS 0735+178, utilizing the Fermi -LAT survey at high-energy γ -rays, several ground-based optical telescopes, and single-dish radio telescopes operating at GHz frequencies. The novelty of our approach is that, by combining long-term and densely sampled intra-night light curves in the optical regime, we were able to construct for the first time the optical power spectrum of the blazar for a time domain extending from 23 years down to minutes. Our analysis reveals that: (1) the optical variability is consistent with a pure red noise, formore » which the power spectral density can be well approximated by a single power law throughout the entire time domain probed; (2) the slope of power spectral density at high-energy γ -rays (∼1) is significantly flatter than that found at radio and optical frequencies (∼2) within the corresponding time variability range; (3) for the derived power spectra, we did not detect any low-frequency flattening, nor do we see any evidence for cutoffs at the highest frequencies down to the noise floor levels due to measurement uncertainties. We interpret our findings in terms of a model where the blazar variability is generated by the underlying single stochastic process (at radio and optical frequencies), or a linear superposition of such processes (in the γ -ray regime). Along with the detailed PSD analysis, we also present the results of our extended (1998–2015) intra-night optical monitoring program and newly acquired optical photo-polarimetric data for the source.« less

Computed tear film and osmolarity dynamics on an eye-shaped domain

PubMed Central

Li, Longfei; Braun, Richard J.; Driscoll, Tobin A.; Henshaw, William D.; Banks, Jeffrey W.; King-Smith, P. Ewen

2016-01-01

The concentration of ions, or osmolarity, in the tear film is a key variable in understanding dry eye symptoms and disease. In this manuscript, we derive a mathematical model that couples osmolarity (treated as a single solute) and fluid dynamics within the tear film on a 2D eye-shaped domain. The model includes the physical effects of evaporation, surface tension, viscosity, ocular surface wettability, osmolarity, osmosis and tear fluid supply and drainage. The governing system of coupled non-linear partial differential equations is solved using the Overture computational framework, together with a hybrid time-stepping scheme, using a variable step backward differentiation formula and a Runge–Kutta–Chebyshev method that were added to the framework. The results of our numerical simulations provide new insight into the osmolarity distribution over the ocular surface during the interblink. PMID:25883248

Isolation of the new antigen receptor from wobbegong sharks, and use as a scaffold for the display of protein loop libraries.

PubMed

Nuttall, S D; Krishnan, U V; Hattarki, M; De Gori, R; Irving, R A; Hudson, P J

2001-08-01

The new antigen receptor (NAR) from nurse sharks consists of an immunoglobulin variable domain attached to five constant domains, and is hypothesised to function as an antigen-binding antibody-like molecule. To determine whether the NAR is present in other species we have isolated a number of new antigen receptor variable domains from the spotted wobbegong shark (Orectolobus maculatus) and compared their structure to that of the nurse shark protein. To determine whether these wNARs can function as antigen-binding proteins, we have used them as scaffolds for the construction of protein libraries in which the CDR3 loop was randomised, and displayed the resulting recombinant domains on the surface of fd bacteriophages. On selection against several protein antigens, the highest affinity wNAR proteins were generated against the Gingipain K protease from Porphyromonas gingivalis. One wNAR protein bound Gingipain K specifically by ELISA and BIAcore analysis and, when expressed in E. coli and purified by affinity chromatography, eluted from an FPLC column as a single peak consistent with folding into a monomeric protein. Naturally occurring nurse shark and wobbegong NAR variable domains exhibit conserved cysteine residues within the CDR1 and CDR3 loops which potentially form disulphide linkages and enhance protein stability; proteins isolated from the in vitro NAR wobbegong library showed similar selection for such paired cysteine residues. Thus, the New Antigen Receptor represents a protein scaffold with possible stability advantages over conventional antibodies when used in in vitro molecular libraries.

A single base pair in the right terminal domain of tomato planta macho viroid is a virulence determinant factor on tomato.

PubMed

Li, Rugang; Padmanabhan, Chellappan; Ling, Kai-Shu

2017-01-01

Tomato planta macho viroid (TPMVd), including isolates previously designated as Mexican papita viroid (MPVd), causes serious disease on tomatoes in North America. Two predominant variants, sharing 93.8% sequence identity, incited distinct severe (MPVd-S) or mild (MPVd-M) symptoms on tomato. To identify virulence determinant factor, a series of chimeric infectious clones were generated using synthetic DNA approach to progressively replace each structural domain between the two variants. In bioassays on tomato 'Rutgers', three chimeras containing Terminal Left and Pathogenicity (MPVd-H1), Central (MPVd-H2), or Variable (MPVd-H3) of MPVd-S, incited mild to intermediate symptoms. However, a chimera containing Terminal Right (T R ) of MPVd-S (MPVd-H4) incited severe symptoms. Only one base-pair mutation in the T R domain between MPVd-M ( 176 U:A 185 ) and MPVd-S ( 174 G:C 183 ) was identified. A reciprocal mutant (MPVd-H5) rendered the chimeric viroid mild on tomato. This single base-pair in the T R domain was determined as the virulence determinant factor for TPMVd. Published by Elsevier Inc.

Day-to-Day Variability of Postural Sway and Its Association With Cognitive Function in Older Adults: A Pilot Study

PubMed Central

Leach, Julia M.; Mancini, Martina; Kaye, Jeffrey A.; Hayes, Tamara L.; Horak, Fay B.

2018-01-01

Introduction: Increased variability in motor function has been observed during the initial stages of cognitive decline. However, the natural variability of postural control, as well as its association with cognitive status and decline, remains unknown. The objective of this pilot study was to characterize the day-to-day variability in postural sway in non-demented older adults. We hypothesized that older adults with a lower cognitive status would have higher day-to-day variability in postural sway. Materials and Methods: A Nintendo Wii balance board (WBB) was used to quantify postural sway in the home twice daily for 30 days in 20 non-demented, community-dwelling older adults: once under a single-task condition and once under a dual-task condition (using a daily word search task administered via a Nook tablet). Mean sway distance, velocity, area, centroidal frequency and frequency dispersion were derived from the center of pressure data acquired from the WBB. Results: Linear relationships were observed between the day-to-day variability in postural sway and cognitive status (indexed by cognitive global z-scores). More variability in time-domain postural sway (sway distance and area) and less variability in frequency-domain postural sway (centroidal sway frequency) were associated with a lower cognitive status under both the single- and dual-task conditions. Additionally, lower cognitive performance rates on the daily word search task were related to a lower cognitive status. Discussion: This small pilot study conducted on a short time scale motivates large-scale implementations over more extended time periods. Tracking longitudinal changes in postural sway may further our understanding of early-stage postural decline and its association with cognitive decline and, in turn, may aid in the early detection of dementia during preclinical stages when the utility of disease-modifying therapies would be greatest. PMID:29780319

Day-to-Day Variability of Postural Sway and Its Association With Cognitive Function in Older Adults: A Pilot Study.

PubMed

Leach, Julia M; Mancini, Martina; Kaye, Jeffrey A; Hayes, Tamara L; Horak, Fay B

2018-01-01

Introduction : Increased variability in motor function has been observed during the initial stages of cognitive decline. However, the natural variability of postural control, as well as its association with cognitive status and decline, remains unknown. The objective of this pilot study was to characterize the day-to-day variability in postural sway in non-demented older adults. We hypothesized that older adults with a lower cognitive status would have higher day-to-day variability in postural sway. Materials and Methods : A Nintendo Wii balance board (WBB) was used to quantify postural sway in the home twice daily for 30 days in 20 non-demented, community-dwelling older adults: once under a single-task condition and once under a dual-task condition (using a daily word search task administered via a Nook tablet). Mean sway distance, velocity, area, centroidal frequency and frequency dispersion were derived from the center of pressure data acquired from the WBB. Results : Linear relationships were observed between the day-to-day variability in postural sway and cognitive status (indexed by cognitive global z-scores). More variability in time-domain postural sway (sway distance and area) and less variability in frequency-domain postural sway (centroidal sway frequency) were associated with a lower cognitive status under both the single- and dual-task conditions. Additionally, lower cognitive performance rates on the daily word search task were related to a lower cognitive status. Discussion : This small pilot study conducted on a short time scale motivates large-scale implementations over more extended time periods. Tracking longitudinal changes in postural sway may further our understanding of early-stage postural decline and its association with cognitive decline and, in turn, may aid in the early detection of dementia during preclinical stages when the utility of disease-modifying therapies would be greatest.

Anti-Staphylococcus aureus single-chain variable region fragments provide protection against mastitis in mice.

PubMed

Wang, Man; Zhang, Yan; Zhu, Jianguo

2016-03-01

Staphylococcus aureus is a leading causative agent of bovine mastitis, which can result in significant economic losses to the dairy industry. However, available vaccines against bovine mastitis do not confer adequate protection, although passive immunization with antibodies may be useful to prevent disease. Hence, we constructed a bovine single-chain variable region fragment (scFv) phage display library using cDNAs from peripheral blood lymphocytes of cows with S. aureus-induced mastitis. After four rounds of selection, eight scFvs that bound S. aureus antigens with high affinity were obtained. The framework regions of the variable domains (VH and VL) of the eight scFvs were highly conserved, and the complementarity-determining regions (CDRs) displayed significant diversity, especially CDR3 of the VH domain. All eight scFvs inhibited S. aureus growth in culture medium. Lactating mice were challenged by injecting S. aureus into the fourth mammary gland. Histopathological analysis showed that treatment with these scFvs prior to bacterial challenge maintained the structure of the mammary acini, decreased infiltration of polymorphonuclear neutrophils, increased levels of interferon-gamma and interleukin-4, and reduced tumor necrosis factor-alpha levels in mammary tissues, as compared with mice treatment with physiological saline (P < 0.05). These novel bovine scFvs may be suitable candidates for therapeutic agents for the prevention of S. aureus-induced bovine mastitis.

Neural Spike Train Synchronisation Indices: Definitions, Interpretations and Applications.

PubMed

Halliday, D M; Rosenberg, J R

2017-04-24

A comparison of previously defined spike train syncrhonization indices is undertaken within a stochastic point process framework. The second order cumulant density (covariance density) is shown to be common to all the indices. Simulation studies were used to investigate the sampling variability of a single index based on the second order cumulant. The simulations used a paired motoneurone model and a paired regular spiking cortical neurone model. The sampling variability of spike trains generated under identical conditions from the paired motoneurone model varied from 50% { 160% of the estimated value. On theoretical grounds, and on the basis of simulated data a rate dependence is present in all synchronization indices. The application of coherence and pooled coherence estimates to the issue of synchronization indices is considered. This alternative frequency domain approach allows an arbitrary number of spike train pairs to be evaluated for statistically significant differences, and combined into a single population measure. The pooled coherence framework allows pooled time domain measures to be derived, application of this to the simulated data is illustrated. Data from the cortical neurone model is generated over a wide range of firing rates (1 - 250 spikes/sec). The pooled coherence framework correctly characterizes the sampling variability as not significant over this wide operating range. The broader applicability of this approach to multi electrode array data is briefly discussed.

Construction, expression, and characterization of a single-chain variable fragment antibody against 2,4-dichlorophenoxyacetic acid in the hemolymph of silkworm larvae.

PubMed

Sakamoto, Seiichi; Pongkitwitoon, Benyakan; Nakamura, Seiko; Sasaki-Tabata, Kaori; Tanizaki, Yusuke; Maenaka, Katsumi; Tanaka, Hiroyuki; Morimoto, Satoshi

2011-07-01

A single-chain variable fragment antibody against herbicide, 2,4-dichlorophenoxyacetic acid (2,4-D-scFv) has been successfully expressed in the hemolymph of silkworm larvae using a rapid Bombyx mori nucleopolyhedrovirus (BmNPV) bacmid DNA system. Variable heavy- and light-chain domains were cloned directly from the cDNA of the hybridoma cell line 2C4 and assembled together with flexible peptide linker (Gly(4)Ser)(3) between two domains. The yield of functional 2,4-D-scFv after purification was 640 μg per 30 ml of hemolymph, which is equivalent to 21.3 mg per liter of hemolymph. The characterization of 2,4-D-scFv using an indirect competitive enzyme-linked immunosorbent assay (icELISA) revealed that it has wide cross-reactivities against 2,4,5-trichlorophenoxyacetic acid (65.5%), 2,4-dichlorophenol (47.9%), and 2,4-dichlorobenzoic acid (26.0%), making it possible to apply 2,4-D-scFv to icELISA for detecting/determining 2,4-D and its metabolites. Judging from its cost and time requirements and its ease of handling, this BmNPV bacmid DNA expression system is more useful for expressing functional scFv than bacterial systems, which frequently require costly and time-consuming refolding.

Genome-wide maps of nuclear lamina interactions in single human cells.

PubMed

Kind, Jop; Pagie, Ludo; de Vries, Sandra S; Nahidiazar, Leila; Dey, Siddharth S; Bienko, Magda; Zhan, Ye; Lajoie, Bryan; de Graaf, Carolyn A; Amendola, Mario; Fudenberg, Geoffrey; Imakaev, Maxim; Mirny, Leonid A; Jalink, Kees; Dekker, Job; van Oudenaarden, Alexander; van Steensel, Bas

2015-09-24

Mammalian interphase chromosomes interact with the nuclear lamina (NL) through hundreds of large lamina-associated domains (LADs). We report a method to map NL contacts genome-wide in single human cells. Analysis of nearly 400 maps reveals a core architecture consisting of gene-poor LADs that contact the NL with high cell-to-cell consistency, interspersed by LADs with more variable NL interactions. The variable contacts tend to be cell-type specific and are more sensitive to changes in genome ploidy than the consistent contacts. Single-cell maps indicate that NL contacts involve multivalent interactions over hundreds of kilobases. Moreover, we observe extensive intra-chromosomal coordination of NL contacts, even over tens of megabases. Such coordinated loci exhibit preferential interactions as detected by Hi-C. Finally, the consistency of NL contacts is inversely linked to gene activity in single cells and correlates positively with the heterochromatic histone modification H3K9me3. These results highlight fundamental principles of single-cell chromatin organization. VIDEO ABSTRACT. Copyright © 2015 Elsevier Inc. All rights reserved.

Isolation and characterization of anti ROR1 single chain fragment variable antibodies using phage display technique.

PubMed

Aghebati-Maleki, Leili; Younesi, Vahid; Jadidi-Niaragh, Farhad; Baradaran, Behzad; Majidi, Jafar; Yousefi, Mehdi

2017-01-01

Receptor tyrosine kinase-like orphan receptor (ROR1) belongs to one of the families of receptor tyrosine kinases (RTKs). RTKs are involved in the various physiologic cellular functions including proliferation, migration, survival, signaling and differentiation. Several RTKs are deregulated in various cancers implying the targeting potential of these molecules in cancer therapy. ROR1 has recently been shown to be expressed in various types of cancer cells but not in normal adult cells. Hence a molecular inhibitor of extracellular domain of ROR1 that inhibits ROR1-cell surface interaction is of great therapeutic importance. In an attempt to develop molecular inhibitors of ROR1, we screened single chain variable fragment (scFv) phage display libraries, Tomlinson I + J, against one specific synthetic oligopeptide from extracellular domain of ROR1 and selected scFvs were characterized using various immunological techniques. Several ROR1 specific scFvs were selected following five rounds of panning procedure. The scFvs showed specific binding to ROR1 using immunological techniques. Our results demonstrate successful isolation and characterization of specific ROR1 scFvs that may have great therapeutic potential in cancer immunotherapy.

Profiling medical school learning environments in Malaysia: a validation study of the Johns Hopkins Learning Environment Scale.

PubMed

Tackett, Sean; Bakar, Hamidah Abu; Shilkofski, Nicole A; Coady, Niamh; Rampal, Krishna; Wright, Scott

2015-01-01

While a strong learning environment is critical to medical student education, the assessment of medical school learning environments has confounded researchers. Our goal was to assess the validity and utility of the Johns Hopkins Learning Environment Scale (JHLES) for preclinical students at three Malaysian medical schools with distinct educational and institutional models. Two schools were new international partnerships, and the third was school leaver program established without international partnership. First- and second-year students responded anonymously to surveys at the end of the academic year. The surveys included the JHLES, a 28-item survey using five-point Likert scale response options, the Dundee Ready Educational Environment Measure (DREEM), the most widely used method to assess learning environments internationally, a personal growth scale, and single-item global learning environment assessment variables. The overall response rate was 369/429 (86%). After adjusting for the medical school year, gender, and ethnicity of the respondents, the JHLES detected differences across institutions in four out of seven domains (57%), with each school having a unique domain profile. The DREEM detected differences in one out of five categories (20%). The JHLES was more strongly correlated than the DREEM to two thirds of the single-item variables and the personal growth scale. The JHLES showed high internal reliability for the total score (α=0.92) and the seven domains (α, 0.56-0.85). The JHLES detected variation between learning environment domains across three educational settings, thereby creating unique learning environment profiles. Interpretation of these profiles may allow schools to understand how they are currently supporting trainees and identify areas needing attention.

Profiling medical school learning environments in Malaysia: a validation study of the Johns Hopkins Learning Environment Scale

PubMed Central

Tackett, Sean; Bakar, Hamidah Abu; Shilkofski, Nicole A.; Coady, Niamh; Rampal, Krishna; Wright, Scott

2015-01-01

Purpose: While a strong learning environment is critical to medical student education, the assessment of medical school learning environments has confounded researchers. Our goal was to assess the validity and utility of the Johns Hopkins Learning Environment Scale (JHLES) for preclinical students at three Malaysian medical schools with distinct educational and institutional models. Two schools were new international partnerships, and the third was school leaver program established without international partnership. Methods: First- and second-year students responded anonymously to surveys at the end of the academic year. The surveys included the JHLES, a 28-item survey using five-point Likert scale response options, the Dundee Ready Educational Environment Measure (DREEM), the most widely used method to assess learning environments internationally, a personal growth scale, and single-item global learning environment assessment variables. Results: The overall response rate was 369/429 (86%). After adjusting for the medical school year, gender, and ethnicity of the respondents, the JHLES detected differences across institutions in four out of seven domains (57%), with each school having a unique domain profile. The DREEM detected differences in one out of five categories (20%). The JHLES was more strongly correlated than the DREEM to two thirds of the single-item variables and the personal growth scale. The JHLES showed high internal reliability for the total score (α=0.92) and the seven domains (α, 0.56-0.85). Conclusion: The JHLES detected variation between learning environment domains across three educational settings, thereby creating unique learning environment profiles. Interpretation of these profiles may allow schools to understand how they are currently supporting trainees and identify areas needing attention. PMID:26165949

[Cloning of VH and VL Gene of Human anti-IL1RAP McAb and Construction of Recombinant Chimeric Receptor].

PubMed

Yin, Ling-Ling; Ruan, Su-Hong; Tian, Yu; Zhao, Kai; Xu, Kai Lin

2015-10-01

To clone the variable region genes of human anti-IL1RAP (IL-1 receptor accessory protein) monoclonal antibodies (McAb) and to construct IL1RAP chimeric antigen receptors (CARs). The VH and VL DNA of IL1RAP single chain antibodies were amplified by RACE and overlap extension PCR from total RNA extracted from 3H6E10 and 10D8A7 hybridoma and ligated into specific IL1RAP single-chain variable fragments (scFv). CD8α transmembrane domain, CD137 intracellular domain, TCR ζ chain, human CD8α signal peptide and scFv-anti-IL1RAP were cloned into plasmid LV-lac. Recombinant lentiviruses were generated by co-transfection of recombinant plasmid LV-lac, pMD2. G, and psPAX2 helper vectors into 293FT packing cells. The VH and VL genes of 2 human anti-IL1RAP McAb were acquired. The 3H6E10 VH and VL genes consisted of 402 bp and 393 bp encoding 134 and 131 aminoacid residues, respectively; 10D8A7 VH and VL genes consisted of 423 bp and 381 bp encoding 141 and 127 amine acid residues, respectively. Recombinant expression vertors LV-3H6E10 scFv-ICD and LV-10D8A7 scFv-ICD (ICD: CD8α transmembrane domain-CD137 intracellular domain-TCR ζ chain) were constructed. The target fragments were demonstrated by sequencing analysis. Recombinant plasmids were transfected into 293FT cells and lentiviral particles were acquired. Human anti-IL1RAP recombinant receptors are constructed successfully and lay a good foundation for the construction of IL1RAP-CAR killer T cell vaccine.

Antibody engineering reveals the important role of J segments in the production efficiency of llama single-domain antibodies in Saccharomyces cerevisiae.

PubMed

Gorlani, A; Hulsik, D Lutje; Adams, H; Vriend, G; Hermans, P; Verrips, T

2012-01-01

Variable domains of llama heavy-chain antibodies (VHH) are becoming a potent tool for a wide range of biotechnological and medical applications. Because of structural features typical of their single-domain nature, they are relatively easy to produce in lower eukaryotes, but it is not uncommon that some molecules have poor secretion efficiency. We therefore set out to study the production yield of VHH. We computationally identified five key residues that are crucial for folding and secretion, and we validated their importance with systematic site-directed mutations. The observation that all key residues were localised in the V segment, in proximity of the J segment of VHH, led us to study the importance of J segment in secretion efficiency. Intriguingly, we found that the use of specific J segments in VHH could strongly influence the production yield. Sequence analysis and expression experiments strongly suggested that interactions with chaperones, especially with the J segment, are a crucial aspect of the production yield of VHH.

Coupling Osmolarity Dynamics within Human Tear Film on an Eye-Shaped Domain

NASA Astrophysics Data System (ADS)

Li, Longfei; Braun, R. J.; Driscoll, T. A.; Henshaw, W. D.; Banks, J. W.; King-Smith, P. E.

2013-11-01

The concentration of ions in the tear film (osmolarity) is a key variable in understanding dry eye symptoms and disease. We derived a mathematical model that couples osmolarity (treated as a single solute) and fluid dynamics within the tear film on a 2D eye-shaped domain. The model concerns the physical effects of evaporation, surface tension, viscosity, ocular surface wettability, osmolarity, osmosis and tear fluid supply and drainage. We solved the governing system of coupled nonlinear PDEs using the Overture computational framework developed at LLNL, together with a new hybrid time stepping scheme (using variable step BDF and RKC) that was added to the framework. Results of our numerical simulations show good agreement with existing 1D models (for both tear film and osmolarity dynamics) and provide new insight about the osmolarity distribution over the ocular surface during the interblink.

Specific binding of the WASP N-terminal domain to Btk is critical for TLR2 signaling in macrophages.

PubMed

Sakuma, Chisato; Sato, Mitsuru; Takenouchi, Takato; Kitani, Hiroshi

2015-02-01

Wiskott-Aldrich syndrome protein (WASP) is an adaptor molecule in immune cells. Recently, we revealed that WASP is involved in lipopolysaccharide-TLR4 signaling in macrophages by association of Bruton's tyrosine kinase (Btk) with the WASP N-terminal domain. Btk has been shown to play important roles in the signaling of several TLRs and to modulate the inflammatory response in macrophages. In this study, we evaluated the importance of the interaction between Btk and WASP in TLR2 signaling by using bone marrow-derived macrophage cell lines from transgenic (Tg) mice expressing anti-WASP N-terminal domain single-chain variable fragment (scFv) or VL single-domain intrabodies. In this Tg bone marrow-derived macrophages, specific interaction between WASP and Btk were strongly inhibited by masking of the binding site in the WASP N-terminal domain. There was impairment of gene expression of TNF-α, IL-6, and IL-1β and phosphorylation of inhibitor of κB α/β (IKKα/β) and nuclear factor (NF)-κB upon stimulation with TLR2 ligands. Furthermore, tyrosine phosphorylation of WASP following TLR2-ligand stimulation was severely inhibited in the Tg bone marrow-derived macrophages, as shown by the impairment in WASP tyrosine phosphorylation following lipopolysaccharide stimulation. These results strongly suggest that the association between the WASP N-terminal domain and Btk plays an important role in the TLR2-signaling pathway in macrophages. Copyright © 2014 Elsevier Ltd. All rights reserved.

Modeling AFM-induced PEVK extension and the reversible unfolding of Ig/FNIII domains in single and multiple titin molecules.

PubMed Central

Zhang, B; Evans, J S

2001-01-01

Molecular elasticity is associated with a select number of polypeptides and proteins, such as titin, Lustrin A, silk fibroin, and spider silk dragline protein. In the case of titin, the globular (Ig) and non-globular (PEVK) regions act as extensible springs under stretch; however, their unfolding behavior and force extension characteristics are different. Using our time-dependent macroscopic method for simulating AFM-induced titin Ig domain unfolding and refolding, we simulate the extension and relaxation of hypothetical titin chains containing Ig domains and a PEVK region. Two different models are explored: 1) a series-linked WLC expression that treats the PEVK region as a distinct entropic spring, and 2) a summation of N single WLC expressions that simulates the extension and release of a discrete number of parallel titin chains containing constant or variable amounts of PEVK. In addition to these simulations, we also modeled the extension of a hypothetical PEVK domain using a linear Hooke's spring model to account for "enthalpic" contributions to PEVK elasticity. We find that the modified WLC simulations feature chain length compensation, Ig domain unfolding/refolding, and force-extension behavior that more closely approximate AFM, laser tweezer, and immunolocalization experimental data. In addition, our simulations reveal the following: 1) PEVK extension overlaps with the onset of Ig domain unfolding, and 2) variations in PEVK content within a titin chain ensemble lead to elastic diversity within that ensemble. PMID:11159428

Efficient generation of monoclonal antibodies from single rhesus macaque antibody secreting cells.

PubMed

Meng, Weixu; Li, Leike; Xiong, Wei; Fan, Xuejun; Deng, Hui; Bett, Andrew J; Chen, Zhifeng; Tang, Aimin; Cox, Kara S; Joyce, Joseph G; Freed, Daniel C; Thoryk, Elizabeth; Fu, Tong-Ming; Casimiro, Danilo R; Zhang, Ningyan; A Vora, Kalpit; An, Zhiqiang

2015-01-01

Nonhuman primates (NHPs) are used as a preclinical model for vaccine development, and the antibody profiles to experimental vaccines in NHPs can provide critical information for both vaccine design and translation to clinical efficacy. However, an efficient protocol for generating monoclonal antibodies from single antibody secreting cells of NHPs is currently lacking. In this study we established a robust protocol for cloning immunoglobulin (IG) variable domain genes from single rhesus macaque (Macaca mulatta) antibody secreting cells. A sorting strategy was developed using a panel of molecular markers (CD3, CD19, CD20, surface IgG, intracellular IgG, CD27, Ki67 and CD38) to identify the kinetics of B cell response after vaccination. Specific primers for the rhesus macaque IG genes were designed and validated using cDNA isolated from macaque peripheral blood mononuclear cells. Cloning efficiency was averaged at 90% for variable heavy (VH) and light (VL) domains, and 78.5% of the clones (n = 335) were matched VH and VL pairs. Sequence analysis revealed that diverse IGHV subgroups (for VH) and IGKV and IGLV subgroups (for VL) were represented in the cloned antibodies. The protocol was tested in a study using an experimental dengue vaccine candidate. About 26.6% of the monoclonal antibodies cloned from the vaccinated rhesus macaques react with the dengue vaccine antigens. These results validate the protocol for cloning monoclonal antibodies in response to vaccination from single macaque antibody secreting cells, which have general applicability for determining monoclonal antibody profiles in response to other immunogens or vaccine studies of interest in NHPs.

Identification, inheritance, and linkage of B-G-like and MHC class I genes in cranes

USGS Publications Warehouse

Jarvi, S.I.; Goto, R.M.; Gee, G.F.; Briles, W.E.; Miller, M.M.

1999-01-01

We identified B-G-like genes in the whooping and Florida sandhill cranes and linked them to the major histocompatibility complex (MHC). We evaluated the inheritance of B-G-like genes in families of whooping and Florida sandhill cranes using restriction fragment patterns (RFPs). Two B-G-like genes, designated wcbgl and wcbg2, were located within 8 kb of one another. The fully sequenced wcbg2 gene encodes a B-G IgV-like domain, an additional Ig-like domain, a transmembrane domain, and a single heptad domain typical of '-helical coiled coils. Patterns of restriction fragments in DNA from the whooping crane and from a number of other species indicate that the B-G-like gene families of cranes are large with diverse sequences. Segregation of RFPs in families of Florida sandhill cranes provide evidence for genetic polymorphism in the B-G-like genes. The restriction fragments generally segregated in concert with MHC haplotypes assigned by serological typing and by single stranded conformational polymorphism (SSCP) assays based in the second exon of the crane MHC class I genes. This study supports the concept of a long-term association of polymorphic B-G-like genes with the MHC. It also establishes SSCP as a means for evaluating MHC genetic variability in cranes.

Identification, inheritance, and linkage of B-G-like and MHC class I genes in cranes.

PubMed

Jarvi, S I; Goto, R M; Gee, G F; Briles, W E; Miller, M M

1999-01-01

We identified B-G-like genes in the whooping and Florida sandhill cranes and linked them to the major histocompatibility complex (MHC). We evaluated the inheritance of B-G-like genes in families of whooping and Florida sandhill cranes using restriction fragment patterns (RFPs). Two B-G-like genes, designated wcbg1 and wcbg2, were located within 8 kb of one another. The fully sequenced wcbg2 gene encodes a B-G IgV-like domain, an additional Ig-like domain, a transmembrane domain, and a single heptad domain typical of alpha-helical coiled coils. Patterns of restriction fragments in DNA from the whooping crane and from a number of other species indicate that the B-G-like gene families of cranes are large with diverse sequences. Segregation of RFPs in families of Florida sandhill cranes provide evidence for genetic polymorphism in the B-G-like genes. The restriction fragments generally segregated in concert with MHC haplotypes assigned by serological typing and by single stranded conformational polymorphism (SSCP) assays based in the second exon of the crane MHC class I genes. This study supports the concept of a long-term association of polymorphic B-G-like genes with the MHC. It also establishes SSCP as a means for evaluating MHC genetic variability in cranes.

Production and characterization of a high-affinity nanobody against human endoglin.

PubMed

Ahmadvand, Davoud; Rasaee, Mohammad J; Rahbarizadeh, Fatemeh; Mohammadi, Mohammad

2008-10-01

Abstract Antibodies or antibody fragments are almost exclusively applied in human therapy and diagnosis. The high affinity and specificity of antibodies makes them suitable for these applications. Nanobody, the variable domain of Camelidae heavy chain antibodies, have superior properties compared with conventional antibodies in that they are small, non-immunogenic, very stable, highly soluble, and easy to produce in large quantities. In the present study, we report the isolation and characterization of a high-affinity binder against human endoglin retrieved from camels' nanobody gene library. Endoglin (CD105), an accessory protein of the transforming growth factor beta receptor complex, has become an attractive molecule for the targeting of the tumor vasculature. Upregulation of endoglin on proliferating endothelial cells is associated with tumor neovascularization. Here, we generated two nanobody gene libraries displayed on phage particles. Some single-domain antibody fragments have been isolated that specifically recognize the recombinant extracellular domain of human endoglin. The other selected anti-endoglin nanobody (AR1-86) showed strong binding to human endoglin expressing endothelial cells (HUVECs), while no binding was observed with the endoglin-negative cell line (HEK293). This high-affinity single-domain antibody could be a good candidate for the generation of vascular or tumor targeting agents in cancer therapy.

Mapping of Heavy Chain Genes for Mouse Immunoglobulins M and D

NASA Astrophysics Data System (ADS)

Liu, Chih-Ping; Tucker, Philip W.; Mushinski, J. Frederic; Blattner, Frederick R.

1980-09-01

A single DNA fragment containing both μ and δ immunoglobulin heavy chain genes has been cloned from normal BALB/c mouse liver DNA with a new λ phage vector Charon 28. The physical distance between the membrane terminal exon of μ and the first domain of δ is 2466 base pairs, with δ on the 3' side of μ . A single transcript could contain a variable region and both μ and δ constant regions. The dual expression of immunoglobulins M and D on spleen B cells may be due to alternate splicing of this transcript.

A stochastic model for density-dependent microwave Snow- and Graupel scattering coefficients of the NOAA JCSDA community radiative transfer model

NASA Astrophysics Data System (ADS)

Stegmann, Patrick G.; Tang, Guanglin; Yang, Ping; Johnson, Benjamin T.

2018-05-01

A structural model is developed for the single-scattering properties of snow and graupel particles with a strongly heterogeneous morphology and an arbitrary variable mass density. This effort is aimed to provide a mechanism to consider particle mass density variation in the microwave scattering coefficients implemented in the Community Radiative Transfer Model (CRTM). The stochastic model applies a bicontinuous random medium algorithm to a simple base shape and uses the Finite-Difference-Time-Domain (FDTD) method to compute the single-scattering properties of the resulting complex morphology.

Epitope mapping of the domains of human angiotensin converting enzyme.

PubMed

Kugaevskaya, Elena V; Kolesanova, Ekaterina F; Kozin, Sergey A; Veselovsky, Alexander V; Dedinsky, Ilya R; Elisseeva, Yulia E

2006-06-01

Somatic angiotensin converting enzyme (sACE), contains in its single chain two homologous domains (called N- and C-domains), each bearing a functional zinc-dependent active site. The present study aims to define the differences between two sACE domains and to localize experimentally revealed antigenic determinants (B-epitopes) in the recently determined three-dimensional structure of testicular tACE. The predicted linear antigenic determinants of human sACE were determined by peptide scanning ("PEPSCAN") approach. Essential difference was demonstrated between locations of the epitopes in the N- and C-domains. Comparison of arrangement of epitopes in the human domains with the corresponding sequences of some mammalian sACEs enabled to classify the revealed antigenic determinants as variable or conserved areas. The location of antigenic determinants with respect to various structural elements and to functionally important sites of the human sACE C-domain was estimated. The majority of antigenic sites of the C-domain were located at the irregular elements and at the boundaries of secondary structure elements. The data show structural differences between the sACE domains. The experimentally revealed antigenic determinants were in agreement with the recently determined crystal tACE structure. New potential applications are open to successfully produce mono-specific and group-specific antipeptide antibodies.

The intervening removable affinity tag (iRAT) production system facilitates Fv antibody fragment‐mediated crystallography

PubMed Central

Nomura, Yayoi; Sato, Yumi; Suno, Ryoji; Horita, Shoichiro

2016-01-01

Abstract Fv antibody fragments have been used as co‐crystallization partners in structural biology, particularly in membrane protein crystallography. However, there are inherent technical issues associated with the large‐scale production of soluble, functional Fv fragments through conventional methods in various expression systems. To circumvent these problems, we developed a new method, in which a single synthetic polyprotein consisting of a variable light (VL) domain, an intervening removable affinity tag (iRAT), and a variable heavy (VH) domain is expressed by a Gram‐positive bacterial secretion system. This method ensures stoichiometric expression of VL and VH from the monocistronic construct followed by proper folding and assembly of the two variable domains. The iRAT segment can be removed by a site‐specific protease during the purification process to yield tag‐free Fv fragments suitable for crystallization trials. In vitro refolding step is not required to obtain correctly folded Fv fragments. As a proof of concept, we tested the iRAT‐based production of multiple Fv fragments, including a crystallization chaperone for a mammalian membrane protein as well as FDA‐approved therapeutic antibodies. The resulting Fv fragments were functionally active and crystallized in complex with the target proteins. The iRAT system is a reliable, rapid and broadly applicable means of producing milligram quantities of Fv fragments for structural and biochemical studies. PMID:27595817

Integrating Algebra and Proof in High School: Students' Work with Multiple Variables and a Single Parameter in a Proof Context

ERIC Educational Resources Information Center

Martinez, Mara V.; Castro Superfine, Alison

2012-01-01

In the United States, researchers argue that proof is largely concentrated in the domain of high school geometry, thus providing students a distorted image of what proof entails, which is at odds with the central role that proof plays in mathematics. Despite the centrality of proof, there is a lack of studies addressing how to integrate proof into…

GalaxyTBM: template-based modeling by building a reliable core and refining unreliable local regions.

PubMed

Ko, Junsu; Park, Hahnbeom; Seok, Chaok

2012-08-10

Protein structures can be reliably predicted by template-based modeling (TBM) when experimental structures of homologous proteins are available. However, it is challenging to obtain structures more accurate than the single best templates by either combining information from multiple templates or by modeling regions that vary among templates or are not covered by any templates. We introduce GalaxyTBM, a new TBM method in which the more reliable core region is modeled first from multiple templates and less reliable, variable local regions, such as loops or termini, are then detected and re-modeled by an ab initio method. This TBM method is based on "Seok-server," which was tested in CASP9 and assessed to be amongst the top TBM servers. The accuracy of the initial core modeling is enhanced by focusing on more conserved regions in the multiple-template selection and multiple sequence alignment stages. Additional improvement is achieved by ab initio modeling of up to 3 unreliable local regions in the fixed framework of the core structure. Overall, GalaxyTBM reproduced the performance of Seok-server, with GalaxyTBM and Seok-server resulting in average GDT-TS of 68.1 and 68.4, respectively, when tested on 68 single-domain CASP9 TBM targets. For application to multi-domain proteins, GalaxyTBM must be combined with domain-splitting methods. Application of GalaxyTBM to CASP9 targets demonstrates that accurate protein structure prediction is possible by use of a multiple-template-based approach, and ab initio modeling of variable regions can further enhance the model quality.

The different climatic response of pedogenic hematite and ferrimagnetic minerals: Evidence from particle-sized modern soils over the Chinese Loess Plateau

NASA Astrophysics Data System (ADS)

Gao, Xinbo; Hao, Qingzhen; Wang, Luo; Oldfield, Frank; Bloemendal, Jan; Deng, Chenglong; Song, Yang; Ge, Junyi; Wu, Haibin; Xu, Bing; Li, Fengjiang; Han, Long; Fu, Yu; Guo, Zhengtang

2018-01-01

In recent years, increasing interest in loess studies has focused on qualitative and quantitative paleoclimatic reconstruction using the imperfect antiferromagnetic mineral hematite. However, the linkage between the hematite formation and climatic variables remains controversial. Here we present the results of a comprehensive investigation of the magnetic properties and statistical analysis of a suite of clay and silt fractions of modern soil samples from 179 sites across the Chinese Loess Plateau (CLP) and adjacent regions. Our objective was to clarify the relationships between modern climatic variables and pedogenic hematite, as well as pedogenic ferrimagnetic minerals. First-order reversal curve measurements were also conducted on representative particle-sized subsamples from a N-S transect to understand the differences in magnetic mineralogy between the two fractions. Our results show that pipette extraction separates the fine-grained superparamagnetic (SP) and most of the single-domain (SD) magnetic grains into the clay fraction, and that the remaining silt fraction displays the magnetic properties of coarse pseudo-single domain (PSD) or a mixture of multidomain (MD)/PSD and a few SD particles. Only the pedogenic clay fraction shows a strong correlation with climatic variables. The application of redundancy analysis helps to distinguish the climate variables controlling the formation of ferrimagnetic minerals and hematite during pedogenesis. On the CLP, pedogenic ferrimagnetic minerals are sensitive to mean annual precipitation, while pedogenic hematite formation is preferentially dependent on mean annual temperature. The confirmation of the temperature-dependent nature of hematite on the CLP provides a new possibility for quantitatively reconstructing the paleotemperature history of Chinese loess/paleosol sequences.

The Different Climatic Response of Pedogenic Hematite and Ferrimagnetic Minerals: Evidence from Particle-Sized Modern Soils over the Chinese Loess Plateau

NASA Astrophysics Data System (ADS)

Gao, X.; Hao, Q.; Luo, W.; Oldfield, F.; Bloemendal, J.; Deng, C.; Song, Y.; Ge, J.; Wu, H.; Xu, B.; Li, F.; Han, L.; Fu, Y.; Guo, Z.

2017-12-01

In recent years, increasing interest in loess studies has focused on qualitative and quantitative paleoclimatic reconstruction using the imperfect antiferromagnetic mineral hematite. However, the linkage between the hematite formation and climatic variables remains controversial. Here we present the results of a comprehensive investigation of the magnetic properties and statistical analysis of a suite of clay and silt fractions of modern soil samples from 179 sites across the Chinese Loess Plateau (CLP) and adjacent regions. Our objective was to clarify the relationships between modern climatic variables and pedogenic hematite, as well as pedogenic ferrimagnetic minerals. First-order reversal curve measurements were also conducted on representative particle-sized subsamples from a N-S transect to understand the differences in magnetic mineralogy between the two fractions. Our results show that pipette extraction separates the fine-grained superparamagnetic (SP) and most of the single-domain (SD) magnetic grains into the clay fraction, and that the remaining silt fraction displays the magnetic properties of coarse pseudo-single domain (PSD) or a mixture of multidomain (MD)/PSD and a few SD particles. Only the pedogenic clay fraction shows a strong correlation with climatic variables. The application of redundancy analysis helps to distinguish the climate variables controlling the formation of ferrimagnetic minerals and hematite during pedogenesis. On the CLP, pedogenic ferrimagnetic minerals are sensitive to mean annual precipitation, while pedogenic hematite formation is preferentially dependent on mean annual temperature. The confirmation of the temperature-dependent nature of hematite on the CLP provides a new possibility for quantitatively reconstructing the paleotemperature history of Chinese loess/paleosol sequences.

Isolation of anti-toxin single domain antibodies from a semi-synthetic spiny dogfish shark display library.

PubMed

Liu, Jinny L; Anderson, George P; Goldman, Ellen R

2007-11-19

Shark heavy chain antibody, also called new antigen receptor (NAR), consists of one single Variable domain (VH), containing only two complementarity-determining regions (CDRs). The antigen binding affinity and specificity are mainly determined by these two CDRs. The good solubility, excellent thermal stability and complex sequence variation of small single domain antibodies (sdAbs) make them attractive alternatives to conventional antibodies. In this report, we construct and characterize a diversity enhanced semi-synthetic NAR V display library based on naturally occurring NAR V sequences. A semi-synthetic shark sdAb display library with a complexity close to 1e9 was constructed. This was achieved by introducing size and sequence variations in CDR3 using randomized CDR3 primers of three different lengths. Binders against three toxins, staphylococcal enterotoxin B (SEB), ricin, and botulinum toxin A (BoNT/A) complex toxoid, were isolated from panning the display library. Soluble sdAbs from selected binders were purified and evaluated using direct binding and thermal stability assays on the Luminex 100. In addition, sandwich assays using sdAb as the reporter element were developed to demonstrate their utility for future sensor applications. We demonstrated the utility of a newly created hyper diversified shark NAR displayed library to serve as a source of thermal stable sdAbs against a variety of toxins.

Isolation of anti-toxin single domain antibodies from a semi-synthetic spiny dogfish shark display library

PubMed Central

Liu, Jinny L; Anderson, George P; Goldman, Ellen R

2007-01-01

Background Shark heavy chain antibody, also called new antigen receptor (NAR), consists of one single Variable domain (VH), containing only two complementarity-determining regions (CDRs). The antigen binding affinity and specificity are mainly determined by these two CDRs. The good solubility, excellent thermal stability and complex sequence variation of small single domain antibodies (sdAbs) make them attractive alternatives to conventional antibodies. In this report, we construct and characterize a diversity enhanced semi-synthetic NAR V display library based on naturally occurring NAR V sequences. Results A semi-synthetic shark sdAb display library with a complexity close to 1e9 was constructed. This was achieved by introducing size and sequence variations in CDR3 using randomized CDR3 primers of three different lengths. Binders against three toxins, staphylococcal enterotoxin B (SEB), ricin, and botulinum toxin A (BoNT/A) complex toxoid, were isolated from panning the display library. Soluble sdAbs from selected binders were purified and evaluated using direct binding and thermal stability assays on the Luminex 100. In addition, sandwich assays using sdAb as the reporter element were developed to demonstrate their utility for future sensor applications. Conclusion We demonstrated the utility of a newly created hyper diversified shark NAR displayed library to serve as a source of thermal stable sdAbs against a variety of toxins. PMID:18021450

Enhancing Induction Coil Reliability

NASA Astrophysics Data System (ADS)

Kreter, K.; Goldstein, R.; Yakey, C.; Nemkov, V.

2014-12-01

In induction hardening, thermal fatigue is one of the main copper failure modes of induction heat treating coils. There have been papers published that describe this failure mode and others that describe some good design practices. The variables previously identified as the sources of thermal fatigue include radiation from the part surface, frequency, current, concentrator losses, water pressure and coil wall thickness. However, there is very little quantitative data on the factors that influence thermal fatigue in induction coils is available in the public domain. By using finite element analysis software this study analyzes the effect of common design variables of inductor cooling, and quantifies the relative importance of these variables. A comprehensive case study for a single shot induction coil with Fluxtrol A concentrator applied is used for the analysis.

Fabrication of Large Domain YBa2Cu3O(x) for Magnetic Suspension Applications

NASA Technical Reports Server (NTRS)

Sengupta, S.; Corpus, J.; Gaines, J. R., Jr.; Todt, V. R.; Zhang, X.; Miller, D. J.

1996-01-01

Large domain YBa2Cu3O(x) levitators have been fabricated using a seeded melt processing technique. Depending upon the seed, either a single or five domained sample can be obtained. The grain boundaries separating each domains in the five domain levitator are found to be 90 degrees. Similar levitation forces can be observed for single and five domained samples. After thermal cycling, however, a small decrease in the levitation force of the five domain levitator was observed as a function of thermal cycles while nearly no change in force was observed in the single domain levitator. Finally, it is shown that both, single and five domain YBCO, behave similarly as a function of sample thickness.

CH3NH3PbI3 perovskites: Ferroelasticity revealed.

PubMed

Strelcov, Evgheni; Dong, Qingfeng; Li, Tao; Chae, Jungseok; Shao, Yuchuan; Deng, Yehao; Gruverman, Alexei; Huang, Jinsong; Centrone, Andrea

2017-04-01

Ferroelectricity has been proposed as a plausible mechanism to explain the high photovoltaic conversion efficiency in organic-inorganic perovskites; however, convincing experimental evidence in support of this hypothesis is still missing. Identifying and distinguishing ferroelectricity from other properties, such as piezoelectricity, ferroelasticity, etc., is typically nontrivial because these phenomena can coexist in many materials. In this work, a combination of microscopic and nanoscale techniques provides solid evidence for the existence of ferroelastic domains in both CH 3 NH 3 PbI 3 polycrystalline films and single crystals in the pristine state and under applied stress. Experiments show that the configuration of CH 3 NH 3 PbI 3 ferroelastic domains in single crystals and polycrystalline films can be controlled with applied stress, suggesting that strain engineering may be used to tune the properties of this material. No evidence of concomitant ferroelectricity was observed. Because grain boundaries have an impact on the long-term stability of organic-inorganic perovskite devices, and because the ferroelastic domain boundaries may differ from regular grain boundaries, the discovery of ferroelasticity provides a new variable to consider in the quest for improving their stability and enabling their widespread adoption.

High stimulus variability in nonnative speech learning supports formation of abstract categories: evidence from Japanese geminates.

PubMed

Sadakata, Makiko; McQueen, James M

2013-08-01

This study reports effects of a high-variability training procedure on nonnative learning of a Japanese geminate-singleton fricative contrast. Thirty native speakers of Dutch took part in a 5-day training procedure in which they identified geminate and singleton variants of the Japanese fricative /s/. Participants were trained with either many repetitions of a limited set of words recorded by a single speaker (low-variability training) or with fewer repetitions of a more variable set of words recorded by multiple speakers (high-variability training). Both types of training enhanced identification of speech but not of nonspeech materials, indicating that learning was domain specific. High-variability training led to superior performance in identification but not in discrimination tests, and supported better generalization of learning as shown by transfer from the trained fricatives to the identification of untrained stops and affricates. Variability thus helps nonnative listeners to form abstract categories rather than to enhance early acoustic analysis.

Maturation of Shark Single-Domain (IgNAR) Antibodies: Evidence for Induced-Fit Binding

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

Stanfield, R.L.; Dooley, H.; Verdino, P.

2007-07-13

Sharks express an unusual heavy-chain isotype called IgNAR, whose variable regions bind antigen as independent soluble domains. To further probe affinity maturation of the IgNAR response, we structurally characterized the germline and somatically matured versions of a type II variable (V) region, both in the presence and absence of its antigen, hen egg-white lysozyme. Despite a disulfide bond linking complementarity determining regions (CDRs) 1 and 3, both germline and somatically matured V regions displayed significant structural changes in these CDRs upon complex formation with antigen. Somatic mutations in the IgNAR V region serve to increase the number of contacts withmore » antigen, as reflected by a tenfold increase in affinity, and one of these mutations appears to stabilize the CDR3 region. In addition, a residue in the HV4 loop plays an important role in antibody-antigen interaction, consistent with the high rate of somatic mutations in this non-CDR loop.« less

Thermal stability of bubble domains in ferromagnetic discs

NASA Astrophysics Data System (ADS)

Hrkac, G.; Bance, S.; Goncharov, A.; Schrefl, T.; Suess, D.

2007-05-01

The transition and thermal stability of disc-shaped ferromagnetic particles at the temperature of T = 300 K with a uniaxial anisotropy along the symmetry axis from a bi-domain to a single domain state has been studied. The nudge elastic band method was used to map the energy landscape and to calculate the energy barrier between the transition states. For single FePt disc-shaped particles with perpendicular anisotropy three transition configurations have been found: single domain, stripe- and stable bubble domains at zero applied field. The single domain configuration along the positive anisotropy axis is reached by an annihilation process of the domain wall and the all-down state by a complex domain expansion process. Magnetization configurations in two interacting discs show an increase in thermal stability compared with single disc systems, which is attributed to the interacting magnetostatic energy between the two particles.

Understanding pathogenic single-nucleotide polymorphisms in multidomain proteins – studies of isolated domains are not enough

PubMed Central

Randles, Lucy G; Dawes, Gwen J S; Wensley, Beth G; Steward, Annette; Nickson, Adrian A; Clarke, Jane

2013-01-01

Studying the effects of pathogenic mutations is more complex in multidomain proteins when compared with single domains: mutations occurring at domain boundaries may have a large effect on a neighbouring domain that will not be detected in a single-domain system. To demonstrate this, we present a study that utilizes well-characterized model protein domains from human spectrin to investigate the effect of disease-and non-disease-causing single point mutations occurring at the boundaries of human spectrin repeats. Our results show that mutations in the single domains have no clear correlation with stability and disease; however, when studied in a tandem model system, the disease-causing mutations are shown to disrupt stabilizing interactions that exist between domains. This results in a much larger decrease in stability than would otherwise have been predicted, and demonstrates the importance of studying such mutations in the correct protein context. PMID:23241237

Antibody repertoire development in camelids.

PubMed

De Genst, Erwin; Saerens, Dirk; Muyldermans, Serge; Conrath, Katja

2006-01-01

The humoral immune response of the Camelidae is unique as these animals are the only known mammals that seem to possess functional homodimeric heavy-chain antibodies besides the classical heteromeric antibodies composed of heavy (H) and light (L) chains. By definition, the heavy-chain antibodies lack the L-chain, and it was noticed that their H-chain is devoid of the typical first constant domain (CH1) and contains a dedicated variable domain, referred to as VHH. The VHH exon is assembled from separate V-D-J gene segments. The recombined VHH region is subjected to somatic hypermutations; however, the timing and actual mechanism of the class switch from mu to the dedicated gamma-isotype remains elusive. Interestingly, antigen-specific VHHs are easily retrieved after panning of a phage-displayed rearranged V-gene pool cloned from an immunised camelid. These single-domain antigen binding entities possess a number of biophysical properties that offer particular advantages in various medical and biotechnological applications.

Anti-WASP intrabodies inhibit inflammatory responses induced by Toll-like receptors 3, 7, and 9, in macrophages

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

Sakuma, Chisato; Sato, Mitsuru, E-mail: mitsuru.sato@affrc.go.jp; Oshima, Takuma

Wiskott-Aldrich syndrome protein (WASP) is an adaptor molecule in immune cells. Recently, we showed that the WASP N-terminal domain interacted with the SH3 domain of Bruton's tyrosine kinase (Btk), and that the complex formed by WASP and Btk was important for TLR2 and TLR4 signaling in macrophages. Several other studies have shown that Btk played important roles in modulating innate immune responses through TLRs in immune cells. Here, we evaluated the significance of the interaction between WASP and Btk in TLR3, TLR7, and TLR9 signaling. We established bone marrow–derived macrophage cell lines from transgenic (Tg) mice that expressed intracellular antibodiesmore » (intrabodies) that specifically targeted the WASP N-terminal domain. One intrabody comprised the single-chain variable fragment and the other comprised the light-chain variable region single domain of an anti-WASP N-terminal monoclonal antibody. Both intrabodies inhibited the specific interaction between WASP and Btk, which impaired the expression of TNF-α, IL-6, and IL-1β in response to TLR3, TLR7, or TLR9 stimulation. Furthermore, the intrabodies inhibited the phosphorylation of both nuclear factor (NF)-κB and WASP in response to TLR3, TLR7, or TLR9 stimulation, in the Tg bone marrow-derived macrophages. These results suggested that WASP plays important roles in TLR3, TLR7, and TLR9 signaling by associating with Btk in macrophages. - Highlights: • The interaction between WASP and Btk is critical for TLR3, TLR7, and TLR9 signaling. • Anti-WASP intrabodies inhibited several TLR pathways that led to cytokine expression. • Phosphorylation of NF-κB via TLR signaling was inhibited by anti-WASP intrabodies. • WASP phosphorylation via several TLR ligands was inhibited by anti-WASP intrabodies.« less

Design of a compensation for an ARMA model of a discrete time system. M.S. Thesis

NASA Technical Reports Server (NTRS)

Mainemer, C. I.

1978-01-01

The design of an optimal dynamic compensator for a multivariable discrete time system is studied. Also the design of compensators to achieve minimum variance control strategies for single input single output systems is analyzed. In the first problem the initial conditions of the plant are random variables with known first and second order moments, and the cost is the expected value of the standard cost, quadratic in the states and controls. The compensator is based on the minimum order Luenberger observer and it is found optimally by minimizing a performance index. Necessary and sufficient conditions for optimality of the compensator are derived. The second problem is solved in three different ways; two of them working directly in the frequency domain and one working in the time domain. The first and second order moments of the initial conditions are irrelevant to the solution. Necessary and sufficient conditions are derived for the compensator to minimize the variance of the output.

Development of an affinity-matured humanized anti-epidermal growth factor receptor antibody for cancer immunotherapy.

PubMed

Nakanishi, Takeshi; Maru, Takamitsu; Tahara, Kazuhiro; Sanada, Hideaki; Umetsu, Mitsuo; Asano, Ryutaro; Kumagai, Izumi

2013-02-01

We showed previously that humanization of 528, a murine anti-epidermal growth factor receptor (EGFR) antibody, causes reduced affinity for its target. Here, to improve the affinity of the humanized antibody for use in cancer immunotherapy, we constructed phage display libraries focused on the complementarity-determining regions (CDRs) of the antibody and carried out affinity selection. Two-step selections using libraries constructed in a stepwise manner enabled a 32-fold affinity enhancement of humanized 528 (h528). Thermodynamic analysis of the interactions between the variable domain fragment of h528 (h528Fv) mutants and the soluble extracellular domain of EGFR indicated that the h528Fv mutants obtained from the first selection showed a large increase in negative enthalpy change due to binding, resulting in affinity enhancement. Furthermore, mutants from the second selection showed a decrease in entropy loss, which led to further affinity maturation. These results suggest that a single mutation in the heavy chain variable domain (i.e. Tyr(52) to Trp) enthalpically contributed for overcoming the energetic barrier to the antigen-antibody interaction, which was a major hurdle for the in vitro affinity maturation of h528. We reported previously that the humanized bispecific diabody hEx3 Db, which targets EGFR and CD3, shows strong anti-tumor activity. hEx3 Db mutants, in which the variable domains of h528 were replaced with those of the affinity-enhanced mutants, were prepared and characterized. In a growth inhibition assay of tumor cells, the hEx3 Db mutants showed stronger anti-tumor activity than that of hEx3 Db, suggesting that affinity enhancement of h528Fv enhances the anti-tumor activity of the bispecific diabody.

Formin homology 2 domains occur in multiple contexts in angiosperms

PubMed Central

Cvrčková, Fatima; Novotný, Marian; Pícková, Denisa; Žárský, Viktor

2004-01-01

Background Involvement of conservative molecular modules and cellular mechanisms in the widely diversified processes of eukaryotic cell morphogenesis leads to the intriguing question: how do similar proteins contribute to dissimilar morphogenetic outputs. Formins (FH2 proteins) play a central part in the control of actin organization and dynamics, providing a good example of evolutionarily versatile use of a conserved protein domain in the context of a variety of lineage-specific structural and signalling interactions. Results In order to identify possible plant-specific sequence features within the FH2 protein family, we performed a detailed analysis of angiosperm formin-related sequences available in public databases, with particular focus on the complete Arabidopsis genome and the nearly finished rice genome sequence. This has led to revision of the current annotation of half of the 22 Arabidopsis formin-related genes. Comparative analysis of the two plant genomes revealed a good conservation of the previously described two subfamilies of plant formins (Class I and Class II), as well as several subfamilies within them that appear to predate the separation of monocot and dicot plants. Moreover, a number of plant Class II formins share an additional conserved domain, related to the protein phosphatase/tensin/auxilin fold. However, considerable inter-species variability sets limits to generalization of any functional conclusions reached on a single species such as Arabidopsis. Conclusions The plant-specific domain context of the conserved FH2 domain, as well as plant-specific features of the domain itself, may reflect distinct functional requirements in plant cells. The variability of formin structures found in plants far exceeds that known from both fungi and metazoans, suggesting a possible contribution of FH2 proteins in the evolution of the plant type of multicellularity. PMID:15256004

Stability of Language in Childhood: A Multi-Age, -Domain, -Measure, and -Source Study

PubMed Central

Bornstein, Marc H.; Putnick, Diane L.

2011-01-01

The stability of language across childhood is traditionally assessed by exploring longitudinal relations between individual language measures. However, language encompasses many domains and varies with different sources (child speech, parental report, experimenter assessment). This study evaluated individual variation in multiple age-appropriate measures of child language derived from multiple sources and stability between their latent variables in 192 young children across more than 2 years. Structural equation modeling demonstrated the loading of multiple measures of child language from different sources on single latent variables of language at ages 20 and 48 months. A large stability coefficient (r = .84) obtained between the 2 language latent variables. This stability obtained even when accounting for family socioeconomic status, maternal verbal intelligence, education, speech, and tendency to respond in a socially desirable fashion, and child social competence. Stability was also equivalent for children in diverse childcare situations and for girls and boys. Across age, from the beginning of language acquisition to just before school entry, aggregating multiple age-appropriate methods and measures at each age and multiple reporters, children show strong stability of individual differences in general language development. PMID:22004343

Porphyromonas gingivalis Uses Specific Domain Rearrangements and Allelic Exchange to Generate Diversity in Surface Virulence Factors.

PubMed

Dashper, Stuart G; Mitchell, Helen L; Seers, Christine A; Gladman, Simon L; Seemann, Torsten; Bulach, Dieter M; Chandry, P Scott; Cross, Keith J; Cleal, Steven M; Reynolds, Eric C

2017-01-01

Porphyromonas gingivalis is a keystone pathogen of chronic periodontitis. The virulence of P. gingivalis is reported to be strain related and there are currently a number of strain typing schemes based on variation in capsular polysaccharide, the major and minor fimbriae and adhesin domains of Lys-gingipain (Kgp), amongst other surface proteins. P. gingivalis can exchange chromosomal DNA between strains by natural competence and conjugation. The aim of this study was to determine the genetic variability of P. gingivalis strains sourced from international locations over a 25-year period and to determine if variability in surface virulence factors has a phylogenetic basis. Whole genome sequencing was performed on 13 strains and comparison made to 10 previously sequenced strains. A single nucleotide polymorphism-based phylogenetic analysis demonstrated a shallow tri-lobed phylogeny. There was a high level of reticulation in the phylogenetic network, demonstrating extensive horizontal gene transfer between the strains. Two highly conserved variants of the catalytic domain of the major virulence factor the Kgp proteinase (Kgp cat I and Kgp cat II) were found. There were three variants of the fourth Kgp C-terminal cleaved adhesin domain. Specific variants of the cell surface proteins FimA, FimCDE, MfaI, RagAB, Tpr, and PrtT were also identified. The occurrence of all these variants in the P. gingivalis strains formed a mosaic that was not related to the SNP-based phylogeny. In conclusion P. gingivalis uses domain rearrangements and genetic exchange to generate diversity in specific surface virulence factors.

Specifying an implementation framework for Veterans Affairs antimicrobial stewardship programmes: using a factor analysis approach.

PubMed

Chou, Ann F; Graber, Christopher J; Zhang, Yue; Jones, Makoto; Goetz, Matthew Bidwell; Madaras-Kelly, Karl; Samore, Matthew; Glassman, Peter A

2018-06-04

Inappropriate antibiotic use poses a serious threat to patient safety. Antimicrobial stewardship programmes (ASPs) may optimize antimicrobial use and improve patient outcomes, but their implementation remains an organizational challenge. Using the Promoting Action on Research Implementation in Health Services (PARiHS) framework, this study aimed to identify organizational factors that may facilitate ASP design, development and implementation. Among 130 Veterans Affairs facilities that offered acute care, we classified organizational variables supporting antimicrobial stewardship activities into three PARiHS domains: evidence to encompass sources of knowledge; contexts to translate evidence into practice; and facilitation to enhance the implementation process. We conducted a series of exploratory factor analyses to identify conceptually linked factor scales. Cronbach's alphas were calculated. Variables with large uniqueness values were left as single factors. We identified 32 factors, including six constructs derived from factor analyses under the three PARiHS domains. In the evidence domain, four factors described guidelines and clinical pathways. The context domain was broken into three main categories: (i) receptive context (15 factors describing resources, affiliations/networks, formalized policies/practices, decision-making, receptiveness to change); (ii) team functioning (1 factor); and (iii) evaluation/feedback (5 factors). Within facilitation, two factors described facilitator roles and tasks and five captured skills and training. We mapped survey data onto PARiHS domains to identify factors that may be adapted to facilitate ASP uptake. Our model encompasses mostly mutable factors whose relationships with performance outcomes may be explored to optimize antimicrobial use. Our framework also provides an analytical model for determining whether leveraging existing organizational processes can potentially optimize ASP performance.

Algorithms for Discovery of Multiple Markov Boundaries

PubMed Central

Statnikov, Alexander; Lytkin, Nikita I.; Lemeire, Jan; Aliferis, Constantin F.

2013-01-01

Algorithms for Markov boundary discovery from data constitute an important recent development in machine learning, primarily because they offer a principled solution to the variable/feature selection problem and give insight on local causal structure. Over the last decade many sound algorithms have been proposed to identify a single Markov boundary of the response variable. Even though faithful distributions and, more broadly, distributions that satisfy the intersection property always have a single Markov boundary, other distributions/data sets may have multiple Markov boundaries of the response variable. The latter distributions/data sets are common in practical data-analytic applications, and there are several reasons why it is important to induce multiple Markov boundaries from such data. However, there are currently no sound and efficient algorithms that can accomplish this task. This paper describes a family of algorithms TIE* that can discover all Markov boundaries in a distribution. The broad applicability as well as efficiency of the new algorithmic family is demonstrated in an extensive benchmarking study that involved comparison with 26 state-of-the-art algorithms/variants in 15 data sets from a diversity of application domains. PMID:25285052

Improvement of single domain antibody stability by disulfide bond introduction.

PubMed

Hagihara, Yoshihisa; Saerens, Dirk

2012-01-01

The successful medical application of single domain antibodies largely depends on their functionality. This feature is partly determined by the intrinsic stability of the single domain. Therefore a lot of research has gone into the elucidation of rules to uniformly increase stability of antibodies. Recently, a novel intra-domain disulfide bond was independently discovered by two research groups, after either rational design or careful investigation of the naturally occurring camelid antibody repertoire. By introducing this particular disulfide bond within a single domain antibody, the conformational stability can be increased in general. In this chapter it is described how to introduce this extra intra-domain disulfide bond and how to estimate the biophysical and biochemical impact of this cystine on the domain.

Eurasian otters, Lutra lutra, have a dominant mtDNA haplotype from the Iberian Peninsula to Scandinavia.

PubMed

Ferrando, Ainhoa; Ponsà, Montserrat; Marmi, Josep; Domingo-Roura, Xavier

2004-01-01

The Eurasian otter, Lutra lutra, has a Palaearctic distribution and has suffered a severe decline throughout Europe during the last century. Previous studies in this and other mustelids have shown reduced levels of variability in mitochondrial DNA, although otter phylogeographic studies were restricted to central-western Europe. In this work we have sequenced 361 bp of the mtDNA control region in 73 individuals from eight countries and added our results to eight sequences available from GenBank and the literature. The range of distribution has been expanded in relation to previous works north towards Scandinavia, east to Russia and Belarus, and south to the Iberian Peninsula. We found a single dominant haplotype in 91.78% of the samples, and six more haplotypes deviating a maximum of two mutations from the dominant haplotype restricted to a single country. Variability was extremely low in western Europe but higher in eastern countries. This, together with the lack of phylogeographical structuring, supports the postglacial recolonization of Europe from a single refugium. The Eurasian otter mtDNA control region has a 220-bp variable minisatellite in Domain III that we sequenced in 29 otters. We found a total of 19 minisatellite haplotypes, but they showed no phylogenetic information.

Development of cell-penetrating bispecific antibodies targeting the N-terminal domain of androgen receptor for prostate cancer therapy.

PubMed

Goicochea, Nancy L; Garnovskaya, Maria; Blanton, Mary G; Chan, Grace; Weisbart, Richard; Lilly, Michael B

2017-12-01

Castration-resistant prostate cancer cells exhibit continued androgen receptor signaling in spite of low levels of ligand. Current therapies to block androgen receptor signaling act by inhibiting ligand production or binding. We developed bispecific antibodies capable of penetrating cells and binding androgen receptor outside of the ligand-binding domain. Half of the bispecific antibody molecule consists of a single-chain variable fragment of 3E10, an anti-DNA antibody that enters cells. The other half is a single-chain variable fragment version of AR441, an anti-AR antibody. The resulting 3E10-AR441 bispecific antibody enters human LNCaP prostate cells and accumulates in the nucleus. The antibody binds to wild-type, mutant and splice variant androgen receptor. Binding affinity of 3E10-AR441 to androgen receptor (284 nM) was lower than that of the parental AR441 mAb (4.6 nM), but could be improved (45 nM) through alternative placement of the affinity tags, and ordering of the VH and VK domains. The 3E10-AR441 bispecific antibody blocked genomic signaling by wild-type or splice variant androgen receptor in LNCaP cells. It also blocked non-genomic signaling by the wild-type receptor. Furthermore, bispecific antibody inhibited the growth of C4-2 prostate cancer cells under androgen-stimulated conditions. The 3E10-AR441 biAb can enter prostate cancer cells and inhibits androgen receptor function in a ligand-independent manner. It may be an attractive prototype agent for prostate cancer therapy. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Crystal structure of the anti-(carcinoembryonic antigen) single-chain Fv antibody MFE-23 and a model for antigen binding based on intermolecular contacts.

PubMed

Boehm, M K; Corper, A L; Wan, T; Sohi, M K; Sutton, B J; Thornton, J D; Keep, P A; Chester, K A; Begent, R H; Perkins, S J

2000-03-01

MFE-23 is the first single-chain Fv antibody molecule to be used in patients and is used to target colorectal cancer through its high affinity for carcinoembryonic antigen (CEA), a cell-surface member of the immunoglobulin superfamily. MFE-23 contains an N-terminal variable heavy-chain domain joined by a (Gly(4)Ser)(3) linker to a variable light-chain (V(L)) domain (kappa chain) with an 11-residue C-terminal Myc-tag. Its crystal structure was determined at 2.4 A resolution by molecular replacement with an R(cryst) of 19.0%. Five of the six antigen-binding loops, L1, L2, L3, H1 and H2, conformed to known canonical structures. The sixth loop, H3, displayed a unique structure, with a beta-hairpin loop and a bifurcated apex characterized by a buried Thr residue. In the crystal lattice, two MFE-23 molecules were associated back-to-back in a manner not seen before. The antigen-binding site displayed a large acidic region located mainly within the H2 loop and a large hydrophobic region within the H3 loop. Even though this structure is unliganded within the crystal, there is an unusually large region of contact between the H1, H2 and H3 loops and the beta-sheet of the V(L) domain of an adjacent molecule (strands DEBA) as a result of intermolecular packing. These interactions exhibited remarkably high surface and electrostatic complementarity. Of seven MFE-23 residues predicted to make contact with antigen, five participated in these lattice contacts, and this model for antigen binding is consistent with previously reported site-specific mutagenesis of MFE-23 and its effect on CEA binding.

Isolation of a pH-Sensitive IgNAR Variable Domain from a Yeast-Displayed, Histidine-Doped Master Library.

PubMed

Könning, Doreen; Zielonka, Stefan; Sellmann, Carolin; Schröter, Christian; Grzeschik, Julius; Becker, Stefan; Kolmar, Harald

2016-04-01

In recent years, engineering of pH-sensitivity into antibodies as well as antibody-derived fragments has become more and more attractive for biomedical and biotechnological applications. Herein, we report the isolation of the first pH-sensitive IgNAR variable domain (vNAR), which was isolated from a yeast-displayed, semi-synthetic master library. This strategy enables the direct identification of pH-dependent binders from a histidine-enriched CDR3 library. Displayed vNAR variants contained two histidine substitutions on average at random positions in their 12-residue CDR3 loop. Upon screening of seven rounds against the proof-of-concept target EpCAM (selection for binding at pH 7.4 and decreased binding at pH 6.0), a single clone was obtained that showed specific and pH-dependent binding as characterized by yeast surface display and biolayer interferometry. Potential applications for such pH-dependent vNAR domains include their employment in tailored affinity chromatography, enabling mild elution protocols. Moreover, utilizing a master library for the isolation of pH-sensitive vNAR variants may be a generic strategy to obtain binding entities with prescribed characteristics for applications in biotechnology, diagnostics, and therapy.

Single-leg squats can predict leg alignment in dancers performing ballet movements in "turnout".

PubMed

Hopper, Luke S; Sato, Nahoko; Weidemann, Andries L

2016-01-01

The physical assessments used in dance injury surveillance programs are often adapted from the sports and exercise domain. Bespoke physical assessments may be required for dance, particularly when ballet movements involve "turning out" or external rotation of the legs beyond that typically used in sports. This study evaluated the ability of the traditional single-leg squat to predict the leg alignment of dancers performing ballet movements with turnout. Three-dimensional kinematic data of dancers performing the single-leg squat and five ballet movements were recorded and analyzed. Reduction of the three-dimensional data into a one-dimensional variable incorporating the ankle, knee, and hip joint center positions provided the strongest predictive model between the single-leg squat and the ballet movements. The single-leg squat can predict leg alignment in dancers performing ballet movements, even in "turned out" postures. Clinicians should pay careful attention to observational positioning and rating criteria when assessing dancers performing the single-leg squat.

Single-leg squats can predict leg alignment in dancers performing ballet movements in “turnout”

PubMed Central

Hopper, Luke S; Sato, Nahoko; Weidemann, Andries L

2016-01-01

The physical assessments used in dance injury surveillance programs are often adapted from the sports and exercise domain. Bespoke physical assessments may be required for dance, particularly when ballet movements involve “turning out” or external rotation of the legs beyond that typically used in sports. This study evaluated the ability of the traditional single-leg squat to predict the leg alignment of dancers performing ballet movements with turnout. Three-dimensional kinematic data of dancers performing the single-leg squat and five ballet movements were recorded and analyzed. Reduction of the three-dimensional data into a one-dimensional variable incorporating the ankle, knee, and hip joint center positions provided the strongest predictive model between the single-leg squat and the ballet movements. The single-leg squat can predict leg alignment in dancers performing ballet movements, even in “turned out” postures. Clinicians should pay careful attention to observational positioning and rating criteria when assessing dancers performing the single-leg squat. PMID:27895518

Mutational landscape of antibody variable domains reveals a switch modulating the interdomain conformational dynamics and antigen binding

PubMed Central

Koenig, Patrick; Lee, Chingwei V.; Walters, Benjamin T.; Janakiraman, Vasantharajan; Stinson, Jeremy; Patapoff, Thomas W.; Fuh, Germaine

2017-01-01

Somatic mutations within the antibody variable domains are critical to the immense capacity of the immune repertoire. Here, via a deep mutational scan, we dissect how mutations at all positions of the variable domains of a high-affinity anti-VEGF antibody G6.31 impact its antigen-binding function. The resulting mutational landscape demonstrates that large portions of antibody variable domain positions are open to mutation, and that beneficial mutations can be found throughout the variable domains. We determine the role of one antigen-distal light chain position 83, demonstrating that mutation at this site optimizes both antigen affinity and thermostability by modulating the interdomain conformational dynamics of the antigen-binding fragment. Furthermore, by analyzing a large number of human antibody sequences and structures, we demonstrate that somatic mutations occur frequently at position 83, with corresponding domain conformations observed for G6.31. Therefore, the modulation of interdomain dynamics represents an important mechanism during antibody maturation in vivo. PMID:28057863

Change of magnetic domain structure by mechanically induced twin boundary motion in Ni-Mn-Ga single crystal

NASA Astrophysics Data System (ADS)

Kopecký, Vít; Heczko, Oleg

2017-10-01

The single variant state exhibits usual labyrinth and band magnetic domains depending on orientation of easy magnetization axis. By the passage of single twin boundary induced by mechanical stress the rake and granular domain patterns are formed. These domain patterns are further modified by repeated passage of the twin boundary resulting in similar domain patterns in the sample even though the orientation of the magnetization is different.

Quality Assurance in the Presence of Variability

NASA Astrophysics Data System (ADS)

Lauenroth, Kim; Metzger, Andreas; Pohl, Klaus

Software Product Line Engineering (SPLE) is a reuse-driven development paradigm that has been applied successfully in information system engineering and other domains. Quality assurance of the reusable artifacts of the product line (e.g. requirements, design, and code artifacts) is essential for successful product line engineering. As those artifacts are reused in several products, a defect in a reusable artifact can affect several products of the product line. A central challenge for quality assurance in product line engineering is how to consider product line variability. Since the reusable artifacts contain variability, quality assurance techniques from single-system engineering cannot directly be applied to those artifacts. Therefore, different strategies and techniques have been developed for quality assurance in the presence of variability. In this chapter, we describe those strategies and discuss in more detail one of those strategies, the so called comprehensive strategy. The comprehensive strategy aims at checking the quality of all possible products of the product line and thus offers the highest benefits, since it is able to uncover defects in all possible products of the product line. However, the central challenge for applying the comprehensive strategy is the complexity that results from the product line variability and the large number of potential products of a product line. In this chapter, we present one concrete technique that we have developed to implement the comprehensive strategy that addresses this challenge. The technique is based on model checking technology and allows for a comprehensive verification of domain artifacts against temporal logic properties.

The application of the Routh approximation method to turbofan engine models

NASA Technical Reports Server (NTRS)

Merrill, W. C.

1977-01-01

The Routh approximation technique is applied in the frequency domain to a 16th order state variable turbofan engine model. The results obtained motivate the extension of the frequency domain formulation of the Routh method to the time domain to handle the state variable formulation directly. The time domain formulation is derived, and a characterization, which specifies all possible Routh similarity transformations, is given. The characterization is computed by the solution of two eigenvalue eigenvector problems. The application of the time domain Routh technique to the state variable engine model is described, and some results are given.

Nonviral RNA transfection to transiently modify T cells with chimeric antigen receptors for adoptive therapy.

PubMed

Riet, Tobias; Holzinger, Astrid; Dörrie, Jan; Schaft, Niels; Schuler, Gerold; Abken, Hinrich

2013-01-01

Redirecting T cells with a chimeric antigen receptor (CAR) of predefined specificity showed remarkable efficacy in the adoptive therapy trials of malignant diseases. The CAR consists of a single chain fragment of variable region (scFv) antibody targeting domain covalently linked to the CD3ζ signalling domain of the T cell receptor complex to mediate T cell activation upon antigen engagement. By using an antibody-derived targeting domain a CAR can potentially redirect T cells towards any target expressed on the cell surface as long as a binding domain is available. Antibody-mediated targeting moreover circumvents MHC restriction of the targeted antigen, thereby broadening the potential of applicability of adoptive T cell therapy. While T cells were so far genetically modified by viral transduction, transient modification with a CAR by RNA transfection gained increasing interest during the last years. This chapter focuses on methods to modify human T cells from peripheral blood with a CAR by electroporation of in vitro transcribed RNA and to test modified T cells for function for use in adoptive immunotherapy.

Intrinsic motions in the N-terminal domain of an ionotropic glutamate receptor detected by fluorescence correlation spectroscopy.

PubMed

Jensen, Mette H; Sukumaran, Madhav; Johnson, Christopher M; Greger, Ingo H; Neuweiler, Hannes

2011-11-18

Ionotropic glutamate receptors (iGluRs) mediate excitatory neurotransmission in the central nervous system and play key roles in brain development and disease. iGluRs have two distinct extracellular domains, but the functional role of the distal N-terminal domain (NTD) is poorly understood. Crystal structures of the NTD from some non-N-methyl-d-aspartate (NMDA) iGluRs are consistent with a rigid body that facilitates receptor assembly but suggest an additional dynamic role that could modulate signaling. Here, we moved beyond spatial and temporal limitations of conventional protein single-molecule spectroscopy by employing correlation analysis of extrinsic oxazine fluorescence fluctuations. We observed nanosecond (ns)-to-microsecond (μs) motions of loop segments and helices within a region of an AMPA-type iGluR NTD, which has been identified previously to be structurally variable. Our data reveal that the AMPA receptor NTD undergoes rapid conformational fluctuations, suggesting an inherent allosteric capacity for this domain in addition to its established assembly function. Copyright © 2011 Elsevier Ltd. All rights reserved.

Voltage control of magnetic single domains in Ni discs on ferroelectric BaTiO3

NASA Astrophysics Data System (ADS)

Ghidini, M.; Zhu, B.; Mansell, R.; Pellicelli, R.; Lesaine, A.; Moya, X.; Crossley, S.; Nair, B.; Maccherozzi, F.; Barnes, C. H. W.; Cowburn, R. P.; Dhesi, S. S.; Mathur, N. D.

2018-06-01

For 1 µm-diameter Ni discs on a BaTiO3 substrate, the local magnetization direction is determined by ferroelectric domain orientation as a consequence of growth strain, such that single-domain discs lie on single ferroelectric domains. On applying a voltage across the substrate, ferroelectric domain switching yields non-volatile magnetization rotations of 90°, while piezoelectric effects that are small and continuous yield non-volatile magnetization reversals that are non-deterministic. This demonstration of magnetization reversal without ferroelectric domain switching implies reduced fatigue, and therefore represents a step towards applications.

Multiresolution analysis of the spatiotemporal variability in global radiation observed by a dense network of 99 pyranometers

NASA Astrophysics Data System (ADS)

Lakshmi Madhavan, Bomidi; Deneke, Hartwig; Witthuhn, Jonas; Macke, Andreas

2017-03-01

The time series of global radiation observed by a dense network of 99 autonomous pyranometers during the HOPE campaign around Jülich, Germany, are investigated with a multiresolution analysis based on the maximum overlap discrete wavelet transform and the Haar wavelet. For different sky conditions, typical wavelet power spectra are calculated to quantify the timescale dependence of variability in global transmittance. Distinctly higher variability is observed at all frequencies in the power spectra of global transmittance under broken-cloud conditions compared to clear, cirrus, or overcast skies. The spatial autocorrelation function including its frequency dependence is determined to quantify the degree of similarity of two time series measurements as a function of their spatial separation. Distances ranging from 100 m to 10 km are considered, and a rapid decrease of the autocorrelation function is found with increasing frequency and distance. For frequencies above 1/3 min-1 and points separated by more than 1 km, variations in transmittance become completely uncorrelated. A method is introduced to estimate the deviation between a point measurement and a spatially averaged value for a surrounding domain, which takes into account domain size and averaging period, and is used to explore the representativeness of a single pyranometer observation for its surrounding region. Two distinct mechanisms are identified, which limit the representativeness; on the one hand, spatial averaging reduces variability and thus modifies the shape of the power spectrum. On the other hand, the correlation of variations of the spatially averaged field and a point measurement decreases rapidly with increasing temporal frequency. For a grid box of 10 km × 10 km and averaging periods of 1.5-3 h, the deviation of global transmittance between a point measurement and an area-averaged value depends on the prevailing sky conditions: 2.8 (clear), 1.8 (cirrus), 1.5 (overcast), and 4.2 % (broken clouds). The solar global radiation observed at a single station is found to deviate from the spatial average by as much as 14-23 (clear), 8-26 (cirrus), 4-23 (overcast), and 31-79 W m-2 (broken clouds) from domain averages ranging from 1 km × 1 km to 10 km × 10 km in area.

Ligand and coactivator identity determines the requirement of the charge clamp for coactivation of the peroxisome proliferator-activated receptor gamma.

PubMed

Wu, Yifei; Chin, William W; Wang, Yong; Burris, Thomas P

2003-03-07

The activation function 2 (AF-2)-dependent recruitment of coactivator is essential for gene activation by nuclear receptors. We show that the peroxisome proliferator-activated receptor gamma (PPARgamma) (NR1C3) coactivator-1 (PGC-1) requires both the intact AF-2 domain of PPARgamma and the LXXLL domain of PGC-1 for ligand-dependent and ligand-independent interaction and coactivation. Although the AF-2 domain of PPARgamma is absolutely required for PGC-1-mediated coactivation, this coactivator displayed a unique lack of requirement for the charge clamp of the ligand-binding domain of the receptor that is thought to be essential for LXXLL motif recognition. The mutation of a single serine residue adjacent to the core LXXLL motif of PGC-1 led to restoration of the typical charge clamp requirement. Thus, the unique structural features of the PGC-1 LXXLL motif appear to mediate an atypical mode of interaction with PPARgamma. Unexpectedly, we discovered that various ligands display variability in terms of their requirement for the charge clamp of PPARgamma for coactivation by PGC-1. This ligand-selective variable requirement for the charge clamp was coactivator-specific. Thus, distinct structural determinants, which may be unique for a particular ligand, are utilized by the receptor to recognize the coactivator. Our data suggest that even subtle differences in ligand structure are perceived by the receptor and translated into a unique display of the coactivator-binding surface of the ligand-binding domain, allowing for differential recognition of coactivators that may underlie distinct pharmacological profiles observed for ligands of a particular nuclear receptor.

Acute Effects of Different Types of Resistance Training on Cardiac Autonomic Modulation in COPD.

PubMed

Vanderlei, Franciele M; Zandonadi, Fernando; de Lima, Fabiano Franciso; Silva, Bruna S A; Freire, Ana Paula C F; Ramos, Dionei; Ramos, Ercy Mara C

2018-05-22

An exercise modality that has been gaining significant importance in the rehabilitation of subjects with COPD is resistance training. When considering that patients with COPD present alterations in autonomic cardiac modulation caused by the disease itself, it is necessary to investigate the behavior of the autonomic nervous system in relation to this type of exercise. Thus, the objective of this study was to compare the acute effects of resistance training with elastic tubes, elastic bands, and conventional weightlifitng on the behavior of cardiac autonomic modulation in post-exercise recovery in subjects with COPD. Thirty-four subjects with COPD performed an single session of resistance training divided according to the therapeutic resource used: elastic tubes ( n = 10), elastic bands ( n = 11), and conventional bodybuilding ( n = 13). For analysis of cardiac autonomic modulation, the heart rate was obtained beat to beat at rest and immediately after the end of the session for 60 min in a seated position. Heart rate variability indices were obtained in the time and frequency domains. The 3 therapeutic resource types used in the single session of resistance training promoted changes in heart rate variability linear indices in the time and frequency domains; however, post-exercise recovery time was similar for all protocols performed. After single resistance training the elastic tubes group presented a minimum alteration in the post-exercise recovery of cardiac autonomic modulation in the subjects with COPD; however, at 5 min after exercising, the subjects with COPD had already recovered. Therefore, if the purpose of the training is to restore autonomic cardiac modulation, the use of elastic tubes is suggested, when considering their low cost and versatility. Copyright © 2018 by Daedalus Enterprises.

How adolescents construct their future: the effect of loneliness on future orientation.

PubMed

Seginer, Rachel; Lilach, Efrat

2004-12-01

This study examined the effect of loneliness, gender, and two dimensions of prospective life domains on adolescent future orientation. Future orientation was studied in four prospective domains: social relations, marriage and family, higher education and work and career. These domains are described in terms of two dimensions: theme (relational vs. instrumental) and distance (near vs. distant future). Data collected from Israeli Jewish adolescents (11th graders) were analysed by repeated measures ANOVAs and ANCOVAs (covariate: depressive experiences) for seven future orientation variables: value, expectance, control (motivational variables), hopes, fears (cognitive representation variables), exploration, commitment (behavioural variables). As predicted, lonely adolescents scored lower than socially embedded adolescents on future orientation variables applied to the relational and near future domains and lonely boys scored lower than lonely girls. However, effects were found only on the three future orientation motivational variables and not on the cognitive representation and behavioural variables. Contrary to prediction controlling for the effect of depressive experiences did not reduce the effect of loneliness on the future orientation variables, but reduced the tendency of adolescents to score higher on all future orientation variables in the instrumental than in the relational prospective domains. The contribution of these findings to the understanding of adolescent loneliness and future orientation was discussed and directions for future research were suggested.

Optical Variability and Classification of High Redshift (3.5 < z < 5.5) Quasars on SDSS Stripe 82

NASA Astrophysics Data System (ADS)

AlSayyad, Yusra; McGreer, Ian D.; Fan, Xiaohui; Connolly, Andrew J.; Ivezic, Zeljko; Becker, Andrew C.

2015-01-01

Recent studies have shown promise in combining optical colors with variability to efficiently select and estimate the redshifts of low- to mid-redshift quasars in upcoming ground-based time-domain surveys. We extend these studies to fainter and less abundant high-redshift quasars using light curves from 235 sq. deg. and 10 years of Stripe 82 imaging reprocessed with the prototype LSST data management stack. Sources are detected on the i-band co-adds (5σ: i ~ 24) but measured on the single-epoch (ugriz) images, generating complete and unbiased lightcurves for sources fainter than the single-epoch detection threshold. Using these forced photometry lightcurves, we explore optical variability characteristics of high redshift quasars and validate classification methods with particular attention to the low signal limit. In this low SNR limit, we quantify the degradation of the uncertainties and biases on variability parameters using simulated light curves. Completeness/efficiency and redshift accuracy are verified with new spectroscopic observations on the MMT and APO 3.5m. These preliminary results are part of a survey to measure the z~4 luminosity function for quasars (i < 23) on Stripe 82 and to validate purely photometric classification techniques for high redshift quasars in LSST.

Generation and characterization of high affinity humanized fab against hepatitis B surface antigen.

PubMed

Tiwari, Ashutosh; Dutta, Durgashree; Khanna, Navin; Acharya, Subrat K; Sinha, Subrata

2009-09-01

5S is a mouse monoclonal IgG1 that binds to the 'a' epitope of the Hepatitis B surface antigen (HBsAg) and tested positive in an in vitro test for virus neutralization. We have earlier reported the generation of humanized single chain variable fragment (scFv) from the same. In this article we report the generation of a recombinant Fab molecule by fusing humanized variable domains of 5S with the constant domains of human IgG1. The humanized Fab expressed in E. coli and subsequently purified, retained a high binding affinity (K(D) = 3.63 nmol/L) to HBsAg and bound to the same epitope of HBsAg as the parent molecule. The humanized Fab also maintained antigen binding in the presence of various destabilizing agents like 3 M NaCl, 30% DMSO, 8 M urea, and extreme pH. This high affinity humanized Fab provides a basis for the development of therapeutic molecules that can be safely utilized for the prophylaxis and treatment for Hepatitis B infection.

Reduced heart rate variability in chronic severe traumatic brain injury: Association with impaired emotional and social functioning, and potential for treatment using biofeedback.

PubMed

Francis, Heather M; Fisher, Alana; Rushby, Jacqueline A; McDonald, Skye

2016-01-01

Heart rate variability (HRV) may provide an index of capacity for social functioning and may be remediated by HRV biofeedback. Given reductions in HRV are found following traumatic brain injury (TBI), the present study aimed to determine whether lower HRV in TBI is associated with social function, and whether HRV biofeedback might be a useful remediation technique in this population. Resting state HRV and measures of social and emotional processing were collected in 30 individuals with severe TBI (3-34 years post-injury) and 30 controls. This was followed by a single session of HRV biofeedback. HRV was positively associated with social cognition and empathy, and negatively associated with alexithymia for the TBI group. Both TBI and control groups showed significantly increased HRV on both time-domain (i.e., SDNN, rMSSD) and frequency-domain measures (LF, HF, LF:HF ratio) during biofeedback compared to baseline. These results suggest that decreased HRV is linked to social and emotional function following severe TBI, and may be a novel target for therapy using HRV biofeedback techniques.

Fab-based bispecific antibody formats with robust biophysical properties and biological activity.

PubMed

Wu, Xiufeng; Sereno, Arlene J; Huang, Flora; Lewis, Steven M; Lieu, Ricky L; Weldon, Caroline; Torres, Carina; Fine, Cody; Batt, Micheal A; Fitchett, Jonathan R; Glasebrook, Andrew L; Kuhlman, Brian; Demarest, Stephen J

2015-01-01

A myriad of innovative bispecific antibody (BsAb) platforms have been reported. Most require significant protein engineering to be viable from a development and manufacturing perspective. Single-chain variable fragments (scFvs) and diabodies that consist only of antibody variable domains have been used as building blocks for making BsAbs for decades. The drawback with Fv-only moieties is that they lack the native-like interactions with CH1/CL domains that make antibody Fab regions stable and soluble. Here, we utilize a redesigned Fab interface to explore 2 novel Fab-based BsAbs platforms. The redesigned Fab interface designs limit heavy and light chain mixing when 2 Fabs are co-expressed simultaneously, thus allowing the use of 2 different Fabs within a BsAb construct without the requirement of one or more scFvs. We describe the stability and activity of a HER2×HER2 IgG-Fab BsAb, and compare its biophysical and activity properties with those of an IgG-scFv that utilizes the variable domains of the same parental antibodies. We also generated an EGFR × CD3 tandem Fab protein with a similar format to a tandem scFv (otherwise known as a bispecific T cell engager or BiTE). We show that the Fab-based BsAbs have superior biophysical properties compared to the scFv-based BsAbs. Additionally, the Fab-based BsAbs do not simply recapitulate the activity of their scFv counterparts, but are shown to possess unique biological activity.

Fab-based bispecific antibody formats with robust biophysical properties and biological activity

PubMed Central

Wu, Xiufeng; Sereno, Arlene J; Huang, Flora; Lewis, Steven M; Lieu, Ricky L; Weldon, Caroline; Torres, Carina; Fine, Cody; Batt, Micheal A; Fitchett, Jonathan R; Glasebrook, Andrew L; Kuhlman, Brian; Demarest, Stephen J

2015-01-01

A myriad of innovative bispecific antibody (BsAb) platforms have been reported. Most require significant protein engineering to be viable from a development and manufacturing perspective. Single-chain variable fragments (scFvs) and diabodies that consist only of antibody variable domains have been used as building blocks for making BsAbs for decades. The drawback with Fv-only moieties is that they lack the native-like interactions with CH1/CL domains that make antibody Fab regions stable and soluble. Here, we utilize a redesigned Fab interface to explore 2 novel Fab-based BsAbs platforms. The redesigned Fab interface designs limit heavy and light chain mixing when 2 Fabs are co-expressed simultaneously, thus allowing the use of 2 different Fabs within a BsAb construct without the requirement of one or more scFvs. We describe the stability and activity of a HER2×HER2 IgG-Fab BsAb, and compare its biophysical and activity properties with those of an IgG-scFv that utilizes the variable domains of the same parental antibodies. We also generated an EGFR × CD3 tandem Fab protein with a similar format to a tandem scFv (otherwise known as a bispecific T cell engager or BiTE). We show that the Fab-based BsAbs have superior biophysical properties compared to the scFv-based BsAbs. Additionally, the Fab-based BsAbs do not simply recapitulate the activity of their scFv counterparts, but are shown to possess unique biological activity. PMID:25774965

Performance metrics and variance partitioning reveal sources of uncertainty in species distribution models

USGS Publications Warehouse

Watling, James I.; Brandt, Laura A.; Bucklin, David N.; Fujisaki, Ikuko; Mazzotti, Frank J.; Romañach, Stephanie; Speroterra, Carolina

2015-01-01

Species distribution models (SDMs) are widely used in basic and applied ecology, making it important to understand sources and magnitudes of uncertainty in SDM performance and predictions. We analyzed SDM performance and partitioned variance among prediction maps for 15 rare vertebrate species in the southeastern USA using all possible combinations of seven potential sources of uncertainty in SDMs: algorithms, climate datasets, model domain, species presences, variable collinearity, CO2 emissions scenarios, and general circulation models. The choice of modeling algorithm was the greatest source of uncertainty in SDM performance and prediction maps, with some additional variation in performance associated with the comprehensiveness of the species presences used for modeling. Other sources of uncertainty that have received attention in the SDM literature such as variable collinearity and model domain contributed little to differences in SDM performance or predictions in this study. Predictions from different algorithms tended to be more variable at northern range margins for species with more northern distributions, which may complicate conservation planning at the leading edge of species' geographic ranges. The clear message emerging from this work is that researchers should use multiple algorithms for modeling rather than relying on predictions from a single algorithm, invest resources in compiling a comprehensive set of species presences, and explicitly evaluate uncertainty in SDM predictions at leading range margins.

Design of state-feedback controllers including sensitivity reduction, with applications to precision pointing

NASA Technical Reports Server (NTRS)

Hadass, Z.

1974-01-01

The design procedure of feedback controllers was described and the considerations for the selection of the design parameters were given. The frequency domain properties of single-input single-output systems using state feedback controllers are analyzed, and desirable phase and gain margin properties are demonstrated. Special consideration is given to the design of controllers for tracking systems, especially those designed to track polynomial commands. As an example, a controller was designed for a tracking telescope with a polynomial tracking requirement and some special features such as actuator saturation and multiple measurements, one of which is sampled. The resulting system has a tracking performance comparing favorably with a much more complicated digital aided tracker. The parameter sensitivity reduction was treated by considering the variable parameters as random variables. A performance index is defined as a weighted sum of the state and control convariances that sum from both the random system disturbances and the parameter uncertainties, and is minimized numerically by adjusting a set of free parameters.

Empowerment variables for rehabilitation clients on perceived beliefs concerning work quality of life domains.

PubMed

Tschopp, Molly K; Frain, Michael P; Bishop, Malachy

2009-01-01

This article describes and presents an initial analysis of variables generally associated with empowerment towards perceived beliefs concerning quality of life work domains for individuals with disabilities. The model examines the domains of importance, satisfaction, control and degree of interference of disability that an individual feels towards work. The internet based study used results from 70 individuals with disabilities in varying aspects of work. The variables composing empowerment that correlated strongly with the work domains include: self-advocacy, self-efficacy, perceived stigma, and family resiliency as measured through coping. Quality of Life concerning work was measured through the DSC-C a domain specific QOL instrument.

Visualizing Spatially Varying Distribution Data

NASA Technical Reports Server (NTRS)

Kao, David; Luo, Alison; Dungan, Jennifer L.; Pang, Alex; Biegel, Bryan A. (Technical Monitor)

2002-01-01

Box plot is a compact representation that encodes the minimum, maximum, mean, median, and quarters information of a distribution. In practice, a single box plot is drawn for each variable of interest. With the advent of more accessible computing power, we are now facing the problem of visual icing data where there is a distribution at each 2D spatial location. Simply extending the box plot technique to distributions over 2D domain is not straightforward. One challenge is reducing the visual clutter if a box plot is drawn over each grid location in the 2D domain. This paper presents and discusses two general approaches, using parametric statistics and shape descriptors, to present 2D distribution data sets. Both approaches provide additional insights compared to the traditional box plot technique

Nature of the protein universe

PubMed Central

Levitt, Michael

2009-01-01

The protein universe is the set of all proteins of all organisms. Here, all currently known sequences are analyzed in terms of families that have single-domain or multidomain architectures and whether they have a known three-dimensional structure. Growth of new single-domain families is very slow: Almost all growth comes from new multidomain architectures that are combinations of domains characterized by ≈15,000 sequence profiles. Single-domain families are mostly shared by the major groups of organisms, whereas multidomain architectures are specific and account for species diversity. There are known structures for a quarter of the single-domain families, and >70% of all sequences can be partially modeled thanks to their membership in these families. PMID:19541617

A residue-specific shift in stability and amyloidogenicity of antibody variable domains.

PubMed

Nokwe, Cardine N; Zacharias, Martin; Yagi, Hisashi; Hora, Manuel; Reif, Bernd; Goto, Yuji; Buchner, Johannes

2014-09-26

Variable (V) domains of antibodies are essential for antigen recognition by our adaptive immune system. However, some variants of the light chain V domains (VL) form pathogenic amyloid fibrils in patients. It is so far unclear which residues play a key role in governing these processes. Here, we show that the conserved residue 2 of VL domains is crucial for controlling its thermodynamic stability and fibril formation. Hydrophobic side chains at position 2 stabilize the domain, whereas charged residues destabilize and lead to amyloid fibril formation. NMR experiments identified several segments within the core of the VL domain to be affected by changes in residue 2. Furthermore, molecular dynamic simulations showed that hydrophobic side chains at position 2 remain buried in a hydrophobic pocket, and charged side chains show a high flexibility. This results in a predicted difference in the dissociation free energy of ∼10 kJ mol(-1), which is in excellent agreement with our experimental values. Interestingly, this switch point is found only in VL domains of the κ family and not in VLλ or in VH domains, despite a highly similar domain architecture. Our results reveal novel insight into the architecture of variable domains and the prerequisites for formation of amyloid fibrils. This might also contribute to the rational design of stable variable antibody domains. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Single-domain epitaxial silicene on diboride thin films

DOE PAGES

Fleurence, A.; Gill, T. G.; Friedlein, R.; ...

2016-04-12

Epitaxial silicene, which forms spontaneously on ZrB 2(0001) thin films grown on Si(111) wafers, has a periodic stripe domain structure. By adsorbing additional Si atoms on this surface, we find that the domain boundaries vanish, and a single-domain silicene sheet can be prepared without altering its buckled honeycomb structure. The amount of Si required to induce this change suggests that the domain boundaries are made of a local distortion of the silicene honeycomb lattice. LastlThe realization of a single domain sheet with structural and electronic properties close to those of the original striped state demonstrates the high structural flexibility ofmore » silicene.« less

Single-domain epitaxial silicene on diboride thin films

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

Fleurence, A., E-mail: antoine@jaist.ac.jp; Friedlein, R.; Aoyagi, K.

2016-04-11

Epitaxial silicene, which forms spontaneously on ZrB{sub 2}(0001) thin films grown on Si(111) wafers, has a periodic stripe domain structure. By adsorbing additional Si atoms on this surface, we find that the domain boundaries vanish, and a single-domain silicene sheet can be prepared without altering its buckled honeycomb structure. The amount of Si required to induce this change suggests that the domain boundaries are made of a local distortion of the silicene honeycomb lattice. The realization of a single domain sheet with structural and electronic properties close to those of the original striped state demonstrates the high structural flexibility ofmore » silicene.« less

The Antitumor Effect of Single-domain Antibodies Directed Towards Membrane-associated Catalase and Superoxide Dismutase.

PubMed

Bauer, Georg; Motz, Manfred

2016-11-01

Neutralizing single-domain antibodies directed towards catalase or superoxide dismutase (SOD) caused efficient reactivation of intercellular reactive oxygen species/reactive nitrogen species (ROS/RNS)-dependent apoptosis-inducing signaling specifically in human tumor cells. Single-domain antibodies targeted tumor cell-specific membrane-associated SOD and catalase, but not the corresponding intracellular enzymes. They were shown to be about 200-fold more effective than corresponding classical recombinant antigen-binding fragments and more than four log steps more efficient than monoclonal antibodies. Combined addition of single-domain antibodies against catalase and SOD caused a remarkable synergistic effect. Proof-of-concept experiments in immunocompromised mice using human tumor xenografts and single-domain antibodies directed towards SOD showed an inhibition of tumor growth. Neutralizing single-domain antibodies directed to catalase and SOD also caused a very strong synergistic effect with the established chemotherapeutic agent taxol, indicating an overlap of signaling pathways. This effect might also be useful in order to avoid unwanted side-effects and to drastically lower the costs for taxol-based therapy. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

A consensus for the development of a vector model to assess clinical complexity.

PubMed

Corazza, Gino Roberto; Klersy, Catherine; Formagnana, Pietro; Lenti, Marco Vincenzo; Padula, Donatella

2017-12-01

The progressive rise in multimorbidity has made management of complex patients one of the most topical and challenging issues in medicine, both in clinical practice and for healthcare organizations. To make this easier, a score of clinical complexity (CC) would be useful. A vector model to evaluate biological and extra-biological (socio-economic, cultural, behavioural, environmental) domains of CC was proposed a few years ago. However, given that the variables that grade each domain had never been defined, this model has never been used in clinical practice. To overcome these limits, a consensus meeting was organised to grade each domain of CC, and to establish the hierarchy of the domains. A one-day consensus meeting consisting of a multi-professional panel of 25 people was held at our Hospital. In a preliminary phase, the proponents selected seven variables as qualifiers for each of the five above-mentioned domains. In the course of the meeting, the panel voted for five variables considered to be the most representative for each domain. Consensus was established with 2/3 agreement, and all variables were dichotomised. Finally, the various domains were parametrized and ranked within a feasible vector model. A Clinical Complexity Index was set up using the chosen variables. All the domains were graphically represented through a vector model: the biological domain was chosen as the most significant (highest slope), followed by the behavioural and socio-economic domains (intermediate slope), and lastly by the cultural and environmental ones (lowest slope). A feasible and comprehensive tool to evaluate CC in clinical practice is proposed herein.

Isolation and characterization of anti c-met single chain fragment variable (scFv) antibodies.

PubMed

Qamsari, Elmira Safaie; Sharifzadeh, Zahra; Bagheri, Salman; Riazi-Rad, Farhad; Younesi, Vahid; Abolhassani, Mohsen; Ghaderi, Sepideh Safaei; Baradaran, Behzad; Somi, Mohammad Hossein; Yousefi, Mehdi

2017-12-01

The receptor tyrosine kinase (RTK) Met is the cell surface receptor for hepatocyte growth factor (HGF) involved in invasive growth programs during embryogenesis and tumorgenesis. There is compelling evidence suggesting important roles for c-Met in colorectal cancer proliferation, migration, invasion, angiogenesis, and survival. Hence, a molecular inhibitor of an extracellular domain of c-Met receptor that blocks c-Met-cell surface interactions could be of great thera-peutic importance. In an attempt to develop molecular inhibitors of c-Met, single chain variable fragment (scFv) phage display libraries Tomlinson I + J against a specific synthetic oligopeptide from the extracellular domain of c-Met receptor were screened; selected scFv were then characterized using various immune techniques. Three c-Met specific scFv (ES1, ES2, and ES3) were selected following five rounds of panning procedures. The scFv showed specific binding to c-Met receptor, and significantly inhibited proliferation responses of a human colorectal carcinoma cell line (HCT-116). Moreover, anti- apoptotic effects of selected scFv antibodies on the HCT-116 cell line were also evaluated using Annexin V/PI assays. The results demonstrated rates of apoptotic cell death of 46.0, 25.5, and 37.8% among these cells were induced by use of ES1, ES2, and ES3, respectively. The results demonstrated ability to successfully isolate/char-acterize specific c-Met scFv that could ultimately have a great therapeutic potential in immuno-therapies against (colorectal) cancers.

Facile Affinity Maturation of Antibody Variable Domains Using Natural Diversity Mutagenesis

PubMed Central

Tiller, Kathryn E.; Chowdhury, Ratul; Li, Tong; Ludwig, Seth D.; Sen, Sabyasachi; Maranas, Costas D.; Tessier, Peter M.

2017-01-01

The identification of mutations that enhance antibody affinity while maintaining high antibody specificity and stability is a time-consuming and laborious process. Here, we report an efficient methodology for systematically and rapidly enhancing the affinity of antibody variable domains while maximizing specificity and stability using novel synthetic antibody libraries. Our approach first uses computational and experimental alanine scanning mutagenesis to identify sites in the complementarity-determining regions (CDRs) that are permissive to mutagenesis while maintaining antigen binding. Next, we mutagenize the most permissive CDR positions using degenerate codons to encode wild-type residues and a small number of the most frequently occurring residues at each CDR position based on natural antibody diversity. This mutagenesis approach results in antibody libraries with variants that have a wide range of numbers of CDR mutations, including antibody domains with single mutations and others with tens of mutations. Finally, we sort the modest size libraries (~10 million variants) displayed on the surface of yeast to identify CDR mutations with the greatest increases in affinity. Importantly, we find that single-domain (VHH) antibodies specific for the α-synuclein protein (whose aggregation is associated with Parkinson’s disease) with the greatest gains in affinity (>5-fold) have several (four to six) CDR mutations. This finding highlights the importance of sampling combinations of CDR mutations during the first step of affinity maturation to maximize the efficiency of the process. Interestingly, we find that some natural diversity mutations simultaneously enhance all three key antibody properties (affinity, specificity, and stability) while other mutations enhance some of these properties (e.g., increased specificity) and display trade-offs in others (e.g., reduced affinity and/or stability). Computational modeling reveals that improvements in affinity are generally not due to direct interactions involving CDR mutations but rather due to indirect effects that enhance existing interactions and/or promote new interactions between the antigen and wild-type CDR residues. We expect that natural diversity mutagenesis will be useful for efficient affinity maturation of a wide range of antibody fragments and full-length antibodies. PMID:28928732

Crystal structure of a 3B3 variant - A broadly neutralizing HIV-1 scFv antibody

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

Clark, K. Reed; Walsh, Scott T.R.; NCH)

2009-12-10

We present the crystal structure determination of an anti-HIV-1 gp120 single-chain variable fragment antibody variant, 3B3, at 2.5 {angstrom} resolution. This 3B3 variant was derived from the b12 antibody, using phage display and site-directed mutagenesis of the variable heavy chain (V{sub H}) complementary-determining regions (CDRs). 3B3 exhibits enhanced binding affinity and neutralization activity against several cross-clade primary isolates of HIV-1 by interaction with the recessed CD4-binding site on the gp120 envelope protein. Comparison with the structures of the unbound and bound forms of b12, the 3B3 structure closely resembles these structures with minimal differences with two notable exceptions. First, theremore » is a reorientation of the CDR-H3 of the V{sub H} domain where the primary sequences evolved from b12 to 3B3. The structural changes in CDR-H3 of 3B3, in light of the b12-gp120 complex structure, allow for positioning an additional Trp side chain in the binding interface with gp120. Finally, the second region of structural change involves two peptide bond flips in CDR-L3 of the variable light (VL) domain triggered by a point mutation in CDR-H3 of Q100eY resulting in changes in the intramolecular hydrogen bonding patterning between the VL and VH domains. Thus, the enhanced binding affinities and neutralization capabilities of 3B3 relative to b12 probably result from higher hydrophobic driving potential by burying more aromatic residues at the 3B3-gp120 interface and by indirect stabilization of intramolecular contacts of the core framework residues between the VL and VH domains possibly through more favorable entropic effect through the expulsion of water.« less

The variability of the rainfall rate as a function of area

NASA Astrophysics Data System (ADS)

Jameson, A. R.; Larsen, M. L.

2016-01-01

Distributions of drop sizes can be expressed as DSD = Nt × PSD, where Nt is the total number of drops in a sample and PSD is the frequency distribution of drop diameters (D). Their discovery permitted remote sensing techniques for rainfall estimation using radars and satellites measuring over large domains of several kilometers. Because these techniques depend heavily on higher moments of the PSD, there has been a bias toward attributing the variability of the intrinsic rainfall rates R over areas (σR) to the variability of the PSDs. While this variability does increase up to a point with increasing domain dimension L, the variability of the rainfall rate R also depends upon the variability in the total number of drops Nt. We show that while the importance of PSDs looms large for small domains used in past studies, it is the variability of Nt that dominates the variability of R as L increases to 1 km and beyond. The PSDs contribute to the variability of R through the relative dispersion of χ = D3Vt, where Vt is the terminal fall speed of drops of diameter D. However, the variability of χ is inherently limited because drop sizes and fall speeds are physically limited. In contrast, it is shown that the variance of Nt continuously increases as the domain expands for physical reasons explained below. Over domains larger than around 1 km, it is shown that Nt dominates the variance of the rainfall rate with increasing L regardless of the PSD.

Genome-nuclear lamina interactions: from cell populations to single cells.

PubMed

Yáñez-Cuna, J Omar; van Steensel, Bas

2017-04-01

Lamina-associated domains (LADs) are large genomic regions that interact with the nuclear lamina (NL) and help to guide the spatial folding of chromosomes in the interphase nucleus. LADs have been linked to gene repression and other functions. Recent studies have begun to uncover some of the molecular players that drive LAD-NL interactions. A picture emerges in which DNA sequence, chromatin components and nuclear lamina proteins play an important role. Complementary to this, imaging and single-cell genomics approaches have revealed that some LAD-NL interactions are variable from cell to cell, while others are very stable. Understanding LADs can provide a unique perspective into the general process of genome organization. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Changes in magnetic domain structure during twin boundary motion in single crystal Ni-Mn-Ga exhibiting magnetic shape memory effect

NASA Astrophysics Data System (ADS)

Kopecký, V.; Fekete, L.; Perevertov, O.; Heczko, O.

2016-05-01

The complexity of Ni-Mn-Ga single crystal originates from the interplay between ferromagnetic domain structure and ferroelastic twinned microstructure. Magnetic domain structure in the vicinity of single twin boundary was studied using magneto-optical indicator film and magnetic force microscopy technique. The single twin boundary of Type I was formed mechanically and an initial magnetization state in both variants were restored by local application of magnetic field (≈40 kA/m). The differently oriented variants exhibited either stripe or labyrinth magnetic domain pattern in agreement with the uniaxial magnetocrystalline anisotropy of the martensite. The twin boundary was then moved by compressive or tensile stress. The passage of the boundary resulted in the formation of granular or rake domains, respectively. Additionally, the specific magnetic domains pattern projected by twin boundary gradually vanished during twin boundary motion.

Crystal structure of a novel conformational state of the flavivirus NS3 protein: implications for polyprotein processing and viral replication.

PubMed

Assenberg, René; Mastrangelo, Eloise; Walter, Thomas S; Verma, Anil; Milani, Mario; Owens, Raymond J; Stuart, David I; Grimes, Jonathan M; Mancini, Erika J

2009-12-01

The flavivirus genome comprises a single strand of positive-sense RNA, which is translated into a polyprotein and cleaved by a combination of viral and host proteases to yield functional proteins. One of these, nonstructural protein 3 (NS3), is an enzyme with both serine protease and NTPase/helicase activities. NS3 plays a central role in the flavivirus life cycle: the NS3 N-terminal serine protease together with its essential cofactor NS2B is involved in the processing of the polyprotein, whereas the NS3 C-terminal NTPase/helicase is responsible for ATP-dependent RNA strand separation during replication. An unresolved question remains regarding why NS3 appears to encode two apparently disconnected functionalities within one protein. Here we report the 2.75-A-resolution crystal structure of full-length Murray Valley encephalitis virus NS3 fused with the protease activation peptide of NS2B. The biochemical characterization of this construct suggests that the protease has little influence on the helicase activity and vice versa. This finding is in agreement with the structural data, revealing a single protein with two essentially segregated globular domains. Comparison of the structure with that of dengue virus type 4 NS2B-NS3 reveals a relative orientation of the two domains that is radically different between the two structures. Our analysis suggests that the relative domain-domain orientation in NS3 is highly variable and dictated by a flexible interdomain linker. The possible implications of this conformational flexibility for the function of NS3 are discussed.

Evolutionary origins of a novel host plant detoxification gene in butterflies.

PubMed

Fischer, Hanna M; Wheat, Christopher W; Heckel, David G; Vogel, Heiko

2008-05-01

Chemical interactions between plants and their insect herbivores provide an excellent opportunity to study the evolution of species interactions on a molecular level. Here, we investigate the molecular evolutionary events that gave rise to a novel detoxifying enzyme (nitrile-specifier protein [NSP]) in the butterfly family Pieridae, previously identified as a coevolutionary key innovation. By generating and sequencing expressed sequence tags, genomic libraries, and screening databases we found NSP to be a member of an insect-specific gene family, which we characterized and named the NSP-like gene family. Members consist of variable tandem repeats, are gut expressed, and are found across Insecta evolving in a dynamic, ongoing birth-death process. In the Lepidoptera, multiple copies of single-domain major allergen genes are present and originate via tandem duplications. Multiple domain genes are found solely within the brassicaceous-feeding Pieridae butterflies, one of them being NSP and another called major allergen (MA). Analyses suggest that NSP and its paralog MA have a unique single-domain evolutionary origin, being formed by intragenic domain duplication followed by tandem whole-gene duplication. Duplicates subsequently experienced a period of relaxed constraint followed by an increase in constraint, perhaps after neofunctionalization. NSP and its ortholog MA are still experiencing high rates of change, reflecting a dynamic evolution consistent with the known role of NSP in plant-insect interactions. Our results provide direct evidence to the hypothesis that gene duplication is one of the driving forces for speciation and adaptation, showing that both within- and whole-gene tandem duplications are a powerful force underlying evolutionary adaptation.

Sensitivity of the Carolina Coastal Ocean Circulation to Open Boundary and Atmospheric Forcing

NASA Astrophysics Data System (ADS)

Liu, X.; Xie, L.; Pietrafesa, L.

2003-12-01

The ocean circulation on the continental shelf off the Carolina coast is characterized by a complex flow regime and temporal variability, which is influenced by atmospheric forcing, the Gulf Stream system, complex coastline and bathymetry, river discharge and tidal forcing. In this study, a triple-nested, HYbrid Coordinate Ocean Model (HYCOM) is used to simulate the coastal ocean circulation on the continental shelf off the Carolina coast and its interactions with the offshore large-scale ocean circulation system. The horizontal mesh size in the innermost domain was set to 1 km, whereas the outermost domain coincides with the near real-time 1/12­’ Atlantic HYCOM Nowcast/Forecast System operated at the Naval Research Laboratory. The intermediate domain uses a mesh size of 3 km. Atmospheric forcing fields for the Carolina coastal region are derived from the NOAA operational ETA model, the ECMWF reanalysis fields and NCEP/NCAR reanalysis fields. These forcing fields are derived at 0.8›¦, 1.125›¦ and 1.875›¦ resolutions, and at intervals of 6 hour, daily and monthly. The sensitivity of the model results to the spatial and temporal resolution of the atmospheric forcing fields is analyzed. To study the dependence of the model sensitivity on the model grid size, single-window simulations at resolutions of 1km, 3km and 9km are carried out using the same forcing fields that were applied to the nested system. Comparisons between the nested and the single domain simulation results will be presented.

A fusion-protein approach enabling mammalian cell production of tumor targeting protein domains for therapeutic development.

PubMed

Hu, Jia; Chen, Xiang; Zhang, Xuhua; Yuan, Xiaopeng; Yang, Mingjuan; Dai, Hui; Yang, Wei; Zhou, Qinghua; Wen, Weihong; Wang, Qirui; Qin, Weijun; Zhao, Aizhi

2018-05-01

A single chain Fv fragment (scFv) is a fusion of the variable regions of heavy (V H ) and light (V L ) chains of immunoglobulins. They are important elements of chimeric antigen receptors for cancer therapy. We sought to produce a panel of 16 extracellular protein domains of tumor markers for use in scFv yeast library screenings. A series of vectors comprising various combinations of expression elements was made, but expression was unpredictable and more than half of the protein domains could not be produced using any of the constructs. Here we describe a novel fusion expression system based on mouse TEM7 (tumor endothelial marker 7), which could facilitate protein expression. With this approach we could produce all but one of the tumor marker domains that could not otherwise be expressed. In addition, we demonstrated that the tumor associated antigen hFZD10 produced as a fusion protein with mTEM7 could be used to enrich scFv antibodies from a yeast display library. Collectively our study demonstrates the potential of specific fusion proteins based on mTEM7 in enabling mammalian cell production of tumor targeting protein domains for therapeutic development. © 2018 The Protein Society.

Important clinical descriptors to include in the examination and assessment of patients with femoroacetabular impingement syndrome: an international and multi-disciplinary Delphi survey.

PubMed

Reiman, M P; Thorborg, K; Covington, K; Cook, C E; Hölmich, P

2017-06-01

Determine which examination findings are key clinical descriptors of femoroacetabular impingement syndrome (FAIS) through use of an international, multi-disciplinary expert panel. A three-round Delphi survey utilizing an international, multi-disciplinary expert panel operationally defined from international publications and presentations was utilized. All six domains (subjective examination, patient-reported outcome measures, physical examination, special tests, physical performance measures, and diagnostic imaging) had at least one descriptor with 75% consensus agreement for diagnosis and assessment of FAIS. Diagnostic imaging was the domain with the highest level of agreement. Domains such as patient-reported outcome measures (PRO's) and physical examination were identified as non-diagnostic measures (rather as assessments of disease impact). Although it also had the greatest level of variability in description of examination domains, diagnostic imaging continues to be the preeminent diagnostic measure for FAIS. No single domain should be utilized as the sole diagnostic or assessment parameter for FAIS. While not all investigated domains provide diagnostic capability for FAIS, those that do not are able to serve purpose as a measure of disease impact (e.g., impairments and activity limitations). The clinical relevance of this Delphi survey is the understanding that a comprehensive assessment measuring both diagnostic capability and disease impact most accurately reflects the patient with FAIS. V.

Capturing Three-Dimensional Genome Organization in Individual Cells by Single-Cell Hi-C.

PubMed

Nagano, Takashi; Wingett, Steven W; Fraser, Peter

2017-01-01

Hi-C is a powerful method to investigate genome-wide, higher-order chromatin and chromosome conformations averaged from a population of cells. To expand the potential of Hi-C for single-cell analysis, we developed single-cell Hi-C. Similar to the existing "ensemble" Hi-C method, single-cell Hi-C detects proximity-dependent ligation events between cross-linked and restriction-digested chromatin fragments in cells. A major difference between the single-cell Hi-C and ensemble Hi-C protocol is that the proximity-dependent ligation is carried out in the nucleus. This allows the isolation of individual cells in which nearly the entire Hi-C procedure has been carried out, enabling the production of a Hi-C library and data from individual cells. With this new method, we studied genome conformations and found evidence for conserved topological domain organization from cell to cell, but highly variable interdomain contacts and chromosome folding genome wide. In addition, we found that the single-cell Hi-C protocol provided cleaner results with less technical noise suggesting it could be used to improve the ensemble Hi-C technique.

Malachite green mediates homodimerization of antibody VL domains to form a fluorescent ternary complex with singular symmetric interfaces

PubMed Central

Szent-Gyorgyi, Chris; Stanfield, Robyn L.; Andreko, Susan; Dempsey, Alison; Ahmed, Mushtaq; Capek, Sara; Waggoner, Alan; Wilson, Ian A.; Bruchez, Marcel P.

2013-01-01

We report that a symmetric small molecule ligand mediates the assembly of antibody light chain variable domains (VLs) into a correspondent symmetric ternary complex with novel interfaces. The L5* Fluorogen Activating Protein (FAP) is a VL domain that binds malachite green dye (MG) to activate intense fluorescence. Crystallography of liganded L5* reveals a 2:1 protein:ligand complex with inclusive C2 symmetry, where MG is almost entirely encapsulated between an antiparallel arrangement of the two VL domains. Unliganded L5* VL domains crystallize as a similar antiparallel VL/VL homodimer. The complementarity determining regions (CDRs) are spatially oriented to form novel VL/VL and VL/ligand interfaces that tightly constrain a propeller conformer of MG. Binding equilibrium analysis suggests highly cooperative assembly to form a very stable VL/MG/VL complex, such that MG behaves as a strong chemical inducer of dimerization. Fusion of two VL domains into a single protein tightens MG binding over 1,000-fold to low picomolar affinity without altering the large binding enthalpy, suggesting that bonding interactions with ligand and restriction of domain movements make independent contributions to binding. Fluorescence activation of a symmetrical fluorogen provides a selection mechanism for the isolation and directed evolution of ternary complexes where unnatural symmetric binding interfaces are favored over canonical antibody interfaces. As exemplified by L5*, these self-reporting complexes may be useful as modulators of protein association or as high affinity protein tags and capture reagents. PMID:23978698

SdAb heterodimer formation using leucine zippers

NASA Astrophysics Data System (ADS)

Goldman, Ellen R.; Anderson, George P.; Brozozog-Lee, P. Audrey; Zabetakis, Dan

2013-05-01

Single domain antibodies (sdAb) are variable domains cloned from camel, llama, or shark heavy chain only antibodies, and are among the smallest known naturally derived antigen binding fragments. SdAb derived from immunized llamas are able to bind antigens with high affinity, and most are capable of refolding after heat or chemical denaturation to bind antigen again. We hypothesized that the ability to produce heterodimeric sdAb would enable reagents with the robust characteristics of component sdAb, but with dramatically improved overall affinity through increased avidity. Previously we had constructed multimeric sdAb by genetically linking sdAb that bind non-overlapping epitopes on the toxin, ricin. In this work we explored a more flexible approach; the construction of multivalent binding reagents using multimerization domains. We expressed anti-ricin sdAb that recognize different epitopes on the toxin as fusions with differently charged leucine zippers. When the initially produced homodimers are mixed the leucine zipper domains will pair to produce heterodimers. We used fluorescence resonance energy transfer to confirm heterodimer formation. Surface plasmon resonance, circular dichroism, enzyme linked immunosorbent assays, and fluid array assays were used to characterize the multimer constructs, and evaluate their utility in toxin detection.

Russell body inducing threshold depends on the variable domain sequences of individual human IgG clones and the cellular protein homeostasis.

PubMed

Stoops, Janelle; Byrd, Samantha; Hasegawa, Haruki

2012-10-01

Russell bodies are intracellular aggregates of immunoglobulins. Although the mechanism of Russell body biogenesis has been extensively studied by using truncated mutant heavy chains, the importance of the variable domain sequences in this process and in immunoglobulin biosynthesis remains largely unknown. Using a panel of structurally and functionally normal human immunoglobulin Gs, we show that individual immunoglobulin G clones possess distinctive Russell body inducing propensities that can surface differently under normal and abnormal cellular conditions. Russell body inducing predisposition unique to each immunoglobulin G clone was corroborated by the intrinsic physicochemical properties encoded in the heavy chain variable domain/light chain variable domain sequence combinations that define each immunoglobulin G clone. While the sequence based intrinsic factors predispose certain immunoglobulin G clones to be more prone to induce Russell bodies, extrinsic factors such as stressful cell culture conditions also play roles in unmasking Russell body propensity from immunoglobulin G clones that are normally refractory to developing Russell bodies. By taking advantage of heterologous expression systems, we dissected the roles of individual subunit chains in Russell body formation and examined the effect of non-cognate subunit chain pair co-expression on Russell body forming propensity. The results suggest that the properties embedded in the variable domain of individual light chain clones and their compatibility with the partnering heavy chain variable domain sequences underscore the efficiency of immunoglobulin G biosynthesis, the threshold for Russell body induction, and the level of immunoglobulin G secretion. We propose that an interplay between the unique properties encoded in variable domain sequences and the state of protein homeostasis determines whether an immunoglobulin G expressing cell will develop the Russell body phenotype in a dynamic cellular setting. Copyright © 2012 Elsevier B.V. All rights reserved.

Iterative refinement of implicit boundary models for improved geological feature reproduction

NASA Astrophysics Data System (ADS)

Martin, Ryan; Boisvert, Jeff B.

2017-12-01

Geological domains contain non-stationary features that cannot be described by a single direction of continuity. Non-stationary estimation frameworks generate more realistic curvilinear interpretations of subsurface geometries. A radial basis function (RBF) based implicit modeling framework using domain decomposition is developed that permits introduction of locally varying orientations and magnitudes of anisotropy for boundary models to better account for the local variability of complex geological deposits. The interpolation framework is paired with a method to automatically infer the locally predominant orientations, which results in a rapid and robust iterative non-stationary boundary modeling technique that can refine locally anisotropic geological shapes automatically from the sample data. The method also permits quantification of the volumetric uncertainty associated with the boundary modeling. The methodology is demonstrated on a porphyry dataset and shows improved local geological features.

Pore and Continuum Scale Study of the Effect of Subgrid Transport Heterogeneity on Redox Reaction Rates

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

Liu, Yuanyuan; Liu, Chongxuan; Zhang, Changyong

2015-08-01

A micromodel system with a pore structure for heterogeneous flow and transport was used to investigate the effect of subgrid transport heterogeneity on redox reaction rates. Hematite reductive dissolution by injecting a reduced form of flavin mononucleotide (FMNH2) at variable flow rates was used as an example to probe the variations of redox reaction rates in different subgrid transport domains. Experiments, pore-scale simulations, and macroscopic modeling were performed to measure and simulate in-situ hematite reduction and to evaluate the scaling behavior of the redox reaction rates from the pore to macroscopic scales. The results indicated that the measured pore-scale ratesmore » of hematite reduction were consistent with the predictions from a pore scale reactive transport model. A general trend is that hematite reduction followed reductant transport pathways, starting from the advection-dominated pores toward the interior of diffusion-dominated domains. Two types of diffusion domains were considered in the micromodel: a micropore diffusion domain, which locates inside solid grains or aggregates where reactant transport is limited by diffusion; and a macropore diffusion domain, which locates at wedged, dead-end pore spaces created by the grain-grain contacts. The rate of hematite reduction in the advection-dominated domain was faster than those in the diffusion-controlled domains, and the rate in the macropore diffusion domain was faster than that in the micropore domain. The reduction rates in the advection and macropore diffusion domains increased with increasing flow rate, but were affected by different mechanisms. The rate increase in the advection domain was controlled by the mass action effect as a faster flow supplied more reactants, and the rate increase in the macropore domain was more affected by the rate of mass exchange with the advection domain, which increased with increasing flow rate. The hematite reduction rate in the micropore domain was, however, not affected by the flow rate because molecular diffusion limits reductant supply to the micropore domain interior. Domain-based macroscopic models were evaluated to scale redox reaction rates from the pore to macroscopic scales. A single domain model, which ignores subgrid transport heterogeneity deviated significantly from the pore-scale results. Further analysis revealed that the rate expression for hematite reduction was not scalable from the pore to porous media using the single domain model. A three-domain model, which effectively considers subgrid reactive diffusion in the micropore and macropore domains, significantly improved model description. Overall this study revealed the importance of subgrid transport heterogeneity in the manifestation of redox reaction rates in porous media and in scaling reactions from the pore to porous media. The research also supported that the domain-based scaling approach can be used to directly scale redox reactions in porous media with subgrid transport heterogeneity.« less

Discrete sensitivity derivatives of the Navier-Stokes equations with a parallel Krylov solver

NASA Technical Reports Server (NTRS)

Ajmani, Kumud; Taylor, Arthur C., III

1994-01-01

This paper solves an 'incremental' form of the sensitivity equations derived by differentiating the discretized thin-layer Navier Stokes equations with respect to certain design variables of interest. The equations are solved with a parallel, preconditioned Generalized Minimal RESidual (GMRES) solver on a distributed-memory architecture. The 'serial' sensitivity analysis code is parallelized by using the Single Program Multiple Data (SPMD) programming model, domain decomposition techniques, and message-passing tools. Sensitivity derivatives are computed for low and high Reynolds number flows over a NACA 1406 airfoil on a 32-processor Intel Hypercube, and found to be identical to those computed on a single-processor Cray Y-MP. It is estimated that the parallel sensitivity analysis code has to be run on 40-50 processors of the Intel Hypercube in order to match the single-processor processing time of a Cray Y-MP.

Retargeting of adenovirus vectors through genetic fusion of a single-chain or single-domain antibody to capsid protein IX.

PubMed

Poulin, Kathy L; Lanthier, Robert M; Smith, Adam C; Christou, Carin; Risco Quiroz, Milagros; Powell, Karen L; O'Meara, Ryan W; Kothary, Rashmi; Lorimer, Ian A; Parks, Robin J

2010-10-01

Adenovirus (Ad) vectors are the most commonly used system for gene therapy applications, due in part to their ability to infect a wide array of cell types and tissues. However, many therapies would benefit from the ability to target the Ad vector only to specific cells, such as tumor cells for cancer gene therapy. In this study, we investigated the utility of capsid protein IX (pIX) as a platform for the presentation of single-chain variable-fragment antibodies (scFv) and single-domain antibodies (sdAb) for virus retargeting. We show that scFv can be displayed on the capsid through genetic fusion to native pIX but that these molecules fail to retarget the virus, due to improper folding of the scFv. Redirecting expression of the fusion protein to the endoplasmic reticulum (ER) results in correct folding of the scFv and allows it to recognize its epitope; however, ER-targeted pIX-scFv was incorporated into the Ad capsid at a very low level which was not sufficient to retarget virus infection. In contrast, a pIX-sdAb construct was efficiently incorporated into the Ad capsid and enhanced virus infection of cells expressing the targeted receptor. Taken together, our data indicate that pIX is an effective platform for presentation of large targeting polypeptides on the surface of the virus capsid, but the nature of the ligand can significantly affect its association with virions.

Physical Performance and Physical Activity in Older Adults: Associated but Separate Domains of Physical Function in Old Age

PubMed Central

van Lummel, Rob C.; Walgaard, Stefan; Pijnappels, Mirjam; Elders, Petra J. M.; Garcia-Aymerich, Judith; van Dieën, Jaap H.; Beek, Peter J.

2015-01-01

Background Physical function is a crucial factor in the prevention and treatment of health conditions in older adults and is usually measured objectively with physical performance tests and/or physical activity monitoring. Objective To examine whether 1) physical performance (PP) and physical activity (PA) constitute separate domains of physical function; 2) differentiation of PA classes is more informative than overall PA. Design Cross-sectional study to explore the relationships within and among PP and PA measures. Methods In 49 older participants (83±7 years; M±SD), performance-based tests were conducted and PA was measured for one week. Activity monitor data were reduced in terms of duration, periods, and mean duration of periods of lying, sitting, standing and locomotion. The relation between and within PP scores and PA outcomes were analysed using rank order correlation and factor analysis. Results Factor structure after varimax rotation revealed two orthogonal factors explaining 78% of the variance in the data: one comprising all PA variables and one comprising all PP variables. PP scores correlated moderately with PA in daily life. Differentiation of activity types and quantification of their duration, intensity and frequency of occurrence provided stronger associations with PP, as compared to a single measure of acceleration expressing overall PA. Limitations For independent validation, the conclusions about the validity of the presented conceptual framework and its clinical implications need to be confirmed in other studies. Conclusions PP and PA represent associated but separate domains of physical function, suggesting that an improvement of PP does not automatically imply an increase of PA, i.e. a change to a more active lifestyle. Differentiation of activity classes in the analysis of PA provides more insights into PA and its association with PP than using a single overall measure of acceleration. PMID:26630268

Anomalous domain inversion in LiNbO3 single crystals investigated by scanning probe microscopy

NASA Astrophysics Data System (ADS)

Lilienblum, M.; Soergel, E.

2011-09-01

Ferroelectric domains were written in lithium niobate (LiNbO3) single crystals by applying voltage pulses to the tip of a scanning force microscope. The generated domains are subsequently imaged by piezoresponse force microscopy. As it has been previously observed not only full domains but also doughnut-shaped ones arise from tip-based domain formation. In this contribution, we present our experiments which were carried out with 10-20 μm thin LiNbO3 single crystals. We show that by choosing appropriate writing parameters, domains of predetermined shape (full or doughnut) can be reliably generated. In addition to the duration and the amplitude of the voltage pulse the moment of the retraction of the tip from the sample surface was found to be a crucial parameter for reproducible domain formation.

An overlapping region between the two terminal folding units of the outer surface protein A (OspA) controls its folding behavior.

PubMed

Makabe, Koki; Nakamura, Takashi; Dhar, Debanjan; Ikura, Teikichi; Koide, Shohei; Kuwajima, Kunihiro

2018-04-27

Although many naturally occurring proteins consist of multiple domains, most studies on protein folding to date deal with single-domain proteins or isolated domains of multi-domain proteins. Studies of multi-domain protein folding are required for further advancing our understanding of protein folding mechanisms. Borrelia outer surface protein A (OspA) is a β-rich two-domain protein, in which two globular domains are connected by a rigid and stable single-layer β-sheet. Thus, OspA is particularly suited as a model system for studying the interplays of domains in protein folding. Here, we studied the equilibria and kinetics of the urea-induced folding-unfolding reactions of OspA probed with tryptophan fluorescence and ultraviolet circular dichroism. Global analysis of the experimental data revealed compelling lines of evidence for accumulation of an on-pathway intermediate during kinetic refolding and for the identity between the kinetic intermediate and a previously described equilibrium unfolding intermediate. The results suggest that the intermediate has the fully native structure in the N-terminal domain and the single layer β-sheet, with the C-terminal domain still unfolded. The observation of the productive on-pathway folding intermediate clearly indicates substantial interactions between the two domains mediated by the single-layer β-sheet. We propose that a rigid and stable intervening region between two domains creates an overlap between two folding units and can energetically couple their folding reactions. Copyright © 2018. Published by Elsevier Ltd.

Variable-Domain Displacement Transfer Functions for Converting Surface Strains into Deflections for Structural Deformed Shape Predictions

NASA Technical Reports Server (NTRS)

Ko, William L.; Fleischer, Van Tran

2015-01-01

Variable-Domain Displacement Transfer Functions were formulated for shape predictions of complex wing structures, for which surface strain-sensing stations must be properly distributed to avoid jointed junctures, and must be increased in the high strain gradient region. Each embedded beam (depth-wise cross section of structure along a surface strain-sensing line) was discretized into small variable domains. Thus, the surface strain distribution can be described with a piecewise linear or a piecewise nonlinear function. Through discretization, the embedded beam curvature equation can be piece-wisely integrated to obtain the Variable-Domain Displacement Transfer Functions (for each embedded beam), which are expressed in terms of geometrical parameters of the embedded beam and the surface strains along the strain-sensing line. By inputting the surface strain data into the Displacement Transfer Functions, slopes and deflections along each embedded beam can be calculated for mapping out overall structural deformed shapes. A long tapered cantilever tubular beam was chosen for shape prediction analysis. The input surface strains were analytically generated from finite-element analysis. The shape prediction accuracies of the Variable- Domain Displacement Transfer Functions were then determined in light of the finite-element generated slopes and deflections, and were fofound to be comparable to the accuracies of the constant-domain Displacement Transfer Functions

Magnetic force microscopy study of domain walls in Co{sub 2}Z ferrite

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

Qin, Lang; Verweij, Henk, E-mail: verweij.1@osu.edu

2014-03-01

Graphical abstract: - Highlights: • Hexaferrite Co{sub 2}Z is synthesized through the modified Pechini method. • Magnetic domains are observed in anisotropic Co{sub 2}Z single grain using MFM. • Observed single grain domain thickness is in good agreement with Dotsh model. - Abstract: Hexaferrite Co{sub 2}Z was synthesized through the modified Pechini method. Partially oriented samples were obtained after consolidation with uniaxial pressing and calcination/sintering at 1300 °C/1330 °C. The sample composition and morphology was identified with X-ray diffractometry (XRD) and scanning electron microscopy (SEM) with energy-dispersive X-ray spectrometry (EDS). MFM studies of the single grains revealed a domain structuremore » with 0.7 μm wide. The Co{sub 2}Z static magnetization was measured with a vibrating sample magnetometer (VSM), and was used to calculate a single grain domain with a thickness of 4.8 μm. This result is in good agreement with SEM observations of the single grain thickness.« less

Electric-field-induced domain intersection in BaTiO3 single crystal

NASA Astrophysics Data System (ADS)

He, Ming; Wang, Mengxia; Zhang, Zhihua

2017-03-01

Large-angle convergent beam electron diffraction was used to determine the directions of polarization vectors in a BaTiO3 single crystal. Domain intersections driven by an electric field were investigated by in situ transmission electron microscopy. The dark triangles observed in the domain intersection region can be accounted for by dislocations and the strain field. Domains nucleate at the domain tip depending on the dislocations and strain field to relieve the accumulated stress. Schematic representations of the intersecting domains and the microscopic structure are given, clarifying the special electric-field-induced domain structure.

Construction of an environmental quality index for public health research

PubMed Central

2014-01-01

Background A more comprehensive estimate of environmental quality would improve our understanding of the relationship between environmental conditions and human health. An environmental quality index (EQI) for all counties in the U.S. was developed. Methods The EQI was developed in four parts: domain identification; data source acquisition; variable construction; and data reduction. Five environmental domains (air, water, land, built and sociodemographic) were recognized. Within each domain, data sources were identified; each was temporally (years 2000–2005) and geographically (county) restricted. Variables were constructed for each domain and assessed for missingness, collinearity, and normality. Domain-specific data reduction was accomplished using principal components analysis (PCA), resulting in domain-specific indices. Domain-specific indices were then combined into an overall EQI using PCA. In each PCA procedure, the first principal component was retained. Both domain-specific indices and overall EQI were stratified by four rural–urban continuum codes (RUCC). Higher values for each index were set to correspond to areas with poorer environmental quality. Results Concentrations of included variables differed across rural–urban strata, as did within-domain variable loadings, and domain index loadings for the EQI. In general, higher values of the air and sociodemographic indices were found in the more metropolitan areas and the most thinly populated areas have the lowest values of each of the domain indices. The less-urbanized counties (RUCC 3) demonstrated the greatest heterogeneity and range of EQI scores (−4.76, 3.57) while the thinly populated strata (RUCC 4) contained counties with the most positive scores (EQI score ranges from −5.86, 2.52). Conclusion The EQI holds promise for improving our characterization of the overall environment for public health. The EQI describes the non-residential ambient county-level conditions to which residents are exposed and domain-specific EQI loadings indicate which of the environmental domains account for the largest portion of the variability in the EQI environment. The EQI was constructed for all counties in the United States, incorporating a variety of data to provide a broad picture of environmental conditions. We undertook a reproducible approach that primarily utilized publically-available data sources. PMID:24886426

Implementing the undergraduate mini-CEX: a tailored approach at Southampton University.

PubMed

Hill, Faith; Kendall, Kathleen; Galbraith, Kevin; Crossley, Jim

2009-04-01

The mini-clinical evaluation exercise (mini-CEX) is widely used in the UK to assess clinical competence, but there is little evidence regarding its implementation in the undergraduate setting. This study aimed to estimate the validity and reliability of the undergraduate mini-CEX and discuss the challenges involved in its implementation. A total of 3499 mini-CEX forms were completed. Validity was assessed by estimating associations between mini-CEX score and a number of external variables, examining the internal structure of the instrument, checking competency domain response rates and profiles against expectations, and by qualitative evaluation of stakeholder interviews. Reliability was evaluated by overall reliability coefficient (R), estimation of the standard error of measurement (SEM), and from stakeholders' perceptions. Variance component analysis examined the contribution of relevant factors to students' scores. Validity was threatened by various confounding variables, including: examiner status; case complexity; attachment specialty; patient gender, and case focus. Factor analysis suggested that competency domains reflect a single latent variable. Maximum reliability can be achieved by aggregating scores over 15 encounters (R = 0.73; 95% confidence interval [CI] +/- 0.28 based on a 6-point assessment scale). Examiner stringency contributed 29% of score variation and student attachment aptitude 13%. Stakeholder interviews revealed staff development needs but the majority perceived the mini-CEX as more reliable and valid than the previous long case. The mini-CEX has good overall utility for assessing aspects of the clinical encounter in an undergraduate setting. Strengths include fidelity, wide sampling, perceived validity, and formative observation and feedback. Reliability is limited by variable examiner stringency, and validity by confounding variables, but these should be viewed within the context of overall assessment strategies.

The association between sexual satisfaction and body image in women.

PubMed

Pujols, Yasisca; Seal, Brooke N; Meston, Cindy M

2010-02-01

Although sexual functioning has been linked to sexual satisfaction, it only partially explains the degree to which women report being sexually satisfied. Other factors include quality of life, relational variables, and individual factors such as body image. Of the few studies that have investigated the link between body image and sexual satisfaction, most have considered body image to be a single construct and have shown mixed results. The present study assessed multiple body image variables in order to better understand which aspects of body image influence multiple domains of sexual satisfaction, including sexual communication, compatibility, contentment, personal concern, and relational concern in a community sample of women. Women between the ages of 18 and 49 years in sexual relationships (N = 154) participated in an Internet survey that assessed sexual functioning, five domains of sexual satisfaction, and several body image variables. Body image variables included the sexual attractiveness, weight concern, and physical condition subscales of the Body Esteem Scale, the appearance-based subscale of the Cognitive Distractions During Sexual Activity Scale, and body mass index. Total score of the Sexual Satisfaction Scale for Women was the main outcome measure. Sexual functioning was measured by a modified Female Sexual Function Index. Consistent with expectations, correlations indicated significant positive relationships between sexual functioning, sexual satisfaction, and all body image variables. A multiple regression analysis revealed that sexual satisfaction was predicted by high body esteem and low frequency of appearance-based distracting thoughts during sexual activity, even after controlling for sexual functioning status. Several aspects of body image, including weight concern, physical condition, sexual attractiveness, and thoughts about the body during sexual activity predict sexual satisfaction in women. The findings suggest that women who experience low sexual satisfaction may benefit from treatments that target these specific aspects of body image.

Single-Domain Antibodies and the Promise of Modular Targeting in Cancer Imaging and Treatment.

PubMed

Iezzi, María Elena; Policastro, Lucía; Werbajh, Santiago; Podhajcer, Osvaldo; Canziani, Gabriela Alicia

2018-01-01

Monoclonal antibodies and their fragments have significantly changed the outcome of cancer in the clinic, effectively inhibiting tumor cell proliferation, triggering antibody-dependent immune effector cell activation and complement mediated cell death. Along with a continued expansion in number, diversity, and complexity of validated tumor targets there is an increasing focus on engineering recombinant antibody fragments for lead development. Single-domain antibodies (sdAbs), in particular those engineered from the variable heavy-chain fragment (VHH gene) found in Camelidae heavy-chain antibodies (or IgG2 and IgG3), are the smallest fragments that retain the full antigen-binding capacity of the antibody with advantageous properties as drugs. For similar reasons, growing attention is being paid to the yet smaller variable heavy chain new antigen receptor (VNAR) fragments found in Squalidae. sdAbs have been selected, mostly from immune VHH libraries, to inhibit or modulate enzyme activity, bind soluble factors, internalize cell membrane receptors, or block cytoplasmic targets. This succinct review is a compilation of recent data documenting the application of engineered, recombinant sdAb in the clinic as epitope recognition "modules" to build monomeric, dimeric and multimeric ligands that target, tag and stall solid tumor growth in vivo . Size, affinity, specificity, and the development profile of sdAbs drugs are seemingly consistent with desirable clinical efficacy and safety requirements. But the hepatotoxicity of the tetrameric anti-DR5-VHH drug in patients with pre-existing anti-drug antibodies halted the phase I clinical trial and called for a thorough pre-screening of the immune and poly-specific reactivities of the sdAb leads.

Development and characterization of a camelid single-domain antibody directed to human CD22 biomarker.

PubMed

Faraji, Fatemeh; Tajik, Nader; Behdani, Mahdi; Shokrgozar, Mohammad Ali; Zarnani, Amir Hassan; Shahhosseini, Fatemeh; Habibi-Anbouhi, Mahdi

2018-03-15

CD22 is a B-cell-specific trans-membrane glycoprotein, which is found on the surface of the most B cells and modulates their function, survival, and apoptosis. Recently, targeting this cell surface biomarker in B-cell malignancies and disorders has attracted a lot of attention. The variable domain of camelid single-chain antibodies (VHH, nanobody) is a form of antibodies with novel properties including small size (15-17 kDa), thermal and chemical stability, high affinity and homology to human antibody sequences. In this study, a novel anti-CD22-specific VHH (Nb) has been developed and characterized by the screening of an immunized phage display library and its binding to CD22 + B cells is evaluated. Produced anti-CD22 VHH had a single protein band about 17 kDa of molecular size in Western blotting and its binding affinity was approximately 9 × 10 -9  M. Also, this product had high specificity and it was able to recognize the natural CD22 antigen in CD22+ cell lysate as well as on the cell surface (93%). This anti-CD22 VHH with both high affinity and specificity recognizes CD22 antigen well and can be used in diagnosis and treatment of B cell disorders and malignancies. © 2018 International Union of Biochemistry and Molecular Biology, Inc.

First molecular and biochemical analysis of in vivo affinity maturation in an ectothermic vertebrate.

PubMed

Dooley, Helen; Stanfield, Robyn L; Brady, Rebecca A; Flajnik, Martin F

2006-02-07

The cartilaginous fish are the oldest phylogenetic group in which Igs have been found. Sharks produce a unique Ig isotype, IgNAR, a heavy-chain homodimer that does not associate with light chains. Instead, the variable (V) regions of IgNAR bind antigen as soluble single domains. Our group has shown that IgNAR plays an integral part in the humoral response of nurse sharks (Ginglymostoma cirratum) upon antigen challenge. Here, we generated phage-displayed libraries of IgNAR V regions from an immunized animal and found a family of clones derived from the same rearrangement event but differentially mutated during expansion. Because of the cluster organization of shark Ig genes and the paucicopy nature of IgNAR, we were able to construct the putative ancestor of this family. By studying mutations in the context of clone affinities, we found evidence that affinity maturation occurs for this isotype. Subsequently, we were able to identify mutations important in the affinity improvement of this family. Because the family clones were all obtained after immunization, they provide insight into the in vivo maturation mechanisms, in general, and for single-domain antibody fragments.

Dynamic working memory performance in individuals with single-domain amnestic mild cognitive impairment.

PubMed

Guild, Emma B; Vasquez, Brandon P; Maione, Andrea M; Mah, Linda; Ween, Jon; Anderson, Nicole D

2014-01-01

Previous studies have observed poorer working memory performance in individuals with amnestic mild cognitive impairment than in healthy older adults. It is unclear, however, whether these difficulties are true only of the multiple-domain clinical subtype in whom poorer executive functioning is common. The current study examined working memory, as measured by the self-ordered pointing task (SOPT) and an n-back task, in healthy older adults and adults with single-domain amnestic mild cognitive impairment (aMCI). Individuals with single-domain aMCI committed more errors and required longer to develop an organizational strategy on the SOPT. The single-domain aMCI group did not differ from healthy older adults on the 1-back or 2-back, but had poorer discrimination on the 3-back task. This is, to our knowledge, the first characterization of dynamic working memory performance in a single-domain aMCI group. These results lend support for the idea that clinical amnestic MCI subtypes may reflect different stages on a continuum of progression to dementia and question whether standardized measures of working memory (span tasks) are sensitive enough to capture subtle changes in performance.

Magnetic properties of iron oxide photolytically produced from Fe(CO)5 impregnated porous glass

NASA Astrophysics Data System (ADS)

Borelli, N. F.; Morse, D. L.; Schreurs, J. W. H.

1983-06-01

This article discusses the magnetic properties observed in porous glasses impregnated with metal carbonyls after exposure to light. In the photolyzed and consolidated glasses both superparamagnetic and single domain ferrimagnetic particles were found to be present, with the single domain particles having an exceedingly high coercive force. The concentration ratio between superparamagnetic and single domain particles depends strongly on temperature. An analysis of the observed phenomena is given.

Coupled variational formulations of linear elasticity and the DPG methodology

NASA Astrophysics Data System (ADS)

Fuentes, Federico; Keith, Brendan; Demkowicz, Leszek; Le Tallec, Patrick

2017-11-01

This article presents a general approach akin to domain-decomposition methods to solve a single linear PDE, but where each subdomain of a partitioned domain is associated to a distinct variational formulation coming from a mutually well-posed family of broken variational formulations of the original PDE. It can be exploited to solve challenging problems in a variety of physical scenarios where stability or a particular mode of convergence is desired in a part of the domain. The linear elasticity equations are solved in this work, but the approach can be applied to other equations as well. The broken variational formulations, which are essentially extensions of more standard formulations, are characterized by the presence of mesh-dependent broken test spaces and interface trial variables at the boundaries of the elements of the mesh. This allows necessary information to be naturally transmitted between adjacent subdomains, resulting in coupled variational formulations which are then proved to be globally well-posed. They are solved numerically using the DPG methodology, which is especially crafted to produce stable discretizations of broken formulations. Finally, expected convergence rates are verified in two different and illustrative examples.

Unbound motion on a Schwarzschild background: Practical approaches to frequency domain computations

NASA Astrophysics Data System (ADS)

Hopper, Seth

2018-03-01

Gravitational perturbations due to a point particle moving on a static black hole background are naturally described in Regge-Wheeler gauge. The first-order field equations reduce to a single master wave equation for each radiative mode. The master function satisfying this wave equation is a linear combination of the metric perturbation amplitudes with a source term arising from the stress-energy tensor of the point particle. The original master functions were found by Regge and Wheeler (odd parity) and Zerilli (even parity). Subsequent work by Moncrief and then Cunningham, Price and Moncrief introduced new master variables which allow time domain reconstruction of the metric perturbation amplitudes. Here, I explore the relationship between these different functions and develop a general procedure for deriving new higher-order master functions from ones already known. The benefit of higher-order functions is that their source terms always converge faster at large distance than their lower-order counterparts. This makes for a dramatic improvement in both the speed and accuracy of frequency domain codes when analyzing unbound motion.

Visualizing ferromagnetic domains in undoped and Fe-doped Sr4Ru3O10

NASA Astrophysics Data System (ADS)

Sass, Paul; Wu, Weida; Mao, Zhiqiang; Li, Peigang

Transition-metal oxides have proven to be a great source of interesting phenomena and new quantum phases of matter with high potential for developing exciting technologies. A remarkable sub-class of these materials with layer dependent properties is the ruthenium perovskites of the Ruddlesden-Popper series, specifically Srn + 1RunO3 n + 1 , exhibiting a range of behavior from ferromagnetism and metamagnetic quantum criticality to p-wave superconductivity. The triple layered oxide Sr4Ru3O10 exhibits coexistence of ferro- (TC < 105 K) and meta- (TM < 50 K) magnetism with strong anisotropy. Despite many studies on bulk magnetic properties of this material, the microscopic nature of the magnetic phase is still unclear. What is lacking is the real space imaging of magnetic domains. To this end, we report our variable temperature magnetic force microscopy studies on floating-zone grown undoped and Fe-doped Sr4Ru3O10 single crystals. Various stripe and branch-like domain patterns were observed below This work is supported by DOE BES under award DE-SC0008147.

Intergenerational transmission of prejudice, sex role stereotyping, and intolerance.

PubMed

O'Bryan, Megan; Fishbein, Harold D; Ritchey, P Neal

2004-01-01

The attitudes of 111 ninth and eleventh graders and both of their biological parents were independently assessed for prejudice against people with HIV/ AIDS, homosexuals, Blacks, and fat people, as well as for male and female sex role stereotyping. This study corrected for two shortcomings in previous research: neglecting to assess both parents and assessing only a single domain of prejudice. We addressed the intergenerational transmission of prejudice and stereotyping using three competing models: same-sex, parent equivalent, and differential effects. Using multiple regressions in which parents' scores were entered separately, along with control variables, different maternal and paternal influences were detected. Mothers were the primary influence for prejudice regarding HIV/AIDS, fatness, and race, and fathers were the primary influence for male and female stereotyping and prejudice against homosexuals, supporting the differential effects model. We also established that prejudice and stereotyping in specific domains reflected a more general proclivity to be intolerant. In contrast to prejudice and stereotyping in specific domains, fathers and mothers about equally shaped the adolescents' intolerance, supporting the parent equivalent model.

Distributions in the error space: goal-directed movements described in time and state-space representations.

PubMed

Fisher, Moria E; Huang, Felix C; Wright, Zachary A; Patton, James L

2014-01-01

Manipulation of error feedback has been of great interest to recent studies in motor control and rehabilitation. Typically, motor adaptation is shown as a change in performance with a single scalar metric for each trial, yet such an approach might overlook details about how error evolves through the movement. We believe that statistical distributions of movement error through the extent of the trajectory can reveal unique patterns of adaption and possibly reveal clues to how the motor system processes information about error. This paper describes different possible ordinate domains, focusing on representations in time and state-space, used to quantify reaching errors. We hypothesized that the domain with the lowest amount of variability would lead to a predictive model of reaching error with the highest accuracy. Here we showed that errors represented in a time domain demonstrate the least variance and allow for the highest predictive model of reaching errors. These predictive models will give rise to more specialized methods of robotic feedback and improve previous techniques of error augmentation.

Physical and Structural Studies on the Cryo-cooling of Insulin Crystals

NASA Technical Reports Server (NTRS)

Lovelace, J.; Bellamy, H.; Snell, E. H.; Borgstahl, G.

2003-01-01

Reflection profiles were analyzed from microgravity-(mg) and earth-grown insulin crystals to measure mosaicity (h) and to reveal mosaic domain structure and composition. The effects of cryocooling on single and multi-domain crystals were compared. The effects of cryocooling on insulin structure were also re-examined. Microgravity crystals were larger, more homogeneous, and more perfect than earth crystals. Several mg crystals contained primarily a single mosaic domain with havg of 0.005deg. The earth crystals varied in quality and all contained multiple domains with havg of 0.031deg. Cryocooling caused a 43-fold increase in h for mg crystals (havg=0.217deg) and an %fold increase for earth crystals (havg=0.246deg). These results indicate that very well-ordered crystals are not completely protected from the stresses associated with cryocooling, especially when structural perturbations occur. However, there were differences in the reflection profiles. For multi-mosaic domain crystals, each domain individually broadened and separated from the other domains upon cryo-cooling. Cryo-cooling did not cause an increase in the number of domains. A crystal composed of a single domain retained this domain structure and the reflection profiles simply broadened. Therefore, an improved signal-to-noise ratio for each reflection was measured from cryo-cooled single domain crystals relative to cryo-cooled multi-domain crystals. This improved signal, along with the increase in crystal size, facilitated the measurement of the weaker high- resolution reflections. The observed broadening of reflection profiles indicates increased variation in unit cell dimensions which may be linked to cryo-cooling-associated structural changes and disorder.

[Analysis of time domain and frequency domain heart rate variability in fighter pilot before and after upright tilt].

PubMed

Wang, L; Wu, L; Ji, G; Zhang, X; Chen, T; Wang, L

1998-12-01

Effects of upright tilt on mechanism of autonomic nervous regulation of cardiovascular system and characteristics of heart rate variability (HRV) were observed in sixty healthy male pilots. Relation between time domain and frequency domain indexes of short-time HRV (5 min) were analysed before and after upright tilt. The results showed that there are significant difference in short time HRV parameters before and after upright tilt. Significant relationship was formed between time domain and frequency domain indexes of HRV. It suggests that time domain and frequency domain HRV analysis is capable of revealing certain informations embedded in a short series of R-R intervals and can help to evaluate the status of autonomic regulation of cardiovascular function in pilots.

Analysis of the binding loops configuration and surface adaptation of different crystallized single-domain antibodies in response to various antigens.

PubMed

Al Qaraghuli, Mohammed M; Ferro, Valerie A

2017-04-01

Monoclonal antibodies have revolutionized the biomedical field through their ubiquitous utilization in different diagnostics and therapeutic applications. Despite this widespread use, their large size and structural complexity have limited their versatility in specific applications. The antibody variable region that is responsible for binding antigen is embodied within domains that can be rescued individually as single-domain antibody (sdAb) fragments. Because of the unique characteristics of sdAbs, such as low molecular weight, high physicochemical stability, and the ability to bind antigens inaccessible to conventional antibodies, they represent a viable alternative to full-length antibodies. Consequently, 149 crystal structures of sdAbs, originating from human (VH), camelids (VHH), or sharks (VNAR), were retrieved from the Protein Data Bank, and their structures were compared. The 3 types of sdAbs displayed complementarity determining regions (CDRs) with different lengths and configurations. CDR3 of the VHH and VNAR domains were dominated by pleated and extended orientations, respectively. Although VNAR showed the smallest average molecular weight and molecular surface area compared with VHH and VH antibodies. However, the solvent accessible surface area measurements of the 3 tested sdAbs types were very similar. All the antihapten VHH antibodies showed pleated CDR3, which were sufficient to create a binding pocket to accommodate haptens (methotrexate and azo dyes) in terms of shape and electrostatic potential. The sdAbs that recognized lysozyme showed more diversity in their CDR3 orientation to enable them to recognize various topographies of lysozyme. Subsequently, the three sdAb classes were different in size and surface area and have shown distinguishable ability to optimize their CDR length and orientation to recognize different antigen classes. Copyright © 2016 John Wiley & Sons, Ltd.

Applied Routh approximation

NASA Technical Reports Server (NTRS)

Merrill, W. C.

1978-01-01

The Routh approximation technique for reducing the complexity of system models was applied in the frequency domain to a 16th order, state variable model of the F100 engine and to a 43d order, transfer function model of a launch vehicle boost pump pressure regulator. The results motivate extending the frequency domain formulation of the Routh method to the time domain in order to handle the state variable formulation directly. The time domain formulation was derived and a characterization that specifies all possible Routh similarity transformations was given. The characterization was computed by solving two eigenvalue-eigenvector problems. The application of the time domain Routh technique to the state variable engine model is described, and some results are given. Additional computational problems are discussed, including an optimization procedure that can improve the approximation accuracy by taking advantage of the transformation characterization.

Investigation of multilayer magnetic domain lattice file

NASA Technical Reports Server (NTRS)

Torok, E. J.; Kamin, M.; Tolman, C. H.

1980-01-01

The feasibility of the self structured multilayered bubble domain memory as a mass memory medium for satellite applications is examined. Theoretical considerations of multilayer bubble supporting materials are presented, in addition to the experimental evaluation of current accessed circuitry for various memory functions. The design, fabrication, and test of four device designs is described, and a recommended memory storage area configuration is presented. Memory functions which were demonstrated include the current accessed propagation of bubble domains and stripe domains, pinning of stripe domain ends, generation of single and double bubbles, generation of arrays of coexisting strip and bubble domains in a single garnet layer, and demonstration of different values of the strip out field for single and double bubbles indicating adequate margins for data detection. All functions necessary to develop a multilayer self structured bubble memory device were demonstrated in individual experiments.

Numerical simulation of water flow and Nitrate transport through variably saturated porous media in laboratory condition using HYDRUS 2D

NASA Astrophysics Data System (ADS)

Jahangeer, F.; Gupta, P. K.; Yadav, B. K.

2017-12-01

Due to the reducing availability of water resources and the growing competition for water between residential, industrial, and agricultural users, increasing irrigation efficiency, by several methods like drip irrigation, is a demanding concern for agricultural experts. The understanding of the water and contaminants flow through the subsurface is needed for the sustainable irrigation water management, pollution assessment, polluted site remediation and groundwater recharge. In this study, the Windows-based computer software package HYDRUS-2D, which numerically simulates water and solute movement in two-dimensional, variably-saturated porous media, was used to evaluate the distribution of water and Nitrate in the sand tank. The laboratory and simulation experiments were conducted to evaluate the role of drainage, recharge flux, and infiltration on subsurface flow condition and subsequently, on nitrate movement in the subsurface. The water flow in the unsaturated zone model by Richards' equation, which was highly nonlinear and its parameters were largely dependent on the moisture content and pressure head of the partially saturated zone. Following different cases to be considered to evaluate- a) applying drainage and recharge flux to study domains, b) transient infiltration in a vertical soil column and c) subsequently, nitrate transport in 2D sand tank setup. A single porosity model was used for the simulation of water and nitrate flow in the study domain. The results indicate the transient water table position decreases as the time increase significantly by applying drainage flux at the bottom. Similarly, the water table positions in study domains increasing in the domain by applying recharge flux. Likewise, the water flow profile shows the decreasing water table elevation with increasing water content in the vertical domain. Moreover, the nitrate movement was dominated by advective flux and highly affected by the recharge flux in the vertical direction. The findings of the study help to enhance the understanding of the sustainable soil-water resources management and agricultural practices.

Examining, Documenting, and Modeling the Problem Space of a Variable Domain

DTIC Science & Technology

2002-06-14

Feature-Oriented Domain Analysis ( FODA ) .............................................................................................. 9...development of this proposed process include: Feature-Oriented Domain Analysis ( FODA ) [3,4], Organization Domain Modeling (ODM) [2,5,6], Family-Oriented...configuration knowledge using generators [2]. 8 Existing Methods of Domain Engineering Feature-Oriented Domain Analysis ( FODA ) FODA is a domain

Random mutagenesis of BoNT/E Hc nanobody to construct a secondary phage-display library.

PubMed

Shahi, B; Mousavi Gargari, S L; Rasooli, I; Rajabi Bazl, M; Hoseinpoor, R

2014-08-01

To construct secondary mutant phage-display library of recombinant single variable domain (VHH) against botulinum neurotoxin E by error-prone PCR. The gene coding for specific VHH derived from the camel immunized with binding domain of botulinum neurotoxin E (BoNT/E) was amplified by error-prone PCR. Several biopanning rounds were used to screen the phage-displaying BoNT/E Hc nanobodies. The final nanobody, SHMR4, with increased affinity recognized BoNT/E toxin with no cross-reactivity with other antigens especially with related BoNT toxins. The constructed nanobody could be a suitable candidate for VHH-based biosensor production to detect the Clostridium botulinum type E. Diagnosis and treatment of botulinum neurotoxins are important. Generation of high-affinity antibodies based on the construction of secondary libraries using affinity maturation step leads to the development of reagents for precise diagnosis and therapy. © 2014 The Society for Applied Microbiology.

Phage Display Derived IgNAR V Region Binding Domains for Therapeutic Development.

PubMed

Ubah, Obinna C; Barelle, Caroline J; Buschhaus, Magdalena J; Porter, Andrew J

2016-01-01

Phage display technology has revolutionized the science of drug discovery by transforming the generation and manipulation of ligands, such as antibody fragments, enzymes, and peptides. The basis of this technology is the expression of recombinant proteins or peptides fused to a phage coat protein, and subsequent isolation of ligands based on a variety of catalytic, physicochemical/binding kinetic and/or biological characteristics. An incredible number of diagnostic and therapeutic domains have been successfully isolated using phage display technology. The variable domain of the New Antigen Receptors (VNAR) found in cartilaginous fish, is also amenable to phage display selection. Whilst not an antibody, VNARs are unquestionable the oldest (450 million years), and smallest antigen binding, single-domains so far identified in the vertebrate kingdom. Their role as an integral part of the adaptive immune system of sharks has been well established, enhancing our understanding of the evolutionary origins of humoral immunity and the unusual but divergent ancestry of the VNARs themselves. VNARs exhibit remarkable physicochemical properties, such as small size, stability in extreme conditions, solubility, molecular flexibility, high affinity and selectivity for target. The purpose of this review is to illustrate the important role phage display has played in the isolation and characterization of potent therapeutic and diagnostic VNAR domains. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Llama-derived single domain antibodies specific for Abrus agglutinin.

PubMed

Goldman, Ellen R; Anderson, George P; Zabetakis, Dan; Walper, Scott; Liu, Jinny L; Bernstein, Rachael; Calm, Alena; Carney, James P; O'Brien, Thomas W; Walker, Jennifer L; Garber, Eric A E

2011-11-01

Llama derived single domain antibodies (sdAb), the recombinantly expressed variable heavy domains from the unique heavy-chain only antibodies of camelids, were isolated from a library derived from llamas immunized with a commercial abrin toxoid preparation. Abrin is a potent toxin similar to ricin in structure, sequence and mechanism of action. The selected sdAb were evaluated for their ability to bind to commercial abrin as well as abrax (a recombinant abrin A-chain), purified abrin fractions, Abrus agglutinin (a protein related to abrin but with lower toxicity), ricin, and unrelated proteins. Isolated sdAb were also evaluated for their ability to refold after heat denaturation and ability to be used in sandwich assays as both capture and reporter elements. The best binders were specific for the Abrus agglutinin, showing minimal binding to purified abrin fractions or unrelated proteins. These binders had sub nM affinities and regained most of their secondary structure after heating to 95 °C. They functioned well in sandwich assays. Through gel analysis and the behavior of anti-abrin monoclonal antibodies, we determined that the commercial toxoid preparation used for the original immunizations contained a high percentage of Abrus agglutinin, explaining the selection of Abrus agglutinin binders. Used in conjunction with anti-abrin monoclonal and polyclonal antibodies, these reagents can fill a role to discriminate between the highly toxic abrin and the related, but much less toxic, Abrus agglutinin and distinguish between different crude preparations.

Llama-Derived Single Domain Antibodies Specific for Abrus Agglutinin

PubMed Central

Goldman, Ellen R.; Anderson, George P.; Zabetakis, Dan; Walper, Scott; Liu, Jinny L.; Bernstein, Rachael; Calm, Alena; Carney, James P.; O’Brien, Thomas W.; Walker, Jennifer L.; Garber, Eric A. E.

2011-01-01

Llama derived single domain antibodies (sdAb), the recombinantly expressed variable heavy domains from the unique heavy-chain only antibodies of camelids, were isolated from a library derived from llamas immunized with a commercial abrin toxoid preparation. Abrin is a potent toxin similar to ricin in structure, sequence and mechanism of action. The selected sdAb were evaluated for their ability to bind to commercial abrin as well as abrax (a recombinant abrin A-chain), purified abrin fractions, Abrus agglutinin (a protein related to abrin but with lower toxicity), ricin, and unrelated proteins. Isolated sdAb were also evaluated for their ability to refold after heat denaturation and ability to be used in sandwich assays as both capture and reporter elements. The best binders were specific for the Abrus agglutinin, showing minimal binding to purified abrin fractions or unrelated proteins. These binders had sub nM affinities and regained most of their secondary structure after heating to 95 °C. They functioned well in sandwich assays. Through gel analysis and the behavior of anti-abrin monoclonal antibodies, we determined that the commercial toxoid preparation used for the original immunizations contained a high percentage of Abrus agglutinin, explaining the selection of Abrus agglutinin binders. Used in conjunction with anti-abrin monoclonal and polyclonal antibodies, these reagents can fill a role to discriminate between the highly toxic abrin and the related, but much less toxic, Abrus agglutinin and distinguish between different crude preparations. PMID:22174977

The role of the C-domain of bacteriophage T4 gene 32 protein in ssDNA binding and dsDNA helix-destabilization: Kinetic, single-molecule, and cross-linking studies

PubMed Central

Pant, Kiran; Anderson, Brian; Perdana, Hendrik; Malinowski, Matthew A.; Win, Aye T.; Williams, Mark C.

2018-01-01

The model single-stranded DNA binding protein of bacteriophage T4, gene 32 protein (gp32) has well-established roles in DNA replication, recombination, and repair. gp32 is a single-chain polypeptide consisting of three domains. Based on thermodynamics and kinetics measurements, we have proposed that gp32 can undergo a conformational change where the acidic C-terminal domain binds internally to or near the single-stranded (ss) DNA binding surface in the core (central) domain, blocking ssDNA interaction. To test this model, we have employed a variety of experimental approaches and gp32 variants to characterize this conformational change. Utilizing stopped-flow methods, the association kinetics of wild type and truncated forms of gp32 with ssDNA were measured. When the C-domain is present, the log-log plot of k vs. [NaCl] shows a positive slope, whereas when it is absent (*I protein), there is little rate change with salt concentration, as expected for this model.A gp32 variant lacking residues 292–296 within the C-domain, ΔPR201, displays kinetic properties intermediate between gp32 and *I. The single molecule force-induced DNA helix-destabilizing activitiesas well as the single- and double-stranded DNA affinities of ΔPR201 and gp32 truncated at residue 295 also fall between full-length protein and *I. Finally, chemical cross-linking of recombinant C-domain and gp32 lacking both N- and C-terminal domains is inhibited by increasing concentrations of a short single-stranded oligonucleotide, and the salt dependence of cross-linking mirrors that expected for the model. Taken together, these results provide the first evidence in support of this model that have been obtained through structural probes. PMID:29634784

Same but not alike: Structure, flexibility and energetics of domains in multi-domain proteins are influenced by the presence of other domains

PubMed Central

Vishwanath, Sneha

2018-01-01

The majority of the proteins encoded in the genomes of eukaryotes contain more than one domain. Reasons for high prevalence of multi-domain proteins in various organisms have been attributed to higher stability and functional and folding advantages over single-domain proteins. Despite these advantages, many proteins are composed of only one domain while their homologous domains are part of multi-domain proteins. In the study presented here, differences in the properties of protein domains in single-domain and multi-domain systems and their influence on functions are discussed. We studied 20 pairs of identical protein domains, which were crystallized in two forms (a) tethered to other proteins domains and (b) tethered to fewer protein domains than (a) or not tethered to any protein domain. Results suggest that tethering of domains in multi-domain proteins influences the structural, dynamic and energetic properties of the constituent protein domains. 50% of the protein domain pairs show significant structural deviations while 90% of the protein domain pairs show differences in dynamics and 12% of the residues show differences in the energetics. To gain further insights on the influence of tethering on the function of the domains, 4 pairs of homologous protein domains, where one of them is a full-length single-domain protein and the other protein domain is a part of a multi-domain protein, were studied. Analyses showed that identical and structurally equivalent functional residues show differential dynamics in homologous protein domains; though comparable dynamics between in-silico generated chimera protein and multi-domain proteins were observed. From these observations, the differences observed in the functions of homologous proteins could be attributed to the presence of tethered domain. Overall, we conclude that tethered domains in multi-domain proteins not only provide stability or folding advantages but also influence pathways resulting in differences in function or regulatory properties. PMID:29432415

Same but not alike: Structure, flexibility and energetics of domains in multi-domain proteins are influenced by the presence of other domains.

PubMed

Vishwanath, Sneha; de Brevern, Alexandre G; Srinivasan, Narayanaswamy

2018-02-01

The majority of the proteins encoded in the genomes of eukaryotes contain more than one domain. Reasons for high prevalence of multi-domain proteins in various organisms have been attributed to higher stability and functional and folding advantages over single-domain proteins. Despite these advantages, many proteins are composed of only one domain while their homologous domains are part of multi-domain proteins. In the study presented here, differences in the properties of protein domains in single-domain and multi-domain systems and their influence on functions are discussed. We studied 20 pairs of identical protein domains, which were crystallized in two forms (a) tethered to other proteins domains and (b) tethered to fewer protein domains than (a) or not tethered to any protein domain. Results suggest that tethering of domains in multi-domain proteins influences the structural, dynamic and energetic properties of the constituent protein domains. 50% of the protein domain pairs show significant structural deviations while 90% of the protein domain pairs show differences in dynamics and 12% of the residues show differences in the energetics. To gain further insights on the influence of tethering on the function of the domains, 4 pairs of homologous protein domains, where one of them is a full-length single-domain protein and the other protein domain is a part of a multi-domain protein, were studied. Analyses showed that identical and structurally equivalent functional residues show differential dynamics in homologous protein domains; though comparable dynamics between in-silico generated chimera protein and multi-domain proteins were observed. From these observations, the differences observed in the functions of homologous proteins could be attributed to the presence of tethered domain. Overall, we conclude that tethered domains in multi-domain proteins not only provide stability or folding advantages but also influence pathways resulting in differences in function or regulatory properties.

Identifying subgroups of patients using latent class analysis: should we use a single-stage or a two-stage approach? A methodological study using a cohort of patients with low back pain.

PubMed

Nielsen, Anne Molgaard; Kent, Peter; Hestbaek, Lise; Vach, Werner; Kongsted, Alice

2017-02-01

Heterogeneity in patients with low back pain (LBP) is well recognised and different approaches to subgrouping have been proposed. Latent Class Analysis (LCA) is a statistical technique that is increasingly being used to identify subgroups based on patient characteristics. However, as LBP is a complex multi-domain condition, the optimal approach when using LCA is unknown. Therefore, this paper describes the exploration of two approaches to LCA that may help improve the identification of clinically relevant and interpretable LBP subgroups. From 928 LBP patients consulting a chiropractor, baseline data were used as input to the statistical subgrouping. In a single-stage LCA, all variables were modelled simultaneously to identify patient subgroups. In a two-stage LCA, we used the latent class membership from our previously published LCA within each of six domains of health (activity, contextual factors, pain, participation, physical impairment and psychology) (first stage) as the variables entered into the second stage of the two-stage LCA to identify patient subgroups. The description of the results of the single-stage and two-stage LCA was based on a combination of statistical performance measures, qualitative evaluation of clinical interpretability (face validity) and a subgroup membership comparison. For the single-stage LCA, a model solution with seven patient subgroups was preferred, and for the two-stage LCA, a nine patient subgroup model. Both approaches identified similar, but not identical, patient subgroups characterised by (i) mild intermittent LBP, (ii) recent severe LBP and activity limitations, (iii) very recent severe LBP with both activity and participation limitations, (iv) work-related LBP, (v) LBP and several negative consequences and (vi) LBP with nerve root involvement. Both approaches identified clinically interpretable patient subgroups. The potential importance of these subgroups needs to be investigated by exploring whether they can be identified in other cohorts and by examining their possible association with patient outcomes. This may inform the selection of a preferred LCA approach.

A Parallel Vector Machine for the PM Programming Language

NASA Astrophysics Data System (ADS)

Bellerby, Tim

2016-04-01

PM is a new programming language which aims to make the writing of computational geoscience models on parallel hardware accessible to scientists who are not themselves expert parallel programmers. It is based around the concept of communicating operators: language constructs that enable variables local to a single invocation of a parallelised loop to be viewed as if they were arrays spanning the entire loop domain. This mechanism enables different loop invocations (which may or may not be executing on different processors) to exchange information in a manner that extends the successful Communicating Sequential Processes idiom from single messages to collective communication. Communicating operators avoid the additional synchronisation mechanisms, such as atomic variables, required when programming using the Partitioned Global Address Space (PGAS) paradigm. Using a single loop invocation as the fundamental unit of concurrency enables PM to uniformly represent different levels of parallelism from vector operations through shared memory systems to distributed grids. This paper describes an implementation of PM based on a vectorised virtual machine. On a single processor node, concurrent operations are implemented using masked vector operations. Virtual machine instructions operate on vectors of values and may be unmasked, masked using a Boolean field, or masked using an array of active vector cell locations. Conditional structures (such as if-then-else or while statement implementations) calculate and apply masks to the operations they control. A shift in mask representation from Boolean to location-list occurs when active locations become sufficiently sparse. Parallel loops unfold data structures (or vectors of data structures for nested loops) into vectors of values that may additionally be distributed over multiple computational nodes and then split into micro-threads compatible with the size of the local cache. Inter-node communication is accomplished using standard OpenMP and MPI. Performance analyses of the PM vector machine, demonstrating its scaling properties with respect to domain size and the number of processor nodes will be presented for a range of hardware configurations. The PM software and language definition are being made available under unrestrictive MIT and Creative Commons Attribution licenses respectively: www.pm-lang.org.

Single domain YBa2Cu3Oy thick films on metallic substrates

NASA Astrophysics Data System (ADS)

Reddy, E. S.; Noudem, J. G.; Goodilin, E. A.; Tarka, M.; Schmitz, G. J.

2003-03-01

The fabrication of single domain YBa2Cu3Oy (123) thick films (10-100 mum) on metallic substrates is reported. The process involves the formation of the 123 phase by a peritectic reaction between an air-brushed dense Y2BaCuO5 (211) layer on a Ag12Pd substrate and infiltrated liquid phases containing barium cuprates and copper oxides. Single domain growth is achieved by seeding the green films with a c-axis oriented NdBa2Cu3Oy crystal prior to processing. The maximum processing temperatures are lowered to 970 °C by modifying the characteristics of the liquid phases meant for infiltration by addition of Ag powder. The fabrication technique, processing conditions for single domain growth and the resulting microstructures are discussed.

Invited Article: Generation of one-million-mode continuous-variable cluster state by unlimited time-domain multiplexing

NASA Astrophysics Data System (ADS)

Yoshikawa, Jun-ichi; Yokoyama, Shota; Kaji, Toshiyuki; Sornphiphatphong, Chanond; Shiozawa, Yu; Makino, Kenzo; Furusawa, Akira

2016-09-01

In recent quantum optical continuous-variable experiments, the number of fully inseparable light modes has drastically increased by introducing a multiplexing scheme either in the time domain or in the frequency domain. Here, modifying the time-domain multiplexing experiment reported in the work of Yokoyama et al. [Nat. Photonics 7, 982 (2013)], we demonstrate the successive generation of fully inseparable light modes for more than one million modes. The resulting multi-mode state is useful as a dual-rail continuous variable cluster state. We circumvent the previous problem of optical phase drifts, which has limited the number of fully inseparable light modes to around ten thousands, by continuous feedback control of the optical system.

Providing care to relatives with mental illness: reactions and distress among primary informal caregivers.

PubMed

Chang, Sherilyn; Zhang, Yunjue; Jeyagurunathan, Anitha; Lau, Ying Wen; Sagayadevan, Vathsala; Chong, Siow Ann; Subramaniam, Mythily

2016-03-25

The responsibility of caring for relatives with mental illness often falls on the family members. It has been reported that the reactions to or consequences of providing care are what rendered the role of a caregiver challenging and hence a source of distress. This present study thus aimed to identify socio-demographic correlates of caregiving experiences using the Caregiver Reaction Assessment (CRA) and to examine the associations between reactions to caregiving and psychological distress. A total of 350 caregivers with relatives seeking outpatient care at a tertiary psychiatric hospital were recruited for this study. Distress among caregivers was assessed using the Patient Health Questionnaire (PHQ-9). The CRA was administered to measure reactions from caregiving in four domains including impact on schedule and health (ISH), impact on finance (IF), lack of family support (LFS) and caregiver esteem (CE). Participants also completed a questionnaire that asked for their socio-demographic information. Multivariable linear regression analysis was first used with domains of CRA as outcome variables and socio-demographic variables as predictors in the models. The next set of multivariable linear regression analysis tested for the association between CRA domains and distress with CRA domain scores as outcome variables and PHQ-9 score as predictor, controlling for socio-demographic variables. Socio-demographic correlates of CRA domains identified were age, education, employment, income and ethnicity. Domain scores of CRA were significantly associated with PHQ-9 score even after controlling for socio-demographic variables. A higher distress score was associated with greater impact felt in the domain of ISH (β = 0.080, P < 0.001), IF (β = 0.064, P < 0.001), and LFS (β = 0.057, P < 0.001), and was associated with lower CE domain scores (β = -0.021, P < 0.05). This study identified several socio-demographic correlates of caregiving reaction in the different domains. Each of these domains was found to be significantly associated with caregiver distress. Higher distress was associated with stronger impact on the negative domains and a lower impact in the positive domain of caregiving reaction. Interventions such as educational programs at the caregiver level, and also promoting wider social care support in these domains may help to address caregiver distress.

High processivity polymerases

DOEpatents

Shamoo, Yousif; Sun, Siyang

2014-06-10

Chimeric proteins comprising a sequence nonspecific single-stranded nucleic-acid-binding domain joined to a catalytic nucleic-acid-modifying domain are provided. Methods comprising contacting a nucleic acid molecule with a chimeric protein, as well as systems comprising a nucleic acid molecule, a chimeric protein, and an aqueous solution are also provided. The joining of sequence nonspecific single-stranded nucleic-acid-binding domain and a catalytic nucleic-acid-modifying domain in chimeric proteins, among other things, may prevent the separation of the two domains due to their weak association and thereby enhances processivity while maintaining fidelity.

Dielectric and domain studies on Fe doped KNbO3 single crystal

NASA Astrophysics Data System (ADS)

Shamkuwar, Sanjaykumar H.; Patil, Naresh M.; Korde, Vivek B.; Pradnyakar, Namrata V.

2018-05-01

Synthesis of Fe doped KNbO3 single crystals by flux method is reported here. The effect of Fe-doping on phase transition temperatures of KNbO3 single crystals was investigated using dielectric studies. The phase transition temperatures were found to be 225°C and 425°C which almost same as reported by others. The domain studies were carried out using metallurgical microscope and it shows the presence of 60° and 90° domains in the grown crystals.

We Know the Yin—But Where Is the Yang? Toward a Balanced Approach on Common Source Bias in Public Administration Scholarship

PubMed Central

George, Bert; Pandey, Sanjay K.

2017-01-01

Surveys have long been a dominant instrument for data collection in public administration. However, it has become widely accepted in the last decade that the usage of a self-reported instrument to measure both the independent and dependent variables results in common source bias (CSB). In turn, CSB is argued to inflate correlations between variables, resulting in biased findings. Subsequently, a narrow blinkered approach on the usage of surveys as single data source has emerged. In this article, we argue that this approach has resulted in an unbalanced perspective on CSB. We argue that claims on CSB are exaggerated, draw upon selective evidence, and project what should be tentative inferences as certainty over large domains of inquiry. We also discuss the perceptual nature of some variables and measurement validity concerns in using archival data. In conclusion, we present a flowchart that public administration scholars can use to analyze CSB concerns. PMID:29046599

We Know the Yin-But Where Is the Yang? Toward a Balanced Approach on Common Source Bias in Public Administration Scholarship.

PubMed

George, Bert; Pandey, Sanjay K

2017-06-01

Surveys have long been a dominant instrument for data collection in public administration. However, it has become widely accepted in the last decade that the usage of a self-reported instrument to measure both the independent and dependent variables results in common source bias (CSB). In turn, CSB is argued to inflate correlations between variables, resulting in biased findings. Subsequently, a narrow blinkered approach on the usage of surveys as single data source has emerged. In this article, we argue that this approach has resulted in an unbalanced perspective on CSB. We argue that claims on CSB are exaggerated, draw upon selective evidence, and project what should be tentative inferences as certainty over large domains of inquiry. We also discuss the perceptual nature of some variables and measurement validity concerns in using archival data. In conclusion, we present a flowchart that public administration scholars can use to analyze CSB concerns.

Poliovirus hybrids expressing neutralization epitopes from variable domains I and IV of the major outer membrane protein of Chlamydia trachomatis elicit broadly cross-reactive C. trachomatis-neutralizing antibodies.

PubMed Central

Murdin, A D; Su, H; Klein, M H; Caldwell, H D

1995-01-01

Trachoma and sexually transmitted diseases caused by Chlamydia trachomatis are major health problems worldwide. Epitopes from the variable domains of the major outer membrane protein are candidates for vaccine development. We have constructed hybrid polioviruses expressing sequences from major outer membrane protein variable domains I and IV. Antisera to the hybrids could, in combination, strongly neutralize 8 of the 12 C. trachomatis serovars most commonly associated with oculogenital infections and weakly neutralize the others. PMID:7532625

Macroscopic inhomogeneous deformation behavior arising in single crystal Ni-Mn-Ga foils under tensile loading

NASA Astrophysics Data System (ADS)

Murasawa, Go; Yeduru, Srinivasa R.; Kohl, Manfred

2016-12-01

This study investigated macroscopic inhomogeneous deformation occurring in single-crystal Ni-Mn-Ga foils under uniaxial tensile loading. Two types of single-crystal Ni-Mn-Ga foil samples were examined as-received and after thermo-mechanical training. Local strain and the strain field were measured under tensile loading using laser speckle and digital image correlation. The as-received sample showed a strongly inhomogeneous strain field with intermittence under progressive deformation, but the trained sample result showed strain field homogeneity throughout the specimen surface. The as-received sample is a mainly polycrystalline-like state composed of the domain structure. The sample contains many domain boundaries and large domain structures in the body. Its structure would cause large local strain band nucleation with intermittence. However, the trained one is an ideal single-crystalline state with a transformation preferential orientation of variants after almost all domain boundary and large domain structures vanish during thermo-mechanical training. As a result, macroscopic homogeneous deformation occurs on the trained sample surface during deformation.

Extrapolation of Functions of Many Variables by Means of Metric Analysis

NASA Astrophysics Data System (ADS)

Kryanev, Alexandr; Ivanov, Victor; Romanova, Anastasiya; Sevastianov, Leonid; Udumyan, David

2018-02-01

The paper considers a problem of extrapolating functions of several variables. It is assumed that the values of the function of m variables at a finite number of points in some domain D of the m-dimensional space are given. It is required to restore the value of the function at points outside the domain D. The paper proposes a fundamentally new method for functions of several variables extrapolation. In the presented paper, the method of extrapolating a function of many variables developed by us uses the interpolation scheme of metric analysis. To solve the extrapolation problem, a scheme based on metric analysis methods is proposed. This scheme consists of two stages. In the first stage, using the metric analysis, the function is interpolated to the points of the domain D belonging to the segment of the straight line connecting the center of the domain D with the point M, in which it is necessary to restore the value of the function. In the second stage, based on the auto regression model and metric analysis, the function values are predicted along the above straight-line segment beyond the domain D up to the point M. The presented numerical example demonstrates the efficiency of the method under consideration.

On the likelihood of single-peaked preferences.

PubMed

Lackner, Marie-Louise; Lackner, Martin

2017-01-01

This paper contains an extensive combinatorial analysis of the single-peaked domain restriction and investigates the likelihood that an election is single-peaked. We provide a very general upper bound result for domain restrictions that can be defined by certain forbidden configurations. This upper bound implies that many domain restrictions (including the single-peaked restriction) are very unlikely to appear in a random election chosen according to the Impartial Culture assumption. For single-peaked elections, this upper bound can be refined and complemented by a lower bound that is asymptotically tight. In addition, we provide exact results for elections with few voters or candidates. Moreover, we consider the Pólya urn model and the Mallows model and obtain lower bounds showing that single-peakedness is considerably more likely to appear for certain parameterizations.

Direct observation of interlocked domain walls and topological four-state vortex-like domain patterns in multiferroic YMnO{sub 3} single crystal

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

Tian, Lei; School of Materials Science and Engineering, Dalian Jiaotong University, Dalian, Liaoning 116028; Wang, Yumei, E-mail: wangym@iphy.ac.cn

2015-03-16

Using the advanced spherical aberration-corrected high angle annular dark field scanning transmission electron microscope imaging techniques, we investigated atomic-scale structural features of domain walls and domain patterns in YMnO{sub 3} single crystal. Three different types of interlocked ferroelectric-antiphase domain walls and two abnormal topological four-state vortex-like domain patterns are identified. Each ferroelectric domain wall is accompanied by a translation vector, i.e., 1/6[210] or −1/6[210], demonstrating its interlocked nature. Different from the four-state vortex domain patterns caused by a partial edge dislocation, two four-state vortex-like domain configurations have been obtained at atomic level. These observed phenomena can further extend our understandingmore » of the fascinating vortex domain patterns in multiferroic hexagonal rare-earth manganites.« less

Measuring Conformational Dynamics of Single Biomolecules Using Nanoscale Electronic Devices

NASA Astrophysics Data System (ADS)

Akhterov, Maxim V.; Choi, Yongki; Sims, Patrick C.; Olsen, Tivoli J.; Gul, O. Tolga; Corso, Brad L.; Weiss, Gregory A.; Collins, Philip G.

2014-03-01

Molecular motion can be a rate-limiting step of enzyme catalysis, but motions are typically too quick to resolve with fluorescent single molecule techniques. Recently, we demonstrated a label-free technique that replaced fluorophores with nano-electronic circuits to monitor protein motions. The solid-state electronic technique used single-walled carbon nanotube (SWNT) transistors to monitor conformational motions of a single molecule of T4 lysozyme while processing its substrate, peptidoglycan. As lysozyme catalyzes the hydrolysis of glycosidic bonds, two protein domains undergo 8 Å hinge bending motion that generates an electronic signal in the SWNT transistor. We describe improvements to the system that have extended our temporal resolution to 2 μs . Electronic recordings at this level of detail directly resolve not just transitions between open and closed conformations but also the durations for those transition events. Statistical analysis of many events determines transition timescales characteristic of enzyme activity and shows a high degree of variability within nominally identical chemical events. The high resolution technique can be readily applied to other complex biomolecules to gain insights into their kinetic parameters and catalytic function.

Three-factor model of premorbid adjustment in a sample with chronic schizophrenia and first-episode psychosis.

PubMed

Barajas, Ana; Usall, Judith; Baños, Iris; Dolz, Montserrat; Villalta-Gil, Victoria; Vilaplana, Miriam; Autonell, Jaume; Sánchez, Bernardo; Cervilla, Jorge A; Foix, Alexandrina; Obiols, Jordi E; Haro, Josep Maria; Ochoa, Susana

2013-12-01

The dimensionality of premorbid adjustment (PA) has been a debated issue, with attempts to determine whether PA is a unitary construct or composed of several independent domains characterized by a differential deterioration pattern and specific outcome correlates. This study examines the factorial structure of PA, as well as, the course and correlates of its domains. Retrospective study of 84 adult patients experiencing first-episode psychosis (FEP) (n=33) and individuals with schizophrenia (SCH) (n=51). All patients were evaluated with a comprehensive battery of instruments including clinical, functioning and neuropsychological variables. A principal component analysis accompanied by a varimax rotation method was used to examine the factor structure of the PAS-S scale. Paired t tests and Wilcoxon rank tests were used to assess the changes in PAS domains over time. Bivariate correlation analyses were performed to analyse the relationship between PAS factors and clinical, social and cognitive variables. PA was better explained by three factors (71.65% of the variance): Academic PA, Social PA and Socio-sexual PA. The academic domain showed higher scores of PA from childhood. Social and clinical variables were more strongly related to Social PA and Socio-sexual PA domains, and the Academic PA domain was exclusively associated with cognitive variables. This study supports previous evidence, emphasizing the validity of dividing PA into its sub-components. A differential deterioration pattern and specific correlates were observed in each PA domains, suggesting that impairments in each PA domain might predispose individuals to develop different expressions of psychotic dimensions. © 2013.

Cerebral autoregulation in the preterm newborn using near-infrared spectroscopy: a comparison of time-domain and frequency-domain analyses

NASA Astrophysics Data System (ADS)

Eriksen, Vibeke R.; Hahn, Gitte H.; Greisen, Gorm

2015-03-01

The aim was to compare two conventional methods used to describe cerebral autoregulation (CA): frequency-domain analysis and time-domain analysis. We measured cerebral oxygenation (as a surrogate for cerebral blood flow) and mean arterial blood pressure (MAP) in 60 preterm infants. In the frequency domain, outcome variables were coherence and gain, whereas the cerebral oximetry index (COx) and the regression coefficient were the outcome variables in the time domain. Correlation between coherence and COx was poor. The disagreement between the two methods was due to the MAP and cerebral oxygenation signals being in counterphase in three cases. High gain and high coherence may arise spuriously when cerebral oxygenation decreases as MAP increases; hence, time-domain analysis appears to be a more robust-and simpler-method to describe CA.

Shape of isolated domains in lithium tantalate single crystals at elevated temperatures

NASA Astrophysics Data System (ADS)

Shur, V. Ya.; Akhmatkhanov, A. R.; Chezganov, D. S.; Lobov, A. I.; Baturin, I. S.; Smirnov, M. M.

2013-12-01

The shape of isolated domains has been investigated in congruent lithium tantalate (CLT) single crystals at elevated temperatures and analyzed in terms of kinetic approach. The obtained temperature dependence of the growing domain shape in CLT including circular shape at temperatures above 190 °C has been attributed to increase of relative input of isotropic ionic conductivity. The observed nonstop wall motion and independent domain growth after merging in CLT as opposed to stoichiometric lithium tantalate have been attributed to difference in wall orientation. The computer simulation has confirmed applicability of the kinetic approach to the domain shape explanation.

Single-Domain Antibodies and the Promise of Modular Targeting in Cancer Imaging and Treatment

PubMed Central

Iezzi, María Elena; Policastro, Lucía; Werbajh, Santiago; Podhajcer, Osvaldo; Canziani, Gabriela Alicia

2018-01-01

Monoclonal antibodies and their fragments have significantly changed the outcome of cancer in the clinic, effectively inhibiting tumor cell proliferation, triggering antibody-dependent immune effector cell activation and complement mediated cell death. Along with a continued expansion in number, diversity, and complexity of validated tumor targets there is an increasing focus on engineering recombinant antibody fragments for lead development. Single-domain antibodies (sdAbs), in particular those engineered from the variable heavy-chain fragment (VHH gene) found in Camelidae heavy-chain antibodies (or IgG2 and IgG3), are the smallest fragments that retain the full antigen-binding capacity of the antibody with advantageous properties as drugs. For similar reasons, growing attention is being paid to the yet smaller variable heavy chain new antigen receptor (VNAR) fragments found in Squalidae. sdAbs have been selected, mostly from immune VHH libraries, to inhibit or modulate enzyme activity, bind soluble factors, internalize cell membrane receptors, or block cytoplasmic targets. This succinct review is a compilation of recent data documenting the application of engineered, recombinant sdAb in the clinic as epitope recognition “modules” to build monomeric, dimeric and multimeric ligands that target, tag and stall solid tumor growth in vivo. Size, affinity, specificity, and the development profile of sdAbs drugs are seemingly consistent with desirable clinical efficacy and safety requirements. But the hepatotoxicity of the tetrameric anti-DR5-VHH drug in patients with pre-existing anti-drug antibodies halted the phase I clinical trial and called for a thorough pre-screening of the immune and poly-specific reactivities of the sdAb leads. PMID:29520274

Learning environment assessments of a single curriculum being taught at two medical schools 10,000 miles apart.

PubMed

Tackett, Sean; Shochet, Robert; Shilkofski, Nicole A; Colbert-Getz, Jorie; Rampal, Krishna; Abu Bakar, Hamidah; Wright, Scott

2015-06-17

Perdana University Graduate School of Medicine (PUGSOM), the first graduate-entry medical school in Malaysia, was established in 2011 in collaboration with Johns Hopkins University School of Medicine (JHUSOM), an American medical school. This study compared learning environments (LE) at these two schools, which shared the same overarching curriculum, along with a comparator Malaysian medical school, Cyberjaya University College of Medical Sciences (CUCMS). As a secondary aim, we compared 2 LE assessment tools - the widely-used Dundee Ready Educational Environment Measure (DREEM) and the newer Johns Hopkins Learning Environment Scale (JHLES). Students responded anonymously at the end of their first year of medical school to surveys which included DREEM, JHLES, single-item global LE assessment variables, and demographics questions. Respondents included 24/24 (100 %) students at PUGSOM, 100/120 (83 %) at JHUSOM, and 79/83 (95 %) at CUCMS. PUGSOM had the highest overall LE ratings (p < 0.05) [DREEM 155.3 (SD 21.3); JHLES 116.5 (SD 12.2)], followed by JHUSOM [DREEM 143.3 (SD 22.5); JHLES 111.7 (SD 12.0)] and CUCMS [DREEM 138.5 (SD 22.4); JHLES 106.4 (SD 14.5)]. PUGSOM's overall high LE ratings were driven by responses in "perception of teaching," "meaningful engagement," and "acceptance and safety" domains. JHLES detected significant differences across schools in 5/7 domains and had stronger correlations than DREEM to each global LE assessment variable. The inaugural class of medical students at PUGSOM rated their LE exceptionally highly, providing evidence that transporting a medical school curriculum may be successful. The JHLES showed promise as a LE assessment tool for use in international settings.

Nonintellective Variables and Nontraditional College Students: A Domain-Based Investigation of Academic Achievement

ERIC Educational Resources Information Center

Warden, David N; Myers, Charlsie A.

2017-01-01

The relationship between domain-specific nonintellective variables and academic achievement among nontraditional students was explored to address uninvestigated factors and clarify distinctions between nontraditional and traditional student achievement. College students (nontraditional n = 72, traditional n = 67) completed an online survey…

Simple and fast spectral domain algorithm for quantitative phase imaging of living cells with digital holographic microscopy

NASA Astrophysics Data System (ADS)

Min, Junwei; Yao, Baoli; Ketelhut, Steffi; Kemper, Björn

2017-02-01

The modular combination of optical microscopes with digital holographic microscopy (DHM) has been proven to be a powerful tool for quantitative live cell imaging. The introduction of condenser and different microscope objectives (MO) simplifies the usage of the technique and makes it easier to measure different kinds of specimens with different magnifications. However, the high flexibility of illumination and imaging also causes variable phase aberrations that need to be eliminated for high resolution quantitative phase imaging. The existent phase aberrations compensation methods either require add additional elements into the reference arm or need specimen free reference areas or separate reference holograms to build up suitable digital phase masks. These inherent requirements make them unpractical for usage with highly variable illumination and imaging systems and prevent on-line monitoring of living cells. In this paper, we present a simple numerical method for phase aberration compensation based on the analysis of holograms in spatial frequency domain with capabilities for on-line quantitative phase imaging. From a single shot off-axis hologram, the whole phase aberration can be eliminated automatically without numerical fitting or pre-knowledge of the setup. The capabilities and robustness for quantitative phase imaging of living cancer cells are demonstrated.

Toward an Enhanced Sampling Molecular Dynamics Method for Studying Ligand-Induced Conformational Changes in Proteins.

PubMed

Andersen, Ole Juul; Grouleff, Julie; Needham, Perri; Walker, Ross C; Jensen, Frank

2015-11-19

Current enhanced sampling molecular dynamics methods for studying large conformational changes in proteins suffer from certain limitations. These include, among others, the need for user defined collective variables, the prerequisite of both start and end point structures of the conformational change, and the need for a priori knowledge of the amount by which to boost specific parts of the potential. In this paper, a framework is proposed for a molecular dynamics method for studying ligand-induced conformational changes, in which the nonbonded interactions between the ligand and the protein are used to calculate a biasing force. The method requires only a single input structure, and does not entail the use of collective variables. We provide a proof-of-concept for accelerating conformational changes in three simple test molecules, as well as promising results for two proteins known to undergo domain closure upon ligand binding. For the ribose-binding protein, backbone root-mean-square deviations as low as 0.75 Å compared to the crystal structure of the closed conformation are obtained within 50 ns simulations, whereas no domain closures are observed in unbiased simulations. A skewed closed structure is obtained for the glutamine-binding protein at high bias values, indicating that specific protein-ligand interactions might suppress important protein-protein interactions.

Thermal annealing and single-domain preparation in tetragonal Pb(In1/2Nb1/2)O3-Pb(Mg1/3Nb2/3)O3-PbTiO3 crystal for electro-optic and non-linear optical applications

NASA Astrophysics Data System (ADS)

Zhao, Ye; Wang, Sanhong; Fu, Xiaotian; Zhuang, Yongyong; Yang, Rui; Yang, Zhi; Li, Zhenrong; Xu, Zhuo; Wei, Xiaoyong

2018-02-01

The relaxor-PbTiO3 single crystal has attracted extensive attention in ultrasound transducers, sensors, actuators, and optoelectronics devices due to its excellent piezoelectric response and electro-optic properties. Preparation of a single-domain crystal as a critical process for application in electro-optic and non-linear optical devices suffers from serious and inevitable cracking. Therefore, a pre-poling thermal annealing process was suggested to release residual stress from crystal growth and the ferroelectric-paraelectric phase transition, which significantly reduced the chance of cracking. The effect of thermal annealing on dielectric properties, strain behavior, and domain structure were investigated. As a result, a significant increase of the dielectric constant near room temperature was obtained after annealing, which is close to the dielectric constant of the a-oriented domain. The annealed single crystal showed a lower and sharper strain peak at the coercive electric field compared with the unannealed sample, and the 90° domain walls completely vanished, which was verified by optical microscopy. The crack-free single-domain crystal showed excellent optical quality, with high transmittance of approximately 70% in the visible and near-infrared regions, which indicates that this crystal is a promising candidate for applications in electro-optic and non-linear optical devices.

Photo electron emission microscopy of polarity-patterned materials

NASA Astrophysics Data System (ADS)

Yang, W.-C.; Rodriguez, B. J.; Gruverman, A.; Nemanich, R. J.

2005-04-01

This study presents variable photon energy photo electron emission microscopy (PEEM) of polarity-patterned epitaxial GaN films, and ferroelectric LiNbO3 (LNO) single crystals and PbZrTiO3 (PZT) thin films. The photo electrons were excited with spontaneous emission from the tunable UV free electron laser (FEL) at Duke University. We report PEEM observation of polarity contrast and measurement of the photothreshold of each polar region of the materials. For a cleaned GaN film with laterally patterned Ga- and N-face polarities, we found a higher photoelectric yield from the N-face regions compared with the Ga-face regions. Through the photon energy dependent contrast in the PEEM images of the surfaces, we can deduce that the threshold of the N-face region is less than ~4.9 eV while that of the Ga-face regions is greater than 6.3 eV. In both LNO and PZT, bright emission was detected from the negatively poled domains, indicating that the emission threshold of the negative domain is lower than that of the positive domain. For LNO, the measured photothreshold was ~4.6 eV at the negative domain and ~6.2 eV at the positive domain, while for PZT, the threshold of the negative domain was less than 4.3 eV. Moreover, PEEM observation of the PZT surface at elevated temperatures displayed that the domain contrast disappeared near the Curie temperature of ~300 °C. The PEEM polarity contrast of the polar materials is discussed in terms of internal screening from free carriers and defects and the external screening due to adsorbed ions.

Baseline OCT Measurements in the Idiopathic Intracranial Hypertension Treatment Trial, Part I: Quality Control, Comparisons, and Variability

PubMed Central

2014-01-01

Purpose. Optical coherence tomography (OCT) has been used to investigate papilledema in single-site, mostly retrospective studies. We investigated whether spectral-domain OCT (SD-OCT), which provides thickness and volume measurements of the optic nerve head and retina, could reliably demonstrate structural changes due to papilledema in a prospective multisite clinical trial setting. Methods. At entry, 126 subjects in the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) with mild visual field loss had optic disc and macular scans, using the Cirrus SD-OCT. Images were analyzed by using the proprietary commercial and custom 3D-segmentation algorithms to calculate retinal nerve fiber layer (RNFL), total retinal thickness (TRT), optic nerve head volume (ONHV), and retinal ganglion cell layer (GCL) thickness. We evaluated variability, with interocular comparison and correlation between results for both methods. Results. The average RNFL thickness > 95% of normal controls in 90% of eyes and the RNFL, TRT, ONH height, and ONHV showed strong (r > 0.8) correlations for interocular comparisons. Variability for repeated testing of OCT parameters was low for both methods and intraclass correlations > 0.9 except for the proprietary GCL thickness. The proprietary algorithm–derived RNFL, TRT, and GCL thickness measurements had failure rates of 10%, 16%, and 20% for all eyes respectively, which were uncommon with 3D-segmentation–derived measurements. Only 7% of eyes had GCL thinning that was less than fifth percentile of normal age-matched control eyes by both methods. Conclusions. Spectral-domain OCT provides reliable continuous variables and quantified assessment of structural alterations due to papilledema. (ClinicalTrials.gov number, NCT01003639.) PMID:25370510

Extreme Value Analysis of hydro meteorological extremes in the ClimEx Large-Ensemble

NASA Astrophysics Data System (ADS)

Wood, R. R.; Martel, J. L.; Willkofer, F.; von Trentini, F.; Schmid, F. J.; Leduc, M.; Frigon, A.; Ludwig, R.

2017-12-01

Many studies show an increase in the magnitude and frequency of hydrological extreme events in the course of climate change. However the contribution of natural variability to the magnitude and frequency of hydrological extreme events is not yet settled. A reliable estimate of extreme events is from great interest for water management and public safety. In the course of the ClimEx Project (www.climex-project.org) a new single-model large-ensemble was created by dynamically downscaling the CanESM2 large-ensemble with the Canadian Regional Climate Model version 5 (CRCM5) for an European Domain and a Northeastern North-American domain. By utilizing the ClimEx 50-Member Large-Ensemble (CRCM5 driven by CanESM2 Large-Ensemble) a thorough analysis of natural variability in extreme events is possible. Are the current extreme value statistical methods able to account for natural variability? How large is the natural variability for e.g. a 1/100 year return period derived from a 50-Member Large-Ensemble for Europe and Northeastern North-America? These questions should be answered by applying various generalized extreme value distributions (GEV) to the ClimEx Large-Ensemble. Hereby various return levels (5-, 10-, 20-, 30-, 60- and 100-years) based on various lengths of time series (20-, 30-, 50-, 100- and 1500-years) should be analyzed for the maximum one day precipitation (RX1d), the maximum three hourly precipitation (RX3h) and the streamflow for selected catchments in Europe. The long time series of the ClimEx Ensemble (7500 years) allows us to give a first reliable estimate of the magnitude and frequency of certain extreme events.

Decoupling of superposed textures in an electrically biased piezoceramic with a 100 preferred orientation

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

Fancher, Chris M.; Blendell, John E.; Bowman, Keith J.

2017-02-07

A method leveraging Rietveld full-pattern texture analysis to decouple induced domain texture from a preferred grain orientation is presented in this paper. The proposed method is demonstrated by determining the induced domain texture in a polar polymorph of 100 oriented 0.91Bi 1/2Na 1/2TiO 3-0.07BaTiO 3-0.02K 0.5Na 0.5NbO 3. Domain textures determined using the present method are compared with results obtained via single peak fitting. Texture determined using single peak fitting estimated more domain alignment than that determined using the Rietveld based method. These results suggest that the combination of grain texture and phase transitions can lead to single peak fittingmore » under or over estimating domain texture. Finally, while demonstrated for a bulk piezoelectric, the proposed method can be applied to quantify domain textures in multi-component systems and thin films.« less

Domain characterization of Pb(Zn1/3Nb2/3)O3-(6%-7%)PbTiO3 single crystals using scanning electron acoustic microscopy

NASA Astrophysics Data System (ADS)

Wong, Meng Fei; Heng, Xiangxin; Zeng, Kaiyang

2008-10-01

Domain structures of [001]T and [011]T-cut Pb(Zn1/3Nb2/3)O3-(6%-7%)PbTiO3 (PZN-PT) single crystals are studied using scanning electron acoustic microscope (SEAM) technique. The observation of the orientation of domain walls agree reasonably well with the trigonometric projection of rhombohedral and orthorhombic dipoles on the (001) and (011) surfaces, respectively. After mechanical loading with microindentation, domain switching is also observed to form a hyperbolic butterfly shape and extend preferentially along four diagonal directions, i.e., ⟨110⟩ on (001) surface and ⟨111¯⟩ on (011) surface. The critical shear stress to cause domain switching for PZN-PT crystal is estimated to be approximately 49 MPa for both {110} and {111¯} planes based on theoretical analysis. Generally, the SEAM technique has been successfully demonstrated to be a valid technique for observation of domain structures in single crystal PZN-PTs.

Miniature protein ligands for EVH1 domains: Interplay between affinity, specificity, and cell motility⊥

PubMed Central

Holtzman, Jennifer H.; Woronowicz, Kamil; Golemi-Kotra, Dasantila; Schepartz, Alanna

2008-01-01

Dynamic rearrangements of the actin cytoskeleton power cell motility in contexts ranging from intracellular microbial pathogenesis to axon guidance. The Ena/VASP family proteins--Mena, VASP, and Evl--are believed to control cell motility by serving as a direct link between signaling events and the actin cytoskeleton. Our lab has previously reported a novel miniature protein, pGolemi, which binds with high affinity to the EVH1 domain of Mena (Mena1-112) but not to those of VASP (VASP1-115) or Evl (Evl1-115) and also causes an unusual defect in actin-driven L. monocytogenes motility. Here, we use scanning mutagenesis to examine the effects of single amino acid changes within pGolemi on EVH1 domain affinity and specificity, miniature protein secondary structure, and L. monocytogenes motility. The data suggest that pGolemi contains the expected aPP-like fold and binds Mena1-112 in a manner highly analogous to the proline-rich repeat region of L. monocytogenes ActA protein. Residues throughout pGolemi contribute to both EVH1 domain affinity and paralog specificity. Moreover, the affinities of pGolemi variants for Mena1-112 correlate with selectivity against the EVH1 domains of VASP and Evl. In L. monocytogenes motility assays, speed and speed variability correlate strongly with EVH1 paralog specificity, suggesting that the Ena/VASP paralogs do not play equivalent roles in the process of L. monocytogenes actin tail maturation. PMID:17973491

Nebo: An efficient, parallel, and portable domain-specific language for numerically solving partial differential equations

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

Earl, Christopher; Might, Matthew; Bagusetty, Abhishek

This study presents Nebo, a declarative domain-specific language embedded in C++ for discretizing partial differential equations for transport phenomena on multiple architectures. Application programmers use Nebo to write code that appears sequential but can be run in parallel, without editing the code. Currently Nebo supports single-thread execution, multi-thread execution, and many-core (GPU-based) execution. With single-thread execution, Nebo performs on par with code written by domain experts. With multi-thread execution, Nebo can linearly scale (with roughly 90% efficiency) up to 12 cores, compared to its single-thread execution. Moreover, Nebo’s many-core execution can be over 140x faster than its single-thread execution.

Nebo: An efficient, parallel, and portable domain-specific language for numerically solving partial differential equations

DOE PAGES

Earl, Christopher; Might, Matthew; Bagusetty, Abhishek; ...

2016-01-26

This study presents Nebo, a declarative domain-specific language embedded in C++ for discretizing partial differential equations for transport phenomena on multiple architectures. Application programmers use Nebo to write code that appears sequential but can be run in parallel, without editing the code. Currently Nebo supports single-thread execution, multi-thread execution, and many-core (GPU-based) execution. With single-thread execution, Nebo performs on par with code written by domain experts. With multi-thread execution, Nebo can linearly scale (with roughly 90% efficiency) up to 12 cores, compared to its single-thread execution. Moreover, Nebo’s many-core execution can be over 140x faster than its single-thread execution.

[Application of CWT to extract characteristic monitoring parameters during spine surgery].

PubMed

Chen, Penghui; Wu, Baoming; Hu, Yong

2005-10-01

It is necessary to monitor intraoperative spinal function in order to prevent spinal neurological deficit during spine surgery. This study aims to extract characteristic electrophysiological monitoring parameters during surgical treatment of scoliosis. The problem, "the monitoring parameters in time domain are of great variability and are sensitive to noise", may also be solved in this study. By use of continuous wavelet transform to analyze the intraoperative cortical somatosensory evoked potential (CSEP), three new characteristic monitoring parameters in time-frequency domain (TFD) are extracted. The results indicate that the variability of CSEP characteristic parameters in TFD is lower than the variability of those in time domain. Therefore, the TFD characteristic monitoring parameters are more stable and reliable parameters of latency and amplitude in time domain. The application of TFD monitoring parameters during spine surgery may avoid spinal injury effectively.

Selection of cholera toxin specific IgNAR single-domain antibodies from a naïve shark library.

PubMed

Liu, Jinny L; Anderson, George P; Delehanty, James B; Baumann, Richard; Hayhurst, Andrew; Goldman, Ellen R

2007-03-01

Shark immunoglobulin new antigen receptor (IgNAR, also referred to as NAR) variable domains (Vs) are single-domain antibody (sdAb) fragments containing only two hypervariable loop structures forming 3D topologies for a wide range of antigen recognition and binding. Their small size ( approximately 12kDa) and high solubility, thermostability and binding specificity make IgNARs an exceptional alternative source of engineered antibodies for sensor applications. Here, two new shark NAR V display libraries containing >10(7) unique clones from non-immunized (naïve) adult spiny dogfish (Squalus acanthias) and smooth dogfish (Mustelus canis) sharks were constructed. The most conserved consensus sequences derived from random clone sequence were compared with published nurse shark (Ginglymostoma cirratum) sequences. Cholera toxin (CT) was chosen for panning one of the naïve display libraries due to its severe pathogenicity and commercial availability. Three very similar CT binders were selected and purified soluble monomeric anti-CT sdAbs were characterized using Luminex(100) and traditional ELISA assays. These novel anti-CT sdAbs selected from our newly constructed shark NAR V sdAb library specifically bound to soluble antigen, without cross reacting with other irrelevant antigens. They also showed superior heat stability, exhibiting slow loss of activity over the course of one hour at high temperature (95 degrees C), while conventional antibodies lost all activity in the first 5-10min. The successful isolation of target specific sdAbs from one of our non-biased NAR libraries, demonstrate their ability to provide binders against an unacquainted antigen of interest.

Competitive Selection from Single Domain Antibody Libraries Allows Isolation of High-Affinity Antihapten Antibodies That Are Not Favored in the llama Immune Response

PubMed Central

Rosa, Sofia Tabares-da; Rossotti, Martin; Carleiza, Carmen; Carrión, Federico; Pritsch, Otto; Ahn, Ki Chang; Last, Jerold A.; Hammock, Bruce D; González-Sapienza, Gualberto

2011-01-01

Single-domain antibodies (sdAbs) found in camelids, lack a light chain and their antigen-binding site sits completely in the heavy-chain variable domain (VHH). Their simplicity, thermostability, and ease in expression have made VHHs highly attractive. While this has been successfully exploited for macromolecular antigens, their application to the detection of small molecules is still limited to a very few reports, mostly describing low affinity VHHs. Using triclocarban (TCC) as a model hapten, we found that conventional antibodies, IgG1 fraction, reacted with free TCC with a higher relative affinity (IC50 51.0 ng/mL) than did the sdAbs (IgG2 and IgG3, 497 and 370 ng/mL, respectively). A VHH library was prepared, and by elution of phage with limiting concentrations of TCC and competitive selection of binders, we were able to isolate high-affinity clones, KD 0.98–1.37 nM (SPR) which allowed development of a competitive assay for TCC with an IC50 = 3.5 ng/mL (11 nM). This represents a 100-fold improvement with regard to the performance of the sdAb serum fraction, and it is 100-fold better than the IC50 attained with other anti-hapten VHHs reported thus far. Despite the modest overall anti-hapten sdAbs response in llamas, a small subpopulation of high affinity VHHs are generated that can be isolated by carefully design of the selection process. PMID:21827167

Controlled phase evolution and the occurrence of single domain CoFe2O4 nanoparticles synthesized by PVA assisted sol-gel method

NASA Astrophysics Data System (ADS)

Srinivasa Rao, K.; Ranga Nayakulu, S. V.; Chaitanya Varma, M.; Choudary, G. S. V. R. K.; Rao, K. H.

2018-04-01

The present investigation describes the development of cobalt ferrite nanoparticles having size less than 10 nm, by a sol-gel method using polyvinyl alcohol as chelating agent. X-ray results show all the samples, annealed above 700 °C have spinel structure. The information about phase evolution with reaction temperatures was obtained by subjecting the as-prepared powder for DSC/TGA study. High saturation magnetization of 84.63 emu/g has been observed for a particle size of 8.1 nm, a rare event reported till date. The dM/dH versus H curves suggest that the transition from single domain state to multi-domain state occurs with increasing annealing temperature and the critical size for the single domain nature of CoFe2O4 is around 6.5 nm. The estimated critical diameter for single domain particle (6.7 nm) is in good agreement with that (6.5 nm) obtained from Transmission Electron Micrographs. The highest coercivity (1645 Oe) has been found for a particle of size 6.5 nm.

Frequency-Domain Streak Camera and Tomography for Ultrafast Imaging of Evolving and Channeled Plasma Accelerator Structures

NASA Astrophysics Data System (ADS)

Li, Zhengyan; Zgadzaj, Rafal; Wang, Xiaoming; Reed, Stephen; Dong, Peng; Downer, Michael C.

2010-11-01

We demonstrate a prototype Frequency Domain Streak Camera (FDSC) that can capture the picosecond time evolution of the plasma accelerator structure in a single shot. In our prototype Frequency-Domain Streak Camera, a probe pulse propagates obliquely to a sub-picosecond pump pulse that creates an evolving nonlinear index "bubble" in fused silica glass, supplementing a conventional Frequency Domain Holographic (FDH) probe-reference pair that co-propagates with the "bubble". Frequency Domain Tomography (FDT) generalizes Frequency-Domain Streak Camera by probing the "bubble" from multiple angles and reconstructing its morphology and evolution using algorithms similar to those used in medical CAT scans. Multiplexing methods (Temporal Multiplexing and Angular Multiplexing) improve data storage and processing capability, demonstrating a compact Frequency Domain Tomography system with a single spectrometer.

Magnetic domain wall conduits for single cell applications.

PubMed

Donolato, M; Torti, A; Kostesha, N; Deryabina, M; Sogne, E; Vavassori, P; Hansen, M F; Bertacco, R

2011-09-07

The ability to trap, manipulate and release single cells on a surface is important both for fundamental studies of cellular processes and for the development of novel lab-on-chip miniaturized tools for biological and medical applications. In this paper we demonstrate how magnetic domain walls generated in micro- and nano-structures fabricated on a chip surface can be used to handle single yeast cells labeled with magnetic beads. In detail, first we show that the proposed approach maintains the microorganism viable, as proven by monitoring the division of labeled yeast cells trapped by domain walls over 16 hours. Moreover, we demonstrate the controlled transport and release of individual yeast cells via displacement and annihilation of individual domain walls in micro- and nano-sized magnetic structures. These results pave the way to the implementation of magnetic devices based on domain walls technology in lab-on-chip systems devoted to accurate individual cell trapping and manipulation.

Nucleon axial charge in (2+1)-flavor dynamical-lattice QCD with domain-wall fermions.

PubMed

Yamazaki, T; Aoki, Y; Blum, T; Lin, H W; Lin, M F; Ohta, S; Sasaki, S; Tweedie, R J; Zanotti, J M

2008-05-02

We present results for the nucleon axial charge g{A} at a fixed lattice spacing of 1/a=1.73(3) GeV using 2+1 flavors of domain wall fermions on size 16;{3} x 32 and 24;{3} x 64 lattices (L=1.8 and 2.7 fm) with length 16 in the fifth dimension. The length of the Monte Carlo trajectory at the lightest m_{pi} is 7360 units, including 900 for thermalization. We find finite volume effects are larger than the pion mass dependence at m{pi}=330 MeV. We also find a scaling with the single variable m{pi}L which can also be seen in previous two-flavor domain wall and Wilson fermion calculations. Using this scaling to eliminate the finite-volume effect, we obtain g{A}=1.20(6)(4) at the physical pion mass, m_{pi}=135 MeV, where the first and second errors are statistical and systematic. The observed finite-volume scaling also appears in similar quenched simulations, but disappear when V>or=(2.4 fm);{3}. We argue this is a dynamical quark effect.

Improved theory of time domain reflectometry with variable coaxial cable length for electrical conductivity measurements

USDA-ARS?s Scientific Manuscript database

Although empirical models have been developed previously, a mechanistic model is needed for estimating electrical conductivity (EC) using time domain reflectometry (TDR) with variable lengths of coaxial cable. The goals of this study are to: (1) derive a mechanistic model based on multisection tra...

A 170kDa multi-domain cystatin of Fasciola gigantica is active in the male reproductive system.

PubMed

Geadkaew, Amornrat; Kosa, Nanthawat; Siricoon, Sinee; Grams, Suksiri Vichasri; Grams, Rudi

2014-09-01

Cystatins are functional as intra- and extracellular inhibitors of cysteine proteases and are expressed as single or multi-domain proteins. We have previously described two single domain type 1 cystatins in the trematode Fasciola gigantica that are released into the parasite's intestinal tract and exhibit inhibitory activity against endogenous and host cathepsin L and B proteases. In contrast, the here presented 170kDa multi-domain cystatin (FgMDC) comprises signal peptide and 12 tandem repeated cystatin-like domains with similarity to type 2 single domain cystatins. The domains show high sequence divergence with identity values often <20% and at only 26.8% between the highest matching domains 6 and 10. Several domains contain degenerated QVVAG core motifs and/or lack other important residues of active type 2 cystatins. Domain-specific antisera detected multiple forms of FgMDC ranging from <10 to >120kDa molecular mass in immunoblots of parasite crude extracts and ES product with different banding patterns for each antiserum demonstrating complex processing of the proprotein. The four domains with the highest conserved QVVAG motifs were expressed in Escherichia coli and the refolded recombinant proteins blocked cysteine protease activity in the parasite's ES product. Strikingly, immunohistochemical analysis using seven domain-specific antisera localized FgMDC in testis lobes and sperm. It is speculated that the processed cystatin-like domains have function analogous to the mammalian group of male reproductive tissue-specific type 2 cystatins and are functional in spermiogenesis and fertilization. Copyright © 2014 Elsevier B.V. All rights reserved.

In situ visualization of domain structure evolution during field cooling in 0.67PMN-0.33PT single crystal

NASA Astrophysics Data System (ADS)

Ushakov, A. D.; Esin, A. A.; Chezganov, D. S.; Turygin, A. P.; Akhmatkhanov, A. R.; Hu, Q.; Sun, L.; Wei, X.; Shur, V. Ya

2017-10-01

The evolution of the domain structure during in-field cooling was in situ studied in [001]-cut single crystals of relaxor ferroelectric (1-x)Pb(Mg1/3Nb2/3)O3-xPbTiO3 (PMN-PT) with x = 0.33 with maximum of dielectric permittivity at 150°C. The main stages of domain evolution have been separated. The visualization of the static as-grown and polarized domain structures with high spatial resolution by piezoresponse force microscopy and scanning electron microscopy allowed measuring the characteristic features of maze and needle-like domain structures.

Shape of isolated domains in lithium tantalate single crystals at elevated temperatures

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

Shur, V. Ya., E-mail: vladimir.shur@usu.ru; Akhmatkhanov, A. R.; Baturin, I. S.

2013-12-09

The shape of isolated domains has been investigated in congruent lithium tantalate (CLT) single crystals at elevated temperatures and analyzed in terms of kinetic approach. The obtained temperature dependence of the growing domain shape in CLT including circular shape at temperatures above 190 °C has been attributed to increase of relative input of isotropic ionic conductivity. The observed nonstop wall motion and independent domain growth after merging in CLT as opposed to stoichiometric lithium tantalate have been attributed to difference in wall orientation. The computer simulation has confirmed applicability of the kinetic approach to the domain shape explanation.

DISTINCT ANTIBODY SPECIES: STRUCTURAL DIFFERENCES CREATING THERAPEUTIC OPPORTUNITIES

PubMed Central

Muyldermans, Serge; Smider, Vaughn V.

2016-01-01

Antibodies have been a remarkably successful class of molecules for binding a large number of antigens in therapeutic, diagnostic, and research applications. Typical antibodies derived from mouse or human sources use the surface formed by complementarity determining regions (CDRs) on the variable regions of the heavy chain/light chain heterodimer, which typically forms a relatively flat binding surface. Alternative species, particularly camelids and bovines, provide a unique paradigm for antigen recognition through novel domains which form the antigen binding paratope. For camelids, heavy chain antibodies bind antigen with only a single heavy chain variable region, in the absence of light chains. In bovines, ultralong CDR-H3 regions form an independently folding minidomain, which protrudes from the surface of the antibody and is diverse in both its sequence and disulfide patterns. The atypical paratopes of camelids and bovines potentially provide the ability to interact with different epitopes, particularly recessed or concave surfaces, compared to traditional antibodies. PMID:26922135

A Review of Spectral Methods for Variable Amplitude Fatigue Prediction and New Results

NASA Technical Reports Server (NTRS)

Larsen, Curtis E.; Irvine, Tom

2013-01-01

A comprehensive review of the available methods for estimating fatigue damage from variable amplitude loading is presented. The dependence of fatigue damage accumulation on power spectral density (psd) is investigated for random processes relevant to real structures such as in offshore or aerospace applications. Beginning with the Rayleigh (or narrow band) approximation, attempts at improved approximations or corrections to the Rayleigh approximation are examined by comparison to rainflow analysis of time histories simulated from psd functions representative of simple theoretical and real world applications. Spectral methods investigated include corrections by Wirsching and Light, Ortiz and Chen, the Dirlik formula, and the Single-Moment method, among other more recent proposed methods. Good agreement is obtained between the spectral methods and the time-domain rainflow identification for most cases, with some limitations. Guidelines are given for using the several spectral methods to increase confidence in the damage estimate.

MMI: Multimodel inference or models with management implications?

USGS Publications Warehouse

Fieberg, J.; Johnson, Douglas H.

2015-01-01

We consider a variety of regression modeling strategies for analyzing observational data associated with typical wildlife studies, including all subsets and stepwise regression, a single full model, and Akaike's Information Criterion (AIC)-based multimodel inference. Although there are advantages and disadvantages to each approach, we suggest that there is no unique best way to analyze data. Further, we argue that, although multimodel inference can be useful in natural resource management, the importance of considering causality and accurately estimating effect sizes is greater than simply considering a variety of models. Determining causation is far more valuable than simply indicating how the response variable and explanatory variables covaried within a data set, especially when the data set did not arise from a controlled experiment. Understanding the causal mechanism will provide much better predictions beyond the range of data observed. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.

Time Domain Astrochemistry in Protoplanetary Disks

NASA Astrophysics Data System (ADS)

Cleeves, Lauren Ilsedore

2018-01-01

The chemistry of protoplanetary disks sets the initial composition of newly formed planets and may regulate the efficiency by which planets form. Disk chemical abundances typically evolve over timescales spanning thousands if not millions of years. Consequently, it was a surprise when ALMA observations taken over the course of a single year showed significantly variable emission in H13CO+ relative to the otherwise constant thermal dust emission in the IM Lup protoplanetary disk. HCO+ is a known X-ray sensitive molecule, and by using simple time-evolving chemical models including stellar activity, we demonstrate that stellar X-ray flares are a viable explanation for the observed H13CO+ variability. If this link between chemistry and stellar activity is confirmed, simultaneous observations can provide a new tool to measure (and potentially map) fundamental disk parameters, such as electron density, as the light from X-ray flares propagates across the disk.

Constraints on the Genetic and Antigenic Variability of Measles Virus.

PubMed

Beaty, Shannon M; Lee, Benhur

2016-04-21

Antigenic drift and genetic variation are significantly constrained in measles virus (MeV). Genetic stability of MeV is exceptionally high, both in the lab and in the field, and few regions of the genome allow for rapid genetic change. The regions of the genome that are more tolerant of mutations (i.e., the untranslated regions and certain domains within the N, C, V, P, and M proteins) indicate genetic plasticity or structural flexibility in the encoded proteins. Our analysis reveals that strong constraints in the envelope proteins (F and H) allow for a single serotype despite known antigenic differences among its 24 genotypes. This review describes some of the many variables that limit the evolutionary rate of MeV. The high genomic stability of MeV appears to be a shared property of the Paramyxovirinae, suggesting a common mechanism that biologically restricts the rate of mutation.

Constraints on the Genetic and Antigenic Variability of Measles Virus

PubMed Central

Beaty, Shannon M.; Lee, Benhur

2016-01-01

Antigenic drift and genetic variation are significantly constrained in measles virus (MeV). Genetic stability of MeV is exceptionally high, both in the lab and in the field, and few regions of the genome allow for rapid genetic change. The regions of the genome that are more tolerant of mutations (i.e., the untranslated regions and certain domains within the N, C, V, P, and M proteins) indicate genetic plasticity or structural flexibility in the encoded proteins. Our analysis reveals that strong constraints in the envelope proteins (F and H) allow for a single serotype despite known antigenic differences among its 24 genotypes. This review describes some of the many variables that limit the evolutionary rate of MeV. The high genomic stability of MeV appears to be a shared property of the Paramyxovirinae, suggesting a common mechanism that biologically restricts the rate of mutation. PMID:27110809

A novel T cell receptor single-chain signaling complex mediates antigen-specific T cell activity and tumor control

PubMed Central

Stone, Jennifer D.; Harris, Daniel T.; Soto, Carolina M.; Chervin, Adam S.; Aggen, David H.; Roy, Edward J.; Kranz, David M.

2014-01-01

Adoptive transfer of genetically modified T cells to treat cancer has shown promise in several clinical trials. Two main strategies have been applied to redirect T cells against cancer: 1) introduction of a full-length T cell receptor (TCR) specific for a tumor-associated peptide-MHC, or 2) introduction of a chimeric antigen receptor (CAR), including an antibody fragment specific for a tumor cell surface antigen, linked intracellularly to T cell signaling domains. Each strategy has advantages and disadvantages for clinical applications. Here, we present data on the in vitro and in vivo effectiveness of a single-chain signaling receptor incorporating a TCR variable fragment as the targeting element (referred to as TCR-SCS). This receptor contained a single-chain TCR (Vβ-linker-Vα) from a high-affinity TCR called m33, linked to the intracellular signaling domains of CD28 and CD3ζ. This format avoided mispairing with endogenous TCR chains, and mediated specific T cell activity when expressed in either CD4 or CD8 T cells. TCR-SCS-transduced CD8-negative cells showed an intriguing sensitivity, compared to full-length TCRs, to higher densities of less stable pepMHC targets. T cells that expressed this peptide-specific receptor persisted in vivo, and exhibited polyfunctional responses. Growth of metastatic antigen-positive tumors was significantly inhibited by T cells that expressed this receptor, and tumor cells that escaped were antigen loss variants. TCR-SCS receptors represent an alternative targeting receptor strategy that combines the advantages of single-chain expression, avoidance of TCR chain mispairing, and targeting of intracellular antigens presented in complex with MHC proteins. PMID:25082071

Wavelength and pulse duration tunable ultrafast fiber laser mode-locked with carbon nanotubes.

PubMed

Li, Diao; Jussila, Henri; Wang, Yadong; Hu, Guohua; Albrow-Owen, Tom; C T Howe, Richard; Ren, Zhaoyu; Bai, Jintao; Hasan, Tawfique; Sun, Zhipei

2018-02-09

Ultrafast lasers with tunable parameters in wavelength and time domains are the choice of light source for various applications such as spectroscopy and communication. Here, we report a wavelength and pulse-duration tunable mode-locked Erbium doped fiber laser with single wall carbon nanotube-based saturable absorber. An intra-cavity tunable filter is employed to continuously tune the output wavelength for 34 nm (from 1525 nm to 1559 nm) and pulse duration from 545 fs to 6.1 ps, respectively. Our results provide a novel light source for various applications requiring variable wavelength or pulse duration.

Disk in a groove with friction: An analysis of static equilibrium and indeterminacy

NASA Astrophysics Data System (ADS)

Donolato, Cesare

2018-05-01

This note studies the statics of a rigid disk placed in a V-shaped groove with frictional walls and subjected to gravity and a torque. The two-dimensional equilibrium problem is formulated in terms of the angles that contact forces form with the normal to the walls. This approach leads to a single trigonometric equation in two variables whose domain is determined by Coulomb's law of friction. The properties of solutions (existence, uniqueness, or indeterminacy) as functions of groove angle, friction coefficient and applied torque are derived by a simple geometric representation. The results modify some of the conclusions by other authors on the same problem.

An Evaluation of the Performance Diagnostic Checklist-Human Services (PDC-HS) Across Domains.

PubMed

Wilder, David A; Lipschultz, Joshua; Gehrman, Chana

2018-06-01

The Performance Diagnostic Checklist-Human Services (PDC-HS) is an informant-based tool designed to assess the environmental variables that contribute to poor employee performance in human service settings. Although the PDC-HS has been shown to effectively identify variables contributing to problematic performance, interventions based on only two of the four PDC-HS domains have been evaluated to date. In addition, the extent to which PDC-HS-indicated interventions are more effective than nonindicated interventions for two domains remains unclear. In the current study, we administered the PDC-HS to supervisors to assess the variables contributing to infrequent teaching of verbal operants and use of a timer by therapists at a center-based autism treatment program. Each of the four PDC-HS domains was identified as contributing to poor performance for at least one therapist. We then evaluated PDC-HS-indicated interventions for each domain. In addition, to assess the predictive validity of the tool, we evaluated various nonindicated interventions prior to implementing a PDC-HS-indicated intervention for two of the four domains. Results suggest that the PDC-HS-indicated interventions were effective across all four domains and were more effective than the nonindicated interventions for the two domains for which they were evaluated. Results are discussed in terms of the utility of the PDC-HS to identify appropriate interventions to manage therapist performance in human service settings.

The PH Domain of PDK1 Exhibits a Novel, Phospho-Regulated Monomer-Dimer Equilibrium With Important Implications for Kinase Domain Activation: Single Molecule and Ensemble Studies†

PubMed Central

Ziemba, Brian P.; Pilling, Carissa; Calleja, Véronique; Larijani, Banafshé; Falke, Joseph J.

2013-01-01

Phosphoinositide-Dependent Kinase-1 (PDK1) is an essential master kinase recruited to the plasma membrane by the binding of its C-terminal PH domain to the signaling lipid phosphatidylinositol-3,4-5-trisphosphate (PIP3). Membrane binding leads to PDK1 phospho-activation, but despite the central role of PDK1 in signaling and cancer biology this activation mechanism remains poorly understood. PDK1 has been shown to exist as a dimer in cells, and one crystal structure of its isolated PH domain exhibits a putative dimer interface. It has been proposed that phosphorylation of PH domain residue T513 (or the phospho-mimetic T513E mutation) may regulate a novel PH domain dimer-monomer equilibrium, thereby converting an inactive PDK1 dimer to an active monomer. However, the oligomeric state(s) of the PH domain on the membrane have not yet been determined, nor whether a negative charge at position 513 is sufficient to regulate its oligomeric state. The present study investigates the binding of purified WT and T513E PDK1 PH domains to lipid bilayers containing the PIP3 target lipid, using both single molecule and ensemble measurements. Single molecule analysis of the brightness of fluorescent PH domain shows that the PIP3-bound WT PH domain on membranes is predominantly dimeric, while the PIP3-bound T513E PH domain is monomeric, demonstrating that negative charge at the T513 position is sufficient to dissociate the PH domain dimer and is thus likely to play a central role in PDK1 monomerization and activation. Single molecule analysis of 2-D diffusion of PH domain-PIP3 complexes reveals that the dimeric WT PH domain diffuses at the same rate a single lipid molecule, indicating that only one of its two PIP3 binding sites is occupied and there is little protein penetration into the bilayer as observed for other PH domains. The 2-D diffusion of T513E PH domain is slower, suggesting the negative charge disrupts local structure in a way that enables greater protein insertion into the viscous bilayer, thereby increasing the diffusional friction. Ensemble measurements of PH domain affinity for PIP3 on plasma membrane-like bilayers reveals that dimeric WT PH domain possesses a one-order of magnitude higher target membrane affinity than the previously characterized monomeric PH domains, consistent with a dimerization-triggered, allosterically-enhanced affinity for one PIP3 molecule (a much larger affinity enhancement would be expected for dimerization-triggered binding to two PIP3 molecules). The monomeric T513E PDK1 PH domain, like other monomeric PH domains, exhibits a PIP3 affinity and bound state lifetime that are each a full order of magnitude lower than dimeric WT PH domain, which is predicted to facilitate release of activated, monomeric PDK1 to cytoplasm. Overall, the study yields the first molecular picture of PH domain regulation via electrostatic control of dimer-monomer conversion. PMID:23745598

The PH domain of phosphoinositide-dependent kinase-1 exhibits a novel, phospho-regulated monomer-dimer equilibrium with important implications for kinase domain activation: single-molecule and ensemble studies.

PubMed

Ziemba, Brian P; Pilling, Carissa; Calleja, Véronique; Larijani, Banafshé; Falke, Joseph J

2013-07-16

Phosphoinositide-dependent kinase-1 (PDK1) is an essential master kinase recruited to the plasma membrane by the binding of its C-terminal PH domain to the signaling lipid phosphatidylinositol-3,4,5-trisphosphate (PIP3). Membrane binding leads to PDK1 phospho-activation, but despite the central role of PDK1 in signaling and cancer biology, this activation mechanism remains poorly understood. PDK1 has been shown to exist as a dimer in cells, and one crystal structure of its isolated PH domain exhibits a putative dimer interface. It has been proposed that phosphorylation of PH domain residue T513 (or the phospho-mimetic T513E mutation) may regulate a novel PH domain dimer-monomer equilibrium, thereby converting an inactive PDK1 dimer to an active monomer. However, the oligomeric states of the PH domain on the membrane have not yet been determined, nor whether a negative charge at position 513 is sufficient to regulate its oligomeric state. This study investigates the binding of purified wild-type (WT) and T513E PDK1 PH domains to lipid bilayers containing the PIP3 target lipid, using both single-molecule and ensemble measurements. Single-molecule analysis of the brightness of the fluorescent PH domain shows that the PIP3-bound WT PH domain on membranes is predominantly dimeric while the PIP3-bound T513E PH domain is monomeric, demonstrating that negative charge at the T513 position is sufficient to dissociate the PH domain dimer and is thus likely to play a central role in PDK1 monomerization and activation. Single-molecule analysis of two-dimensional (2D) diffusion of PH domain-PIP3 complexes reveals that the dimeric WT PH domain diffuses at the same rate as a single lipid molecule, indicating that only one of its two PIP3 binding sites is occupied and there is little penetration of the protein into the bilayer as observed for other PH domains. The 2D diffusion of T513E PH domain is slower, suggesting the negative charge disrupts local structure in a way that allows deeper insertion of the protein into the viscous bilayer, thereby increasing the diffusional friction. Ensemble measurements of PH domain affinity for PIP3 on plasma membrane-like bilayers reveal that the dimeric WT PH domain possesses a one order of magnitude higher target membrane affinity than the previously characterized monomeric PH domains, consistent with a dimerization-triggered, allosterically enhanced affinity for one PIP3 molecule (a much larger affinity enhancement would be expected for dimerization-triggered binding to two PIP3 molecules). The monomeric T513E PDK1 PH domain, like other monomeric PH domains, exhibits a PIP3 affinity and bound state lifetime that are each 1 order of magnitude lower than those of the dimeric WT PH domain, which is predicted to facilitate release of activated, monomeric PDK1 to the cytoplasm. Overall, the study yields the first molecular picture of PH domain regulation via electrostatic control of dimer-monomer conversion.

Use of the single cell gel electrophoresis (comet assay) for comparing apoptotic effect of conventional antibodies versus nanobodies

PubMed Central

Shaker, Ghada H.; Melake, Nahla A.

2011-01-01

The large molecular size of antibodies is considered one major factor preventing them from becoming more efficient therapeutically. It is well established that all camelids have unique antibodies circulating in their blood called heavy-chain antibodies (HcAbs). Unlike antibodies from other species, these HcAbs contain a single variable domain and two constant domains (CH2 and CH3). HcAbs are a novel type of immunoglobulin-like, antigen binding protein with beneficial pharmacokinetic properties that are ideally suited to targeting cellular antigens for molecular imaging or therapeutic purposes. Since the antigen-binding site of dromedary HcAb is comprised in one single domain, it was referred to as nanobody. In the present work, the different IgG subclasses from immunized camel (Camelus dromedairus) were purified employing their different affinity for protein A column (PA) and protein G column (PG). Characterization of IgG subclasses was done by using 12% SDS–PAGE under reducing conditions. Protein bands were visualized after staining with Coomassie Brilliant Blue, showing two bands at 50 kDa and 30 kDa in case of IgG1 while IgG2 and IgG3 produce only one band at 46 kDa and 43 kDa respectively. The induction of apoptosis by either conventional or nanobodies was evaluated on two different cell lines, Colon and Hepatic cancer cell (HCT116 and HepG2), using the comet assay. Induced apoptosis were confirmed by visualizing DNA fragmentation bands on 2% agarose gel, and the gel was photographed under UV light. This study demonstrates the successful targeting of human cancer colon cell lines by nanobodies in vitro. It may open perspectives for their future use as tumor target vehicle, due to their small size, soluble behavior and they interact with epitopes that are less antigenic for conventional antibodies. PMID:23960797

Supporting Development of Satellite's Guidance Navigation and Control Software: A Product Line Approach

NASA Technical Reports Server (NTRS)

McComas, David; Stark, Michael; Leake, Stephen; White, Michael; Morisio, Maurizio; Travassos, Guilherme H.; Powers, Edward I. (Technical Monitor)

2000-01-01

The NASA Goddard Space Flight Center Flight Software Branch (FSB) is developing a Guidance, Navigation, and Control (GNC) Flight Software (FSW) product line. The demand for increasingly more complex flight software in less time while maintaining the same level of quality has motivated us to look for better FSW development strategies. The GNC FSW product line has been planned to address the core GNC FSW functionality very similar on many recent low/near Earth missions in the last ten years. Unfortunately these missions have not accomplished significant drops in development cost since a systematic approach towards reuse has not been adopted. In addition, new demands are continually being placed upon the FSW which means the FSB must become more adept at providing GNC FSW functionality's core so it can accommodate additional requirements. These domain features together with engineering concepts are influencing the specification, description and evaluation of FSW product line. Domain engineering is the foundation for emerging product line software development approaches. A product line is 'A family of products designed to take advantage of their common aspects and predicted variabilities'. In our product line approach, domain engineering includes the engineering activities needed to produce reusable artifacts for a domain. Application engineering refers to developing an application in the domain starting from reusable artifacts. The focus of this paper is regarding the software process, lessons learned and on how the GNC FSW product line manages variability. Existing domain engineering approaches do not enforce any specific notation for domain analysis or commonality and variability analysis. Usually, natural language text is the preferred tool. The advantage is the flexibility and adapt ability of natural language. However, one has to be ready to accept also its well-known drawbacks, such as ambiguity, inconsistency, and contradictions. While most domain analysis approaches are functionally oriented, the idea of applying the object-oriented approach in domain analysis is not new. Some authors propose to use UML as the notation underlying domain analysis. Our work is based on the same idea of merging UML and domain analysis. Further, we propose a few extensions to UML in order to express variability, and we define precisely their semantics so that a tool can support them. The extensions are designed to be implemented on the API of a popular industrial CASE tool, with obvious advantages in cost and availability of tool support. The paper outlines the product line processes and identifies where variability must be addressed. Then it describes the product line products with respect to how they accommodate variability. The Celestial Body subdomain is used as a working example. Our results to date are summarized and plans for the future are described.

Construction of an anti-programmed death-ligand 1 chimeric antigen receptor and determination of its antitumor function with transduced cells

PubMed Central

Xie, Jiasen; Zhou, Zishan; Jiao, Shunchang; Li, Xiaokun

2018-01-01

A chimeric antigen receptor (CAR) is a type of fusion protein that comprises an antigen-recognition domain and signaling domains. In the present study, a programmed death-ligand 1 (PD-L1)-specific CAR, comprised of a single-chain variable fragment (scFv) derived from a monoclonal antibody, co-stimulatory domains of cluster of differentiation (CD) 28 and 4-1BB and a T-cell-activation domain derived from CD3ζ, was designed. The construction was cloned and packaged into the lentiviral vector pLVX. Flow cytometry confirmed that peripheral blood mononuclear cells were efficiently transduced and that the CAR was successfully expressed on T cells. The cytotoxicity of transduced T cells was detected using PD-L1-positive NCI-H358 bronchioalveolar carcinoma cells and A549 lung adenocarcinoma cells (with a low expression of PD-L1, only in the A549 cells). The results demonstrated mild cytotoxicity at an effector-to-target ratio of 10:1. An ELISA revealed a significant increase in the level of interferon-γ released from T cells transduced with scFv-28Bz when the cells were co-cultured with PD-L1-positive NCI-H358 cells, while interkeukin-2 and tumor necrosis factor-α levels remained unchanged. These data indicated a potential method for the treatment of solid tumors. PMID:29928397

Domain architectures of the Scm3p protein provide insights into centromere function and evolution.

PubMed

Aravind, L; Iyer, Lakshminarayan M; Wu, Carl

2007-10-15

Recently, Scm3p has been shown to be a nonhistone component of centromeric chromatin that binds stoichiometrically to CenH3-H4 histones, and to be required for the assembly of kinetochores in Saccharomyces cerevisiae. Scm3p is conserved across fungi, and displays a remarkable variation in protein size, ranging from approximately 200 amino acids in S. cerevisiae to approximately 1300 amino acids in Neurospora crassa. This is primarily due a variable C-terminal segment that is linked to a conserved N-terminal, CenH3-interacting domain. We have discovered that the extended C-terminal region of Scm3p is strikingly characterized by lineage-specific fusions of single or multiple predicted DNA-binding domains different versions of the MYB and C2H2 zinc finger domains, AT-hooks, and a novel cysteine-rich metal-chelating cluster that are absent from the small versions of Scm3. Instead, S. cerevisiae point centromeres are recognized by components of the CBF3 DNA binding complex, which are conserved amongst close relatives of budding yeast, but are correspondingly absent from more distant fungi that possess regional centromeres. Hence, the C-terminal DNA binding motifs found in large Scm3p proteins may, along with CenH3, serve as a key epigenetic signal by recognizing and accommodating the lineage-specific diversity of centromere DNA in course of evolution.

Combinatorial Libraries of Arrayable Single-Chain Antibodies

NASA Astrophysics Data System (ADS)

Benhar, Itai

Antibodies that bind their respective targets with high affinity and specificity have proven to be essential reagents for biological research. Antibody phage display has become the leading tool for the rapid isolation of single-chain variable fragment (scFv) antibodies in vitro for research applications, but there is usually a gap between scFv isolation and its application in an array format suitable for high-throughput proteomics. In this chapter, we present our antibody phage display system where antibody isolation and scFv immobilization are facilitated by the design of the phagemid vector used as platform. In our system, the scFvs are fused at their C-termini to a cellulose-binding domain (CBD) and can be immobilized onto cellulose-based filters. This made it possible to develop a unique filter lift screen that allowed the efficient screen for multiple binding specificities, and to directly apply library-derived scFvs in an antibody spotted microarray.

Associations between cognitive and gait performance during single- and dual-task walking in people with Parkinson disease.

PubMed

Stegemöller, Elizabeth L; Wilson, Jonathan P; Hazamy, Audrey; Shelley, Mack C; Okun, Michael S; Altmann, Lori J P; Hass, Chris J

2014-06-01

Cognitive impairments in Parkinson disease (PD) manifest as deficits in speed of processing, working memory, and executive function and attention abilities. The gait impairment in PD is well documented to include reduced speed, shortened step lengths, and increased step-to-step variability. However, there is a paucity of research examining the relationship between overground walking and cognitive performance in people with PD. This study sought to examine the relationship between both the mean and variability of gait spatiotemporal parameters and cognitive performance across a broad range of cognitive domains. A cross-sectional design was used. Thirty-five participants with no dementia and diagnosed with idiopathic PD completed a battery of 12 cognitive tests that yielded 3 orthogonal factors: processing speed, working memory, and executive function and attention. Participants completed 10 trials of overground walking (single-task walking) and 5 trials of overground walking while counting backward by 3's (dual-task walking). All gait measures were impaired by the dual task. Cognitive processing speed correlated with stride length and walking speed. Executive function correlated with step width variability. There were no significant associations with working memory. Regression models relating speed of processing to gait spatiotemporal variables revealed that including dual-task costs in the model significantly improved the fit of the model. Participants with PD were tested only in the on-medication state. Different characteristics of gait are related to distinct types of cognitive processing, which may be differentially affected by dual-task walking due to the pathology of PD. © 2014 American Physical Therapy Association.

Frequency-Domain Streak Camera and Tomography for Ultrafast Imaging of Evolving and Channeled Plasma Accelerator Structures

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

Li Zhengyan; Zgadzaj, Rafal; Wang Xiaoming

2010-11-04

We demonstrate a prototype Frequency Domain Streak Camera (FDSC) that can capture the picosecond time evolution of the plasma accelerator structure in a single shot. In our prototype Frequency-Domain Streak Camera, a probe pulse propagates obliquely to a sub-picosecond pump pulse that creates an evolving nonlinear index 'bubble' in fused silica glass, supplementing a conventional Frequency Domain Holographic (FDH) probe-reference pair that co-propagates with the 'bubble'. Frequency Domain Tomography (FDT) generalizes Frequency-Domain Streak Camera by probing the 'bubble' from multiple angles and reconstructing its morphology and evolution using algorithms similar to those used in medical CAT scans. Multiplexing methods (Temporalmore » Multiplexing and Angular Multiplexing) improve data storage and processing capability, demonstrating a compact Frequency Domain Tomography system with a single spectrometer.« less

Biogeographic patterns in below-ground diversity in New York City's Central Park are similar to those observed globally

PubMed Central

Ramirez, Kelly S.; Leff, Jonathan W.; Barberán, Albert; Bates, Scott Thomas; Betley, Jason; Crowther, Thomas W.; Kelly, Eugene F.; Oldfield, Emily E.; Shaw, E. Ashley; Steenbock, Christopher; Bradford, Mark A.; Wall, Diana H.; Fierer, Noah

2014-01-01

Soil biota play key roles in the functioning of terrestrial ecosystems, however, compared to our knowledge of above-ground plant and animal diversity, the biodiversity found in soils remains largely uncharacterized. Here, we present an assessment of soil biodiversity and biogeographic patterns across Central Park in New York City that spanned all three domains of life, demonstrating that even an urban, managed system harbours large amounts of undescribed soil biodiversity. Despite high variability across the Park, below-ground diversity patterns were predictable based on soil characteristics, with prokaryotic and eukaryotic communities exhibiting overlapping biogeographic patterns. Further, Central Park soils harboured nearly as many distinct soil microbial phylotypes and types of soil communities as we found in biomes across the globe (including arctic, tropical and desert soils). This integrated cross-domain investigation highlights that the amount and patterning of novel and uncharacterized diversity at a single urban location matches that observed across natural ecosystems spanning multiple biomes and continents. PMID:25274366

Heat-induced Irreversible Denaturation of the Camelid Single Domain VHH Antibody Is Governed by Chemical Modifications

PubMed Central

Akazawa-Ogawa, Yoko; Takashima, Mizuki; Lee, Young-Ho; Ikegami, Takahisa; Goto, Yuji; Uegaki, Koichi; Hagihara, Yoshihisa

2014-01-01

The variable domain of camelid heavy chain antibody (VHH) is highly heat-resistant and is therefore ideal for many applications. Although understanding the process of heat-induced irreversible denaturation is essential to improve the efficacy of VHH, its inactivation mechanism remains unclear. Here, we showed that chemical modifications predominantly governed the irreversible denaturation of VHH at high temperatures. After heat treatment, the activity of VHH was dependent only on the incubation time at 90 °C and was insensitive to the number of heating (90 °C)-cooling (20 °C) cycles, indicating a negligible role for folding/unfolding intermediates on permanent denaturation. The residual activity was independent of concentration; therefore, VHH lost its activity in a unimolecular manner, not by aggregation. A VHH mutant lacking Asn, which is susceptible to chemical modifications, had significantly higher heat resistance than did the wild-type protein, indicating the importance of chemical modifications to VHH denaturation. PMID:24739391

Solidification of a binary alloy: Finite-element, single-domain simulation and new benchmark solutions

NASA Astrophysics Data System (ADS)

Le Bars, Michael; Worster, M. Grae

2006-07-01

A finite-element simulation of binary alloy solidification based on a single-domain formulation is presented and tested. Resolution of phase change is first checked by comparison with the analytical results of Worster [M.G. Worster, Solidification of an alloy from a cooled boundary, J. Fluid Mech. 167 (1986) 481-501] for purely diffusive solidification. Fluid dynamical processes without phase change are then tested by comparison with previous numerical studies of thermal convection in a pure fluid [G. de Vahl Davis, Natural convection of air in a square cavity: a bench mark numerical solution, Int. J. Numer. Meth. Fluids 3 (1983) 249-264; D.A. Mayne, A.S. Usmani, M. Crapper, h-adaptive finite element solution of high Rayleigh number thermally driven cavity problem, Int. J. Numer. Meth. Heat Fluid Flow 10 (2000) 598-615; D.C. Wan, B.S.V. Patnaik, G.W. Wei, A new benchmark quality solution for the buoyancy driven cavity by discrete singular convolution, Numer. Heat Transf. 40 (2001) 199-228], in a porous medium with a constant porosity [G. Lauriat, V. Prasad, Non-darcian effects on natural convection in a vertical porous enclosure, Int. J. Heat Mass Transf. 32 (1989) 2135-2148; P. Nithiarasu, K.N. Seetharamu, T. Sundararajan, Natural convective heat transfer in an enclosure filled with fluid saturated variable porosity medium, Int. J. Heat Mass Transf. 40 (1997) 3955-3967] and in a mixed liquid-porous medium with a spatially variable porosity [P. Nithiarasu, K.N. Seetharamu, T. Sundararajan, Natural convective heat transfer in an enclosure filled with fluid saturated variable porosity medium, Int. J. Heat Mass Transf. 40 (1997) 3955-3967; N. Zabaras, D. Samanta, A stabilized volume-averaging finite element method for flow in porous media and binary alloy solidification processes, Int. J. Numer. Meth. Eng. 60 (2004) 1103-1138]. Finally, new benchmark solutions for simultaneous flow through both fluid and porous domains and for convective solidification processes are presented, based on the similarity solutions in corner-flow geometries recently obtained by Le Bars and Worster [M. Le Bars, M.G. Worster, Interfacial conditions between a pure fluid and a porous medium: implications for binary alloy solidification, J. Fluid Mech. (in press)]. Good agreement is found for all tests, hence validating our physical and numerical methods. More generally, the computations presented here could now be considered as standard and reliable analytical benchmarks for numerical simulations, specifically and independently testing the different processes underlying binary alloy solidification.

The Association Between Sexual Satisfaction and Body Image in Women

PubMed Central

Pujols, Yasisca; Meston, Cindy M.; Seal, Brooke N.

2010-01-01

Introduction Although sexual functioning has been linked to sexual satisfaction, it only partially explains the degree to which women report being sexually satisfied. Other factors include quality of life, relational variables, and individual factors such as body image. Of the few studies that have investigated the link between body image and sexual satisfaction, most have considered body image to be a single construct and have shown mixed results. Aim The present study assessed multiple body image variables in order to better understand which aspects of body image influence multiple domains of sexual satisfaction, including sexual communication, compatibility, contentment, personal concern, and relational concern in a community sample of women. Methods Women between the ages of 18 and 49 years in sexual relationships (N = 154) participated in an Internet survey that assessed sexual functioning, five domains of sexual satisfaction, and several body image variables. Main Outcome Measures Body image variables included the sexual attractiveness, weight concern, and physical condition subscales of the Body Esteem Scale, the appearance-based subscale of the Cognitive Distractions During Sexual Activity Scale, and body mass index. Total score of the Sexual Satisfaction Scale for Women was the main outcome measure. Sexual functioning was measured by a modified Female Sexual Function Index. Results Consistent with expectations, correlations indicated significant positive relationships between sexual functioning, sexual satisfaction, and all body image variables. A multiple regression analysis revealed that sexual satisfaction was predicted by high body esteem and low frequency of appearance-based distracting thoughts during sexual activity, even after controlling for sexual functioning status. Conclusion Several aspects of body image, including weight concern, physical condition, sexual attractiveness, and thoughts about the body during sexual activity predict sexual satisfaction in women. The findings suggest that women who experience low sexual satisfaction may benefit from treatments that target these specific aspects of body image. PMID:19968771

Measuring determinants of career satisfaction of anesthesiologists: validation of a survey instrument.

PubMed

Afonso, Anoushka M; Diaz, James H; Scher, Corey S; Beyl, Robbie A; Nair, Singh R; Kaye, Alan David

2013-06-01

To measure the parameter of job satisfaction among anesthesiologists. Survey instrument. Academic anesthesiology departments in the United States. 320 anesthesiologists who attended the annual meeting of the ASA in 2009 (95% response rate). The anonymous 50-item survey collected information on 26 independent demographic variables and 24 dependent ranked variables of career satisfaction among practicing anesthesiologists. Mean survey scores were calculated for each demographic variable and tested for statistically significant differences by analysis of variance. Questions within each domain that were internally consistent with each other within domains were identified by Cronbach's alpha ≥ 0.7. P-values ≤ 0.05 were considered statistically significant. Cronbach's alpha analysis showed strong internal consistency for 10 dependent outcome questions in the practice factor-related domain (α = 0.72), 6 dependent outcome questions in the peer factor-related domain (α = 0.71), and 8 dependent outcome questions in the personal factor-related domain (α = 0.81). Although age was not a variable, full-time status, early satisfaction within the first 5 years of practice, working with respected peers, and personal choice factors were all significantly associated with anesthesiologist job satisfaction. Improvements in factors related to job satisfaction among anesthesiologists may lead to higher early and current career satisfaction. Copyright © 2013 Elsevier Inc. All rights reserved.

Comparing domain interactions within antibody Fabs with kappa and lambda light chains.

PubMed

Toughiri, Raheleh; Wu, Xiufeng; Ruiz, Diana; Huang, Flora; Crissman, John W; Dickey, Mark; Froning, Karen; Conner, Elaine M; Cujec, Thomas P; Demarest, Stephen J

2016-10-01

IgG antibodies are multi-domain proteins with complex inter-domain interactions. Human IgG heavy chains (HCs) associate with light chains (LCs) of the κ or λ isotype to form mature antibodies capable of binding antigen. The HC/LC interaction involves 4 domains: VH and CH1 from the HC and VL and CL from the LC. Human Fabs with κ LCs have been well characterized for their unfolding behaviors and demonstrate a significant level of cooperativity and stabilization when all 4 domains are intact. Very little is known regarding the thermodynamic properties of human Fabs with λ LCs. Here, we dissect the domain contributions to Fab stability for both κ and λ LC-containing Fabs. We find the cooperativity of unfolding between the constant domains, CH1/Cλ, and variable domains, VH/Vλ, within λ LC-containing Fabs is significantly weaker than that of κ LC-containing Fabs. The data suggests there may not be an evolutionary necessity for strong variable/constant domain cooperativity within λ LC-containing Fabs. After investigating the biophysical properties of Fabs with mismatched variable and constant domain subunits (e.g., VH/Vκ paired with CH1/Cλ or T cell receptor Cα/Cβ), the major role of the constant domains for both κ- and λ-containing Fabs may be to reduce the hydrophobic exposure at the VH/VL interface. Even though Fabs with these non-native pairings were thermodynamically less stable, they secreted well from mammalian cells as well behaved monodisperse proteins, which was in contrast to what was observed with the VH/Vκ and VH/Vλ scFvs that secreted as a mixture of monomer and aggregates.

Gene sequence variability of the three surface proteins of human respiratory syncytial virus (HRSV) in Texas.

PubMed

Tapia, Lorena I; Shaw, Chad A; Aideyan, Letisha O; Jewell, Alan M; Dawson, Brian C; Haq, Taha R; Piedra, Pedro A

2014-01-01

Human respiratory syncytial virus (HRSV) has three surface glycoproteins: small hydrophobic (SH), attachment (G) and fusion (F), encoded by three consecutive genes (SH-G-F). A 270-nt fragment of the G gene is used to genotype HRSV isolates. This study genotyped and investigated the variability of the gene and amino acid sequences of the three surface proteins of HRSV strains collected from 1987 to 2005 from one center. Sixty original clinical isolates and 5 prototype strains were analyzed. Sequences containing SH, F and G genes were generated, and multiple alignments and phylogenetic trees were analyzed. Genetic variability by protein domains comparing virus genotypes was assessed. Complete sequences of the SH-G-F genes were obtained for all 65 samples: HRSV-A = 35; HRSV-B = 30. In group A strains, genotypes GA5 and GA2 were predominant. For HRSV-B strains, the genotype GB4 was predominant from 1992 to 1994 and only genotype BA viruses were detected in 2004-2005. Different genetic variability at nucleotide level was detected between the genes, with G gene being the most variable and the highest variability detected in the 270-nt G fragment that is frequently used to genotype the virus. High variability (>10%) was also detected in the signal peptide and transmembrane domains of the F gene of HRSV A strains. Variability among the HRSV strains resulting in non-synonymous changes was detected in hypervariable domains of G protein, the signal peptide of the F protein, a not previously defined domain in the F protein, and the antigenic site Ø in the pre-fusion F. Divergent trends were observed between HRSV -A and -B groups for some functional domains. A diverse population of HRSV -A and -B genotypes circulated in Houston during an 18 year period. We hypothesize that diverse sequence variation of the surface protein genes provide HRSV strains a survival advantage in a partially immune-protected community.

Gene Sequence Variability of the Three Surface Proteins of Human Respiratory Syncytial Virus (HRSV) in Texas

PubMed Central

Tapia, Lorena I.; Shaw, Chad A.; Aideyan, Letisha O.; Jewell, Alan M.; Dawson, Brian C.; Haq, Taha R.; Piedra, Pedro A.

2014-01-01

Human respiratory syncytial virus (HRSV) has three surface glycoproteins: small hydrophobic (SH), attachment (G) and fusion (F), encoded by three consecutive genes (SH-G-F). A 270-nt fragment of the G gene is used to genotype HRSV isolates. This study genotyped and investigated the variability of the gene and amino acid sequences of the three surface proteins of HRSV strains collected from 1987 to 2005 from one center. Sixty original clinical isolates and 5 prototype strains were analyzed. Sequences containing SH, F and G genes were generated, and multiple alignments and phylogenetic trees were analyzed. Genetic variability by protein domains comparing virus genotypes was assessed. Complete sequences of the SH-G-F genes were obtained for all 65 samples: HRSV-A = 35; HRSV-B = 30. In group A strains, genotypes GA5 and GA2 were predominant. For HRSV-B strains, the genotype GB4 was predominant from 1992 to 1994 and only genotype BA viruses were detected in 2004–2005. Different genetic variability at nucleotide level was detected between the genes, with G gene being the most variable and the highest variability detected in the 270-nt G fragment that is frequently used to genotype the virus. High variability (>10%) was also detected in the signal peptide and transmembrane domains of the F gene of HRSV A strains. Variability among the HRSV strains resulting in non-synonymous changes was detected in hypervariable domains of G protein, the signal peptide of the F protein, a not previously defined domain in the F protein, and the antigenic site Ø in the pre-fusion F. Divergent trends were observed between HRSV -A and -B groups for some functional domains. A diverse population of HRSV -A and -B genotypes circulated in Houston during an 18 year period. We hypothesize that diverse sequence variation of the surface protein genes provide HRSV strains a survival advantage in a partially immune-protected community. PMID:24625544

[Preparation of anti-hCG single domain antibody by antibody grafting technique using an antigen-binding peptide].

PubMed

Peng, Jing; Wang, Qiong; Cheng, Xiaoling; Liu, Mengwen; Wang, Mei; Xin, Huawei

2018-04-25

We used the antibody grafting technology to prepare anti-hCG single-domain antibodies on the basis of antigen-binding peptide to simplify the single-domain antibody preparation process and improving the biochemical stability of peptide. By using a universal single-domain antibody backbone (cAbBCII10), CDR1 or CDR3 was replaced by the hCG-binding peptide, and the grafted antibody gene sequences were synthesized and cloned into the prokaryotic expression vector pET30a(+) in fusion with a C-terminal sfGFP gene, i.e. pET30a-(His6)-cAbBCII10-CDR1/hCGBP1-sfGFP and pET30a-(His6)-cAbBCII10-CDR3/hCGBP3-sfGFP. The recombinant plasmids were transformed into E. coli BL21(DE3), and the fusion proteins were induced by IPTG. Highly soluble recombinant fusion proteins were obtained and purified by Ni-NTA affinity column. SDS-PAGE confirmed the purified protein as the target protein. The antigen-antibody binding assay showed that both the CDR1 and CDR3 grafted antibodies have hCG-binding activities. While the titers of the two grafted antibodies were similar, the binding affinity of CDR3 grafted antibody was higher than that of CDR1 grafted protein (about 2-3 times). The grafted antibodies retained the relatively high biochemical stability of the single-domain antibody backbone and were relatively thermostable and alkaline tolerant. The obtained antibodies also had a relatively high antigen-binding specificity to hCG. This study provided a reliable experimental basis for further optimization of anti-hCG single domain antibody by antibody grafting technology using antigen-binding peptide.

Generation of high-affinity, internalizing anti-FGFR2 single-chain variable antibody fragment fused with Fc for targeting gastrointestinal cancers.

PubMed

Borek, Aleksandra; Sokolowska-Wedzina, Aleksandra; Chodaczek, Grzegorz; Otlewski, Jacek

2018-01-01

Fibroblast growth factor receptors (FGFRs) are promising targets for antibody-based cancer therapies, as their substantial overexpression has been found in various tumor cells. Aberrant activation of FGF receptor 2 (FGFR2) signaling through overexpression of FGFR2 and/or its ligands, mutations, or receptor amplification has been reported in multiple cancer types, including gastric, colorectal, endometrial, ovarian, breast and lung cancer. In this paper, we describe application of the phage display technology to produce a panel of high affinity single chain variable antibody fragments (scFvs) against the extracellular ligand-binding domain of FGFR2 (ECD_FGFR2). The binders were selected from the human single chain variable fragment scFv phage display libraries Tomlinson I + J and showed high specificity and binding affinity towards human FGFR2 with nanomolar KD values. To improve the affinity of the best binder selected, scFvF7, we reformatted it to a bivalent diabody format, or fused it with the Fc region (scFvF7-Fc). The scFvF7-Fc antibody construct presented the highest affinity for FGFR2, with a KD of 0.76 nM, and was selectively internalized into cancer cells overexpressing FGFR2, Snu-16 and NCI-H716. Finally, we prepared a conjugate of scFvF7-Fc with the cytotoxic drug monomethyl-auristatin E (MMAE) and evaluated its cytotoxicity. The conjugate delivered MMAE selectively to FGFR2-positive tumor cells. These results indicate that scFvF7-Fc-vcMMAE is a highly potent molecule for the treatment of cancers with FGFR2 overexpression.

Local twin domains and tip-voltage-induced domain switching of monoclinic M C phase in Pb ( M g 1 / 3 N b 2 / 3 ) O 3 - 0.34 PbTi O 3 single crystal revealed by piezoresponse force microscopy

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

Wang, Ruixue; Yang, Bin; Luo, Zhenlin

2016-08-29

Here, the monoclinic (M) phases in high-performance relaxor-based ferroelectric single crystals have been recognized to be a vital structural factor for the outstanding piezoelectric property. However, due to the complexity of the structure in M phases, the understanding about it is still limited. In this paper, the local twin domains and tip-voltage-induced domain switching of the M C phase in Pb(Mg 1/3Nb 2/3)O 3 - 0.34PbTiO 3 (PMN-0.34PT) single crystal have been intensively investigated by piezoresponse force microscopy (PFM). By theoretically analyzing the experimental patterns of domain walls on the (001) C face, the specific M C twin domains inmore » the initial annealed state of a selected area have been clarified, and the polarization orientation of the M C phase in this sample is determined to be at an angle of 29 degrees to the < 001 > C directions. In addition, based on the evolution of domains and the motion of domain walls under the step-increased PFM tip dc voltage (V dc), the switching process and features of different types of M C domain variants are visually revealed« less

Determination of magnetic domain state of carbon coated iron nanoparticles via 57Fe zero-external-field NMR

NASA Astrophysics Data System (ADS)

Manjunatha, M.; Kumar, Rajeev; Sahoo, Balaram; Damle, Ramakrishna; Ramesh, K. P.

2018-05-01

The magnetic domain state of carbon coated iron nanopowder (Fe@C) was studied by the internal field nuclear magnetic resonance (IFNMR) at 77 K using the spin echo technique. The structure and magnetic properties of the sample were further characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), Mössbauer spectroscopy, vibrating sample magnetometry (VSM), thermogravimetric analysis (TGA) and Raman Spectroscopy. The obtained IFNMR results of Fe@C powder were compared with that of micron sized carbonyl iron (CI) and electrolytic iron (EI) powders. The calculated critical size of the single domain iron particles in Fe@C is ∼ 16 nm. A higher enhancement in echo amplitude was observed due to better response of the domain walls of multidomain particles in comparison to the single domain particles. The echo signal of CI and EI particles exhibit a single narrow intense peak corresponding to the domain walls, whereas Fe@C exhibits two low amplitude peaks at two different frequencies: a low frequency (46.6 MHz) peak corresponds to the response of the domain walls of the multidomain particles and the other high frequency (47.2 MHz) signal (a shoulder) corresponding to the response of the magnetic nuclei inside the domain. Our results help in determining the domain state of iron-based magnetic particles using 57Fe-IFNMR.

Comparison of Two Grid Refinement Approaches for High Resolution Regional Climate Modeling: MPAS vs WRF

NASA Astrophysics Data System (ADS)

Leung, L.; Hagos, S. M.; Rauscher, S.; Ringler, T.

2012-12-01

This study compares two grid refinement approaches using global variable resolution model and nesting for high-resolution regional climate modeling. The global variable resolution model, Model for Prediction Across Scales (MPAS), and the limited area model, Weather Research and Forecasting (WRF) model, are compared in an idealized aqua-planet context with a focus on the spatial and temporal characteristics of tropical precipitation simulated by the models using the same physics package from the Community Atmosphere Model (CAM4). For MPAS, simulations have been performed with a quasi-uniform resolution global domain at coarse (1 degree) and high (0.25 degree) resolution, and a variable resolution domain with a high-resolution region at 0.25 degree configured inside a coarse resolution global domain at 1 degree resolution. Similarly, WRF has been configured to run on a coarse (1 degree) and high (0.25 degree) resolution tropical channel domain as well as a nested domain with a high-resolution region at 0.25 degree nested two-way inside the coarse resolution (1 degree) tropical channel. The variable resolution or nested simulations are compared against the high-resolution simulations that serve as virtual reality. Both MPAS and WRF simulate 20-day Kelvin waves propagating through the high-resolution domains fairly unaffected by the change in resolution. In addition, both models respond to increased resolution with enhanced precipitation. Grid refinement induces zonal asymmetry in precipitation (heating), accompanied by zonal anomalous Walker like circulations and standing Rossby wave signals. However, there are important differences between the anomalous patterns in MPAS and WRF due to differences in the grid refinement approaches and sensitivity of model physics to grid resolution. This study highlights the need for "scale aware" parameterizations in variable resolution and nested regional models.

Abundance, diversity and domain architecture variability in prokaryotic DNA-binding transcription factors.

PubMed

Perez-Rueda, Ernesto; Hernandez-Guerrero, Rafael; Martinez-Nuñez, Mario Alberto; Armenta-Medina, Dagoberto; Sanchez, Israel; Ibarra, J Antonio

2018-01-01

Gene regulation at the transcriptional level is a central process in all organisms, and DNA-binding transcription factors, known as TFs, play a fundamental role. This class of proteins usually binds at specific DNA sequences, activating or repressing gene expression. In general, TFs are composed of two domains: the DNA-binding domain (DBD) and an extra domain, which in this work we have named "companion domain" (CD). This latter could be involved in one or more functions such as ligand binding, protein-protein interactions or even with enzymatic activity. In contrast to DBDs, which have been widely characterized both experimentally and bioinformatically, information on the abundance, distribution, variability and possible role of the CDs is scarce. Here, we investigated these issues associated with the domain architectures of TFs in prokaryotic genomes. To this end, 19 families of TFs in 761 non-redundant bacterial and archaeal genomes were evaluated. In this regard we found four main groups based on the abundance and distribution in the analyzed genomes: i) LysR and TetR/AcrR; ii) AraC/XylS, SinR, and others; iii) Lrp, Fis, ArsR, and others; and iv) a group that included only two families, ArgR and BirA. Based on a classification of the organisms according to the life-styles, a major abundance of regulatory families in free-living organisms, in contrast with pathogenic, extremophilic or intracellular organisms, was identified. Finally, the protein architecture diversity associated to the 19 families considering a weight score for domain promiscuity evidenced which regulatory families were characterized by either a large diversity of CDs, here named as "promiscuous" families given the elevated number of variable domains found in those TFs, or a low diversity of CDs. Altogether this information helped us to understand the diversity and distribution of the 19 Prokaryotes TF families. Moreover, initial steps were taken to comprehend the variability of the extra domain in those TFs, which eventually might assist in evolutionary and functional studies.

Characterization of emergent HIV resistance in treatment-naive subjects enrolled in a vicriviroc phase 2 trial.

PubMed

McNicholas, Paul; Wei, Yi; Whitcomb, Jeannette; Greaves, Wayne; Black, Todd A; Tremblay, Cecile L; Strizki, Julie M

2010-05-15

Vicriviroc is a C-C motif chemokine receptor 5 (CCR5) antagonist that is in clinical development for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. This study explored the molecular basis for the development of phenotypically resistant virus. HIV-1 RNA from treatment-naive subjects who experienced virological failure in a phase 2 dose-finding trial was evaluated for coreceptor usage and susceptibility. For viruses that exhibited reduced susceptibility to vicriviroc, envelope clones were phenotypically and genotypically characterized. Twenty-six vicriviroc-treated subjects experienced virological failure; for 24 the virus remained CCR5-tropic, and 2 had dual/X4 virus. Reduced susceptibility to vicriviroc, manifested as decreases in the maximum percent inhibition value (no increase in median inhibitory concentration), was detected in 4 of the 26 subjects who experienced virological failure. Clonal analysis of envelopes in samples from these 4 subjects revealed multiple sequence changes in gp160, principally within the variable domain 1/variable domain 2, variable domain 3, and variable domain 4 loops. However, no consistent pattern of mutations was observed across subjects. In this study, only a small proportion of treatment failures were associated with tropism changes or reduced susceptibility to vicriviroc. Genotypic analysis of cloned env sequences revealed no specific mutational pattern associated with reduced susceptibility to vicriviroc, although numerous changes were observed in the variable domain 3 loop and in other regions of gp160.

Identification of a novel calcium binding motif based on the detection of sequence insertions in the animal peroxidase domain of bacterial proteins.

PubMed

Santamaría-Hernando, Saray; Krell, Tino; Ramos-González, María-Isabel

2012-01-01

Proteins of the animal heme peroxidase (ANP) superfamily differ greatly in size since they have either one or two catalytic domains that match profile PS50292. The orf PP_2561 of Pseudomonas putida KT2440 that we have called PepA encodes a two-domain ANP. The alignment of these domains with those of PepA homologues revealed a variable number of insertions with the consensus G-x-D-G-x-x-[GN]-[TN]-x-D-D. This motif has also been detected in the structure of pseudopilin (pdb 3G20), where it was found to be involved in Ca(2+) coordination although a sequence analysis did not reveal the presence of any known calcium binding motifs in this protein. Isothermal titration calorimetry revealed that a peptide containing this consensus motif bound specifically calcium ions with affinities ranging between 33-79 µM depending on the pH. Microcalorimetric titrations of the purified N-terminal ANP-like domain of PepA revealed Ca(2+) binding with a K(D) of 12 µM and stoichiometry of 1.25 calcium ions per protein monomer. This domain exhibited peroxidase activity after its reconstitution with heme. These data led to the definition of a novel calcium binding motif that we have termed PERCAL and which was abundantly present in animal peroxidase-like domains of bacterial proteins. Bacterial heme peroxidases thus possess two different types of calcium binding motifs, namely PERCAL and the related hemolysin type calcium binding motif, with the latter being located outside the catalytic domains and in their C-terminal end. A phylogenetic tree of ANP-like catalytic domains of bacterial proteins with PERCAL motifs, including single domain peroxidases, was divided into two major clusters, representing domains with and without PERCAL motif containing insertions. We have verified that the recently reported classification of bacterial heme peroxidases in two families (cd09819 and cd09821) is unrelated to these insertions. Sequences matching PERCAL were detected in all kingdoms of life.

Influence of fatigue, depression, and demographic, socioeconomic, and clinical variables on quality of life of patients with epilepsy.

PubMed

Senol, Vesile; Soyuer, Ferhan; Arman, Fehim; Oztürk, Ahmet

2007-02-01

The purpose of this study was to define the influence of fatigue, depression, and clinical, demographic, and socioeconomic factors on the quality of life of patients with epilepsy. The study was performed on 103 adult patients who visited Erciyes University Epilepsy Outpatient Clinic between 2004 and 2005. Patients were evaluated with the Form of Negotiation, Quality of Life in Epilepsy Inventory (QOLIE-89), Beck Depression Inventory, and Fatigue Severity Scale. Mean age of the patients was 34.3+/-12.6, and mean duration of disease was 12.6+/-9.3 years. Among these patients, 52.4% were men, 49.5% were married, 15.5% had a university education, 53.4% had low incomes, 45.6% had generalized seizures, and 35.0% had experienced one or more seizures per month during the preceding year. The most significant variables in the domain of Overall quality of life were seizure frequency (P<0.001), depression (P<0.001), and fatigue (P<0.001); the variables in the domain of Mental Health were seizure frequency (P<0.001) and fatigue (P<0.001); the variable in the Cognitive domain was fatigue (P<0.001); the variables in the domain of Physical Health were social insurance coverage (P<0.01), fatigue (P<0.01), and age (P<0.01); the variables in the Epilepsy Targeted domain were depression (P<0.001), seizure frequency (P<0.001), and fatigue (P<0.01). Although quality of life has multiple determinants, seizure frequency, fatigue, and depression are the most important factors affecting quality of life in patients with epilepsy. One or more seizures per month, severe fatigue, and depression are associated with lower quality of life in some but not all domains. Partial correlations demonstrated that fatigue was a significant independent predictor of quality of life. The present study confirms that fatigue can be a powerful predictor of quality of life.

Mechanical design of proteins studied by single-molecule force spectroscopy and protein engineering.

PubMed

Carrion-Vazquez, M; Oberhauser, A F; Fisher, T E; Marszalek, P E; Li, H; Fernandez, J M

2000-01-01

Mechanical unfolding and refolding may regulate the molecular elasticity of modular proteins with mechanical functions. The development of the atomic force microscopy (AFM) has recently enabled the dynamic measurement of these processes at the single-molecule level. Protein engineering techniques allow the construction of homomeric polyproteins for the precise analysis of the mechanical unfolding of single domains. alpha-Helical domains are mechanically compliant, whereas beta-sandwich domains, particularly those that resist unfolding with backbone hydrogen bonds between strands perpendicular to the applied force, are more stable and appear frequently in proteins subject to mechanical forces. The mechanical stability of a domain seems to be determined by its hydrogen bonding pattern and is correlated with its kinetic stability rather than its thermodynamic stability. Force spectroscopy using AFM promises to elucidate the dynamic mechanical properties of a wide variety of proteins at the single molecule level and provide an important complement to other structural and dynamic techniques (e.g., X-ray crystallography, NMR spectroscopy, patch-clamp).

KIKI-net: cross-domain convolutional neural networks for reconstructing undersampled magnetic resonance images.

PubMed

Eo, Taejoon; Jun, Yohan; Kim, Taeseong; Jang, Jinseong; Lee, Ho-Joon; Hwang, Dosik

2018-04-06

To demonstrate accurate MR image reconstruction from undersampled k-space data using cross-domain convolutional neural networks (CNNs) METHODS: Cross-domain CNNs consist of 3 components: (1) a deep CNN operating on the k-space (KCNN), (2) a deep CNN operating on an image domain (ICNN), and (3) an interleaved data consistency operations. These components are alternately applied, and each CNN is trained to minimize the loss between the reconstructed and corresponding fully sampled k-spaces. The final reconstructed image is obtained by forward-propagating the undersampled k-space data through the entire network. Performances of K-net (KCNN with inverse Fourier transform), I-net (ICNN with interleaved data consistency), and various combinations of the 2 different networks were tested. The test results indicated that K-net and I-net have different advantages/disadvantages in terms of tissue-structure restoration. Consequently, the combination of K-net and I-net is superior to single-domain CNNs. Three MR data sets, the T 2 fluid-attenuated inversion recovery (T 2 FLAIR) set from the Alzheimer's Disease Neuroimaging Initiative and 2 data sets acquired at our local institute (T 2 FLAIR and T 1 weighted), were used to evaluate the performance of 7 conventional reconstruction algorithms and the proposed cross-domain CNNs, which hereafter is referred to as KIKI-net. KIKI-net outperforms conventional algorithms with mean improvements of 2.29 dB in peak SNR and 0.031 in structure similarity. KIKI-net exhibits superior performance over state-of-the-art conventional algorithms in terms of restoring tissue structures and removing aliasing artifacts. The results demonstrate that KIKI-net is applicable up to a reduction factor of 3 to 4 based on variable-density Cartesian undersampling. © 2018 International Society for Magnetic Resonance in Medicine.

Factors associated with quality of life in patients with severe asthma: the impact of pharmacotherapy

PubMed Central

Souza, Daiane Silva; Noblat, Lúcia de Araújo Costa Beisl; Santos, Pablo de Moura

2015-01-01

ABSTRACT OBJECTIVE: To identify, characterize, and quantify associations of various factors with quality of life (QoL) in patients with asthma, according to the pharmacotherapy employed. METHODS: This was a cross-sectional study involving 49 patients (≥ 18 years of age) with severe uncontrolled or refractory asthma treated at a specialized outpatient clinic of the Brazilian Unified Health Care System, regularly using high doses of inhaled corticosteroids (ICs) or other medications, and presenting comorbidities. At a single time point, QoL was assessed with the Asthma Quality of Life Questionnaire (AQLQ). The overall AQLQ score and those of its domains were correlated with demographic variables (gender and age); Asthma Control Questionnaire score; pharmacotherapy (initial IC dose, inhaler devices, and polytherapy); and comorbidities. RESULTS: Better AQLQ scores were associated with asthma control-overall (OR = 0.38; 95% CI: 0.004-0.341; p < 0.001), "symptoms" domain (OR = 0.086; 95% CI: 0.016-0.476; p = 0.001), and "emotional function" domain (OR = 0.086; 95% CI: 0.016-0.476; p = 0.001)-and with IC dose ≤ 800 µg-"activity limitation" domain (OR = 0.249; 95% CI: 0.070-0.885; p = 0.029). Worse AQLQ scores were associated with polytherapy-"activity limitation" domain (OR = 3.651; 95% CI: 1.061-12.561; p = 0.036)-and number of comorbidities ≤ 5-"environmental stimuli" domain (OR = 5.042; 95% CI: 1.316-19.317; p = 0.015). CONCLUSIONS: Our results, the importance of this issue, and the lack of studies taking pharmacotherapy into consideration warrant longitudinal studies to establish a causal relationship between the identified factors and QoL in asthma patients. PMID:26785957

A Walk into the LuxR Regulators of Actinobacteria: Phylogenomic Distribution and Functional Diversity

PubMed Central

Santos, Catarina Lopes; Correia-Neves, Margarida; Moradas-Ferreira, Pedro; Mendes, Marta Vaz

2012-01-01

LuxR regulators are a widely studied group of bacterial helix-turn-helix (HTH) transcription factors involved in the regulation of many genes coding for important traits at an ecological and medical level. This regulatory family is particularly known by their involvement in quorum-sensing (QS) mechanisms, i.e., in the bacterial ability to communicate through the synthesis and binding of molecular signals. However, these studies have been mainly focused on Gram-negative organisms, and the presence of LuxR regulators in the Gram-positive Actinobacteria phylum is still poorly explored. In this manuscript, the presence of LuxR regulators among Actinobacteria was assayed using a domain-based strategy. A total of 991 proteins having one LuxR domain were identified in 53 genome-sequenced actinobacterial species, of which 59% had an additional domain. In most cases (53%) this domain was REC (receiver domain), suggesting that LuxR regulators in Actinobacteria may either function as single transcription factors or as part of two-component systems. The frequency, distribution and evolutionary stability of each of these sub-families of regulators was analyzed and contextualized regarding the ecological niche occupied by each organism. The results show that the presence of extra-domains in the LuxR-regulators was likely driven by a general need to physically uncouple the signal sensing from the signal transduction. Moreover, the total frequency of LuxR regulators was shown to be dependent on genetic, metabolic and ecological variables. Finally, the functional annotation of the LuxR regulators revealed that the bacterial ecological niche has biased the specialization of these proteins. In the case of pathogens, our results suggest that LuxR regulators can be involved in virulence and are therefore promising targets for future studies in the health-related biotechnology field. PMID:23056438

Heating efficiency dependency on size and morphology of magnetite nanoparticles

NASA Astrophysics Data System (ADS)

Parekh, Kinnari; Parmar, Harshida; Sharma, Vinay; Ramanujan, R. V.

2018-04-01

Different size magnetite nanoparticles ranging from superparamagnetic (9 nm) to single domain (27 nm) and multi domain (53 nm) were synthesized using chemical route. Morphology of these particles as seen from TEM images indicates shape change from spherical to cubic with the growth of particles. The saturation magnetization (σs) and Specific Loss Power (SLP) showed maximum for single domain size, 72 emu/g and 102 W/g, respectively then those of multi domain size particles. These samples show higher SLP at relatively low concentration, low frequency and low amplitude compared to samples prepared by other routes.

What Variables are Associated with Successful Weight Loss Outcomes for Bariatric Surgery After One Year?

PubMed Central

Robinson, Athena H.; Adler, Sarah; Stevens, Helen B.; Darcy, Alison M.; Morton, John M.; Safer, Debra L.

2014-01-01

Background Prior evidence indicates that predictors of weight loss outcomes after gastric bypass surgery fall within 5 domains: 1) presurgical factors; 2) postsurgical psychosocial variables (e.g., support group attendance); 3) postsurgical eating patterns; 4) postsurgical physical activity; and 5) follow-up at postsurgical clinic. However, little data exist on which specific behavioral predictors are most associated with successful outcomes (e.g., ≥50% excess weight loss) when considering the 5 domains simultaneously. Objectives Specify the behavioral variables, and their respective cutoff points, most associated with successful weight loss outcomes. Setting On-line survey. Methods Signal Detection Analysis evaluated associations between 84 pre-and postsurgical behavioral variables (within the 5 domains) and successful weight loss at ≥1 year in 274 post-gastric bypass surgery patients. Results Successful weight loss was highest (92.6%) among those reporting dietary adherence of >3 on a 9 point scale (median=5) who grazed no more than once-per-day. Among participants reporting dietary adherence <3 and grazing daily or less, success rates more than doubled when highest lifetime Body Mass Index was <53.7 kg/m2. Success rates also doubled for participants with dietary adherence =3 if attending support groups. No variables from the physical activity or postsurgical follow-up domains were significant, nor were years since surgery. The overall model’s sensitivity =.62, specificity =.92. Conclusions To our knowledge, this is the first study to simultaneously consider the relative contribution of behavioral variables within 5 domains and offer clinicians an assessment algorithm identifying cut-off points for behaviors most associated with successful postsurgical weight loss. Such data may inform prospective study designs and postsurgical interventions. PMID:24913590

The generality of working memory capacity: a latent-variable approach to verbal and visuospatial memory span and reasoning.

PubMed

Kane, Michael J; Hambrick, David Z; Tuholski, Stephen W; Wilhelm, Oliver; Payne, Tabitha W; Engle, Randall W

2004-06-01

A latent-variable study examined whether verbal and visuospatial working memory (WM) capacity measures reflect a primarily domain-general construct by testing 236 participants in 3 span tests each of verbal WM. visuospatial WM, verbal short-term memory (STM), and visuospatial STM. as well as in tests of verbal and spatial reasoning and general fluid intelligence (Gf). Confirmatory' factor analyses and structural equation models indicated that the WM tasks largely reflected a domain-general factor, whereas STM tasks, based on the same stimuli as the WM tasks, were much more domain specific. The WM construct was a strong predictor of Gf and a weaker predictor of domain-specific reasoning, and the reverse was true for the STM construct. The findings support a domain-general view of WM capacity, in which executive-attention processes drive the broad predictive utility of WM span measures, and domain-specific storage and rehearsal processes relate more strongly to domain-specific aspects of complex cognition. ((c) 2004 APA, all rights reserved)

A finite element solution algorithm for the Navier-Stokes equations

NASA Technical Reports Server (NTRS)

Baker, A. J.

1974-01-01

A finite element solution algorithm is established for the two-dimensional Navier-Stokes equations governing the steady-state kinematics and thermodynamics of a variable viscosity, compressible multiple-species fluid. For an incompressible fluid, the motion may be transient as well. The primitive dependent variables are replaced by a vorticity-streamfunction description valid in domains spanned by rectangular, cylindrical and spherical coordinate systems. Use of derived variables provides a uniformly elliptic partial differential equation description for the Navier-Stokes system, and for which the finite element algorithm is established. Explicit non-linearity is accepted by the theory, since no psuedo-variational principles are employed, and there is no requirement for either computational mesh or solution domain closure regularity. Boundary condition constraints on the normal flux and tangential distribution of all computational variables, as well as velocity, are routinely piecewise enforceable on domain closure segments arbitrarily oriented with respect to a global reference frame.

Characterization of System Level Single Event Upset (SEU) Responses using SEU Data, Classical Reliability Models, and Space Environment Data

NASA Technical Reports Server (NTRS)

Berg, Melanie; Label, Kenneth; Campola, Michael; Xapsos, Michael

2017-01-01

We propose a method for the application of single event upset (SEU) data towards the analysis of complex systems using transformed reliability models (from the time domain to the particle fluence domain) and space environment data.

Domain switching in single-phase multiferroics

NASA Astrophysics Data System (ADS)

Jia, Tingting; Cheng, Zhenxiang; Zhao, Hongyang; Kimura, Hideo

2018-06-01

Multiferroics are a time-honoured research subject by reason for their tremendous application potential in the information industry, such as in multi-state information storage devices and new types of sensors. An outburst of studies on multiferroicity has been witnessed in the 21st century, although this field has a long research history since the 19th century. Multiferroicity has now become one of the hottest research topics in condensed matter physics and materials science. Numerous efforts have been made to investigate the cross-coupling phenomena among ferroic orders such as ferroelectricity, (anti-)ferromagnetism, and ferroelasticity, especially the coupling between electric and magnetic orderings that would account for the magnetoelectric (ME) effect in multiferroic materials. The magnetoelectric properties and coupling behavior of single phase multiferroics are dominated by their domain structures. It was also noted that, however, the multiferroic materials exhibit very complicated domain structures. Studies on domain structure characterization and domain switching are a crucial step in the exploration of approaches to the control and manipulation of magnetic (electric) properties using an electric (magnetic) field or other means. In this review, following a concise outline of our current basic knowledge on the magnetoelectric (ME) effect, we summarize some important research activities on domain switching in single-phase multiferroic materials in the form of single crystals and thin films, especially domain switching behavior involving strain and the related physics in the last decade. We also introduce recent developments in characterization techniques for domain structures of ferroelectric or multiferroic materials, which have significantly advanced our understanding of domain switching dynamics and interactions. The effects of a series of issues such as electric field, magnetic field, and stress effects on domain switching are been discussed as well. It is intended that an integrated viewpoint of these issues, as provided here, will further motivate synergistic activities between the various research groups and industry towards the development and characterization of multiferroic materials.

Cognitive Effects of Stimulant, Guanfacine, and Combined Treatment in Child and Adolescent Attention-Deficit/Hyperactivity Disorder

PubMed Central

Bilder, Robert M.; Loo, Sandra; McGough, James J.; Whelan, Fiona; Hellemann, Gerhard; Sugar, Catherine; Del’Homme, Melissa; Sturm, Alexandra; Cowen, Jennifer; Hanada, Grant; McCracken, James T.

2016-01-01

Objective Psychostimulants are partially effective in reducing cognitive dysfunction associated with attention-deficit/hyperactivity disorder (ADHD). Cognitive effects of guanfacine, an alternative treatment, are poorly understood. Given its distinct action on α2A receptors, guanfacine may have different or complementary effects relative to stimulants. This study tested stimulant and guanfacine monotherapies relative to combined treatment on cognitive functions important in ADHD. Method Children with ADHD (n = 182; age 7–14 years) completed an eight-week double blind randomized controlled trial with three arms: d-methylphenidate (DMPH), guanfacine (GUAN), or combination treatment with DMPH and GUAN (COMB). A non-clinical comparison group (n = 93) had baseline testing, and a subset was re-tested 8 weeks later (n = 38). Analyses examined treatment effects in four cognitive domains (working memory, response inhibition, reaction time, and reaction time variability) constructed from 20 variables. Results The ADHD group showed impaired working memory relative to the non-clinical comparison group (effect size = −0.53 SD units). The treatments differed in effects on working memory but not other cognitive domains. Combination treatment improved working memory more than GUAN, but was not significantly better than DMPH alone. Treatment did not fully normalize the initial deficit in ADHD relative to the comparison group. Conclusion Combined treatment with DMPH and GUAN yielded greater improvements in working memory than placebo or GUAN alone, but the combined treatment was not superior to DMPH alone, and did not extend to other cognitive domains. Although GUAN may be a useful add-on treatment to psychostimulants, additional strategies appear necessary to achieve normalization of cognitive function in ADHD. Clinical trial registration information Single Versus Combination Medication Treatment for Children With Attention Deficit Hyperactivity Disorder; http://clinicaltrials.gov/; NCT00429273 PMID:27453080

Hadean silicate differentiation preserved by anomalous 142Nd/144Nd ratios in the Réunion hotspot source

NASA Astrophysics Data System (ADS)

Peters, Bradley J.; Carlson, Richard W.; Day, James M. D.; Horan, Mary F.

2018-03-01

Active volcanic hotspots can tap into domains in Earth’s deep interior that were formed more than two billion years ago. High-precision data on variability in tungsten isotopes have shown that some of these domains resulted from differentiation events that occurred within the first fifty million years of Earth history. However, it has not proved easy to resolve analogous variability in neodymium isotope compositions that would track regions of Earth’s interior whose composition was established by events occurring within roughly the first five hundred million years of Earth history. Here we report 142Nd/144Nd ratios for Réunion Island igneous rocks, some of which are resolvably either higher or lower than the ratios in modern upper-mantle domains. We also find that Réunion 142Nd/144Nd ratios correlate with helium-isotope ratios (3He/4He), suggesting parallel behaviour of these isotopic systems during very early silicate differentiation, perhaps as early as 4.39 billion years ago. The range of 142Nd/144Nd ratios in Réunion basalts is inconsistent with a single-stage differentiation process, and instead requires mixing of a conjugate melt and residue formed in at least one melting event during the Hadean eon, 4.56 billion to 4 billion years ago. Efficient post-Hadean mixing nearly erased the ancient, anomalous 142Nd/144Nd signatures, and produced the relatively homogeneous 143Nd/144Nd composition that is characteristic of Réunion basalts. Our results show that Réunion magmas tap into a particularly ancient, primitive source compared with other volcanic hotspots, offering insight into the formation and preservation of ancient heterogeneities in Earth’s interior.

Supporting multiple domains in a single reuse repository

NASA Technical Reports Server (NTRS)

Eichmann, David A.

1992-01-01

Domain analysis typically results in the construction of a domain-specific repository. Such a repository imposes artificial boundaries on the sharing of similar assets between related domains. A lattice-based approach to repository modeling can preserve a reuser's domain specific view of the repository, while avoiding replication of commonly used assets and supporting a more general perspective on domain interrelationships.

Temperature and electric-field induced phase transitions, and full tensor properties of [011] C-poled domain-engineered tetragonal 0 .63 Pb (M g1 /3N b2 /3) -0 .37 PbTi O3 single crystals

NASA Astrophysics Data System (ADS)

Zheng, Limei; Jing, Yujia; Lu, Xiaoyan; Wang, Ruixue; Liu, Gang; Lü, Weiming; Zhang, Rui; Cao, Wenwu

2016-03-01

The phase-transition sequence of 0.67 Pb (M g1 /3N b2 /3)- 0.37 PbTi O3 (PMN-0.37PT) single crystals driven by the electric (E ) field and temperature is comprehensively studied. Based on the strain-E field loop, polarization-E field loop, and the evolution of domain configurations, the E field along the [011] C induced phase transitions have been confirmed to be as follows: tetragonal (T ) → monoclinic (MC)→ single domain orthorhombic (O ) phase. As the E field decreases, the induced O phase cannot be maintained and transformed to the MC phase, then to the coexistence state of MC and T phases. In addition, the complete sets of dielectric, piezoelectric, and elastic constants for the [011] C-poled domain-engineered PMN-0.37PT single crystal were measured at room temperature, which show high longitudinal dielectric, piezoelectric, and electromechanical properties (ɛ33T=10 661 ,d33=1052 pC /N , and k33= 0.766 ). Our results revealed that the MC phase plays an important role in the high electromechanical properties of this domain-engineered single crystal. The temperature dependence of the domain configuration revealed that the volume fraction of the MC phase decreases with temperature accompanied by the reduction of ɛ33T,d31, and k31 due to the substantially smaller intrinsic properties of the T phase.

The role of charge and multiple faces of the CD8 alpha/alpha homodimer in binding to major histocompatibility complex class I molecules: support for a bivalent model.

PubMed

Giblin, P A; Leahy, D J; Mennone, J; Kavathas, P B

1994-03-01

The CD8 dimer interacts with the alpha 3 domain of major histocompatibility complex class I molecules through two immunoglobulin variable-like domains. In this study a crystal structure-informed mutational analysis has been performed to identify amino acids in the CD8 alpha/alpha homodimer that are likely to be involved in binding to class I. Several key residues are situated on the top face of the dimer within loops analogous to the complementarity-determining regions (CDRs) of immunoglobulin. In addition, other important amino acids are located in the A and B beta-strands on the sides of the dimer. The potential involvement of amino acids on both the top and the side faces of the molecule is consistent with a bivalent model for the interaction between a single CD8 alpha/alpha homodimer and two class I molecules and may have important implications for signal transduction in class I-expressing cells. This study also demonstrates a role for the positive surface potential of CD8 in class I binding and complements previous work demonstrating the importance of a negatively charged loop on the alpha 3 domain of class I for CD8 alpha/alpha-class I interaction. We propose a model whereby residues located on the CDR-like loops of the CD8 homodimer interact with the alpha 3 domain of MHC class I while amino acids on the side of the molecule containing the A and B beta-strands contact the alpha 2 domain of class I.

Baseline Vascular Cognitive Impairment Predicts the Course of Apathetic Symptoms After Stroke: The CASPER Study.

PubMed

Douven, Elles; Köhler, Sebastian; Schievink, Syenna H J; van Oostenbrugge, Robert J; Staals, Julie; Verhey, Frans R J; Aalten, Pauline

2018-03-01

To examine the influence of vascular cognitive impairment (VCI) on the course of poststroke depression (PSD) and poststroke apathy (PSA). Included were 250 stroke patients who underwent neuropsychological and neuropsychiatric assessment 3 months after stroke (baseline) and at a 6- and 12-month follow-up after baseline. Linear mixed models tested the influence of VCI in at least one cognitive domain (any VCI) or multidomain VCI (VCI in multiple cognitive domains) at baseline and domain-specific VCI at baseline on levels of depression and apathy over time, with random effects for intercept and slope. Almost half of the patients showed any VCI at baseline, and any VCI was associated with increasing apathy levels from baseline to the 12-month follow-up. Patients with multidomain VCI had higher apathy scores at the 6- and 12-month follow-up compared with patients with VCI in a single cognitive domain. Domain-specific analyses showed that impaired executive function and slowed information processing speed went together with increasing apathy levels from baseline to 6- and 12-month follow-up. None of the cognitive variables predicted the course of depressive symptoms. Baseline VCI is associated with increasing apathy levels from baseline to the chronic stroke phase, whereas no association was found between baseline VCI and the course of depressive symptoms. Health professionals should be aware that apathy might be absent early after stroke but may evolve over time in patients with VCI. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Analysis of Bacterial Lipooligosaccharides by MALDI-TOF MS with Traveling Wave Ion Mobility

NASA Astrophysics Data System (ADS)

Phillips, Nancy J.; John, Constance M.; Jarvis, Gary A.

2016-07-01

Lipooligosaccharides (LOS) are major microbial virulence factors displayed on the outer membrane of rough-type Gram-negative bacteria. These amphipathic glycolipids are comprised of two domains, a core oligosaccharide linked to a lipid A moiety. Isolated LOS samples are generally heterogeneous mixtures of glycoforms, with structural variability in both domains. Traditionally, the oligosaccharide and lipid A components of LOS have been analyzed separately following mild acid hydrolysis, although important acid-labile moieties can be cleaved. Recently, an improved method was introduced for analysis of intact LOS by MALDI-TOF MS using a thin layer matrix composed of 2,4,6-trihydroxyacetophenone (THAP) and nitrocellulose. In addition to molecular ions, the spectra show in-source "prompt" fragments arising from regiospecific cleavage between the lipid A and oligosaccharide domains. Here, we demonstrate the use of traveling wave ion mobility spectrometry (TWIMS) for IMS-MS and IMS-MS/MS analyses of intact LOS from Neisseria spp. ionized by MALDI. Using IMS, the singly charged prompt fragments for the oligosaccharide and lipid A domains of LOS were readily separated into resolved ion plumes, permitting the extraction of specific subspectra, which led to increased confidence in assigning compositions and improved detection of less abundant ions. Moreover, IMS separation of precursor ions prior to collision-induced dissociation (CID) generated time-aligned, clean MS/MS spectra devoid of fragments from interfering species. Incorporating IMS into the profiling of intact LOS by MALDI-TOF MS exploits the unique domain structure of the molecule and offers a new means of extracting more detailed information from the analysis.

Cortical Thickness Changes Correlate with Cognition Changes after Cognitive Training: Evidence from a Chinese Community Study

PubMed Central

Jiang, Lijuan; Cao, Xinyi; Li, Ting; Tang, Yingying; Li, Wei; Wang, Jijun; Chan, Raymond C.; Li, Chunbo

2016-01-01

The aim of this study was to investigate whether changes in cortical thickness correlated with cognitive function changes in healthy older adults after receiving cognitive training interventions. Moreover, it also aimed to examine the differential impacts of a multi-domain and a single-domain cognitive training interventions. Longitudinal magnetic resonance imaging (MRI) scanning was performed on participants 65–75 years of age using the Siemens 3.0 T Trio Tim with the Magnetization Prepared Rapid Gradient Echo (MPRAGE) sequence. The cortical thickness was determined using FreeSurfer Software. Cognitive functioning was evaluated using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). There were significant group × time interaction effects on the left supramarginal, the left frontal pole cortical regions; and a marginal significant group × time interaction effects on visuospatial/constructional and delayed memory scores. In a multi-domain cognitive training group, a number of cortical region changes were significantly positively correlated with changes in attention, delayed memory, and the total score, but significantly negatively correlated with changes in immediate memory and language scores. In the single-domain cognitive training group, some cortical region changes were significantly positively associated with changes in immediate memory, delayed memory, and the total score, while they were significantly negatively associated with changes in visuospatial/constructional, language, and attention scores. Overall, multi-domain cognitive training offered more advantages in visuospatial/constructional, attention, and delayed memory abilities, while single-domain cognitive training benefited immediate memory ability more effectively. These findings suggest that healthy older adults benefit more from the multi-domain cognitive training than single-domain cognitive training. Cognitive training has impacted on cortical thickness changes in healthy elderly. PMID:27252649

Relaxor-based ferroelectric single crystals: growth, domain engineering, characterization and applications

PubMed Central

Sun, Enwei; Cao, Wenwu

2014-01-01

In the past decade, domain engineered relaxor-PT ferroelectric single crystals, including (1-x)Pb(Mg1/3Nb2/3)O3-xPbTiO3 (PMN-PT), (1-x)Pb(Zn1/3Nb2/3)O3-xPbTiO3 (PZN-PT) and (1-x-y)Pb(In1/2Nb1/2)O3-yPb(Mg1/3Nb2/3)O3-xPbTiO3 (PIN-PMN-PT), with compositions near the morphotropic phase boundary (MPB) have triggered a revolution in electromechanical devices owing to their giant piezoelectric properties and ultra-high electromechanical coupling factors. Compared to traditional PbZr1-xTixO3 (PZT) ceramics, the piezoelectric coefficient d33 is increased by a factor of 5 and the electromechanical coupling factor k33 is increased from < 70% to > 90%. Many emerging rich physical phenomena, such as charged domain walls, multi-phase coexistence, domain pattern symmetries, etc., have posed challenging fundamental questions for scientists. The superior electromechanical properties of these domain engineered single crystals have prompted the design of a new generation electromechanical devices, including sensors, transducers, actuators and other electromechanical devices, with greatly improved performance. It took less than 7 years from the discovery of larger size PMN-PT single crystals to the commercial production of the high-end ultrasonic imaging probe “PureWave”. The speed of development is unprecedented, and the research collaboration between academia and industrial engineers on this topic is truly intriguing. It is also exciting to see that these relaxor-PT single crystals are being used to replace traditional PZT piezoceramics in many new fields outside of medical imaging. The new ternary PIN-PMN-PT single crystals, particularly the ones with Mn-doping, have laid a solid foundation for innovations in high power acoustic projectors and ultrasonic motors, hinting another revolution in underwater SONARs and miniature actuation devices. This article intends to provide a comprehensive review on the development of relaxor-PT single crystals, spanning material discovery, crystal growth techniques, domain engineering concept, and full-matrix property characterization all the way to device innovations. It outlines a truly encouraging story in materials science in the modern era. All key references are provided and 30 complete sets of material parameters for different types of relaxor-PT single crystals are listed in the Appendix. It is the intension of this review article to serve as a resource for those who are interested in basic research and practical applications of these relaxor-PT single crystals. In addition, possible mechanisms of giant piezoelectric properties in these domain-engineered relaxor-PT systems will be discussed based on contributions from polarization rotation and charged domain walls. PMID:25061239

Relaxor-based ferroelectric single crystals: growth, domain engineering, characterization and applications.

PubMed

Sun, Enwei; Cao, Wenwu

2014-08-01

In the past decade, domain engineered relaxor-PT ferroelectric single crystals, including (1- x )Pb(Mg 1/3 Nb 2/3 )O 3 - x PbTiO 3 (PMN-PT), (1- x )Pb(Zn 1/3 Nb 2/3 )O 3 - x PbTiO 3 (PZN-PT) and (1- x - y )Pb(In 1/2 Nb 1/2 )O 3 - y Pb(Mg 1/3 Nb 2/3 )O 3 - x PbTiO 3 (PIN-PMN-PT), with compositions near the morphotropic phase boundary (MPB) have triggered a revolution in electromechanical devices owing to their giant piezoelectric properties and ultra-high electromechanical coupling factors. Compared to traditional PbZr 1- x Ti x O 3 (PZT) ceramics, the piezoelectric coefficient d 33 is increased by a factor of 5 and the electromechanical coupling factor k 33 is increased from < 70% to > 90%. Many emerging rich physical phenomena, such as charged domain walls, multi-phase coexistence, domain pattern symmetries, etc., have posed challenging fundamental questions for scientists. The superior electromechanical properties of these domain engineered single crystals have prompted the design of a new generation electromechanical devices, including sensors, transducers, actuators and other electromechanical devices, with greatly improved performance. It took less than 7 years from the discovery of larger size PMN-PT single crystals to the commercial production of the high-end ultrasonic imaging probe "PureWave". The speed of development is unprecedented, and the research collaboration between academia and industrial engineers on this topic is truly intriguing. It is also exciting to see that these relaxor-PT single crystals are being used to replace traditional PZT piezoceramics in many new fields outside of medical imaging. The new ternary PIN-PMN-PT single crystals, particularly the ones with Mn-doping, have laid a solid foundation for innovations in high power acoustic projectors and ultrasonic motors, hinting another revolution in underwater SONARs and miniature actuation devices. This article intends to provide a comprehensive review on the development of relaxor-PT single crystals, spanning material discovery, crystal growth techniques, domain engineering concept, and full-matrix property characterization all the way to device innovations. It outlines a truly encouraging story in materials science in the modern era. All key references are provided and 30 complete sets of material parameters for different types of relaxor-PT single crystals are listed in the Appendix. It is the intension of this review article to serve as a resource for those who are interested in basic research and practical applications of these relaxor-PT single crystals. In addition, possible mechanisms of giant piezoelectric properties in these domain-engineered relaxor-PT systems will be discussed based on contributions from polarization rotation and charged domain walls.

Analyzing Test-As-You-Fly Single Event Upset (SEU) Responses using SEU Data, Classical Reliability Models, and Space Environment Data

NASA Technical Reports Server (NTRS)

Berg, Melanie; Label, Kenneth; Campola, Michael; Xapsos, Michael

2017-01-01

We propose a method for the application of single event upset (SEU) data towards the analysis of complex systems using transformed reliability models (from the time domain to the particle fluence domain) and space environment data.

Characterization of System on a Chip (SoC) Single Event Upset (SEU) Responses Using SEU Data, Classical Reliability Models, and Space Environment Data

NASA Technical Reports Server (NTRS)

Berg, Melanie; Label, Kenneth; Campola, Michael; Xapsos, Michael

2017-01-01

We propose a method for the application of single event upset (SEU) data towards the analysis of complex systems using transformed reliability models (from the time domain to the particle fluence domain) and space environment data.

Tertiary network in mammalian mitochondrial tRNAAsp revealed by solution probing and phylogeny

PubMed Central

Messmer, Marie; Pütz, Joern; Suzuki, Takeo; Suzuki, Tsutomu; Sauter, Claude; Sissler, Marie; Catherine, Florentz

2009-01-01

Primary and secondary structures of mammalian mitochondrial (mt) tRNAs are divergent from canonical tRNA structures due to highly skewed nucleotide content and large size variability of D- and T-loops. The nonconservation of nucleotides involved in the expected network of tertiary interactions calls into question the rules governing a functional L-shaped three-dimensional (3D) structure. Here, we report the solution structure of human mt-tRNAAsp in its native post-transcriptionally modified form and as an in vitro transcript. Probing performed with nuclease S1, ribonuclease V1, dimethylsulfate, diethylpyrocarbonate and lead, revealed several secondary structures for the in vitro transcribed mt-tRNAAsp including predominantly the cloverleaf. On the contrary, the native tRNAAsp folds into a single cloverleaf structure, highlighting the contribution of the four newly identified post-transcriptional modifications to correct folding. Reactivities of nucleotides and phosphodiester bonds in the native tRNA favor existence of a full set of six classical tertiary interactions between the D-domain and the variable region, forming the core of the 3D structure. Reactivities of D- and T-loop nucleotides support an absence of interactions between these domains. According to multiple sequence alignments and search for conservation of Leontis–Westhof interactions, the tertiary network core building rules apply to all tRNAAsp from mammalian mitochondria. PMID:19767615

Digital holographic tomography method for 3D observation of domain patterns in ferroelectric single crystals

NASA Astrophysics Data System (ADS)

Mokrý, Pavel; Psota, Pavel; Steiger, Kateřina; Václavík, Jan; Vápenka, David; Doleček, Roman; Vojtíšek, Petr; Sládek, Juraj; Lédl, Vít.

2016-11-01

We report on the development and implementation of the digital holographic tomography for the three-dimensio- nal (3D) observations of the domain patterns in the ferroelectric single crystals. Ferroelectric materials represent a group of materials, whose macroscopic dielectric, electromechanical, and elastic properties are greatly in uenced by the presence of domain patterns. Understanding the role of domain patterns on the aforementioned properties require the experimental techniques, which allow the precise 3D measurements of the spatial distribution of ferroelectric domains in the single crystal. Unfortunately, such techniques are rather limited at this time. The most frequently used piezoelectric atomic force microscopy allows 2D observations on the ferroelectric sample surface. Optical methods based on the birefringence measurements provide parameters of the domain patterns averaged over the sample volume. In this paper, we analyze the possibility that the spatial distribution of the ferroelectric domains can be obtained by means of the measurement of the wavefront deformation of the transmitted optical wave. We demonstrate that the spatial distribution of the ferroelectric domains can be determined by means of the measurement of the spatial distribution of the refractive index. Finally, it is demonstrated that the measurements of wavefront deformations generated in ferroelectric polydomain systems with small variations of the refractive index provide data, which can be further processed by means of the conventional tomographic methods.

Students' attitudes towards mathematics in single-sex and coeducational schools

NASA Astrophysics Data System (ADS)

Norton, Stephen J.; Rennie, Léonie J.

1998-04-01

This paper examines students' attitudes towards mathematics at the secondary school level. Using five of the Fennema-Sherman scales, the attitudes of boys and girls in Grades 8 to 12 in four schools were compared: a single-sex boys' and a single-sex girls' private school, and a state and a private coeducational school. Multivariate analysis of variance was used to guide an exploration of how students' attitudes varied according to grade, sex and educational setting. There were no differences between students in the two coeducational schools. In general, students' attitudes were found to be less positive in more senior grades; and overall, boys had more positive attitudes than girls. There were clear differences between boys and girls on the Mathematics as a Male Domain scale, with girls being less stereotyped in their perceptions than boys. Except for this scale, effects related to the sex of the student were small, and effects relating to grade level and school type on all variables were also small. Implications are drawn for future research in this area.

A multilevel meta-analysis of single-case and small-n research on interventions for reducing challenging behavior in persons with intellectual disabilities.

PubMed

Heyvaert, M; Maes, B; Van den Noortgate, W; Kuppens, S; Onghena, P

2012-01-01

The effectiveness of different interventions for challenging behavior (CB) in persons with intellectual disabilities (ID) was reviewed by means of a two-phase study. First, a systematic review of 137 meta-analyses and reviews on group-study interventions for CB in persons with ID was conducted. Based on this review, hypotheses concerning the effectiveness of divergent interventions for CB and concerning the impact of variables moderating treatment effectiveness were systematically generated. Second, these hypotheses were tested by means of a multilevel meta-analysis of single-case and small-n research. Two hundred and eighty-five studies reporting on 598 individuals were examined. The average treatment effect was large and statistically significant. However, this effect varied significantly over the included studies and participants. Compared to the meta-analyses and reviews focusing on group-studies in this research domain, the results of the present multilevel meta-analysis of single-case and small-n intervention research provided more detailed knowledge on which specific CB and intervention components moderate the interventions' effectiveness. Copyright © 2011 Elsevier Ltd. All rights reserved.

Visualizing ferromagnetic domains in magnetic topological insulators

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

Wang, Wenbo; Gu, G. D.; Yang, Fang

2015-05-13

We report a systematic study of ferromagnetic domains in both single-crystal and thin-film specimens of magnetic topological insulators Cr doped (Bi 0.1Sb 0.9) 2Te 3 using magnetic force microscopy (MFM). The temperature and field dependences of MFM and in situ resistance data are consistent with previous bulk transport and magnetic characterization. Bubble-like ferromagnetic domains were observed in both single crystals and thin films. Significantly, smaller domain size (~500 nm) with narrower domain wall (~150 – 300 nm) was observed in thin films of magnetic topological insulators, likely due to vertical confinement effect. As a result, these results suggest that thinmore » films are more promising for visualization of chiral edge states.« less

Nonagonal cadherins: A new protein family found within the Stramenopiles.

PubMed

Fletcher, Kyle I G; van West, Pieter; Gachon, Claire M M

2016-11-15

Cadherins, a group of molecules typically associated with planar cell polarity and Wnt signalling, have been little reported outside of the animal kingdom. Here, we identify a new family of cadherins in the Stramenopiles, termed Nonagonal after their 9 transmembrane passes, which contrast to the one or seven passes found in other known cadherin families. Manual curation and experimental validation reveal two subclasses of nonagonal cadherins, depending on the number of uninterrupted extracellular cadherin (EC) modules presented. Firstly, shorter mono-exonic, unimodular, protein models, with 3 to 12 EC domains occur as duplicate paralogs in the saprotrophic Labyrinthulomycetes Aurantiochytrium limanicum and Schizochytrium aggregatum, the gastrointestinal Blastocystis hominis (Blastocystae) and as a single copy gene in the autotrophic Pelagophyte Aureococcus anophagefferens. Larger, single copy, multi-exonal, tri-modular protein models, with up to 72 EC domain in total, are found in the Oomycete genera Albugo, Phytophthora, Pythium and Eurychasma. No homolog was found in the closely related autotrophic Phaeophyceae (brown algae) or Bacillariophyceae (diatoms), nor in several genera of plant and animal pathogenic oomycetes (Aphanomyces, Saprolegnia and Hyaloperonospora). This potential absence was further investigated by synteny analysis of the genome regions flanking the cadherin gene models, which are found to be highly variable. Novel to this new cadherin family is the presence of intercalated laminin and putative carbohydrate binding in tri-modular oomycete cadherins and at the N-terminus of thraustochytrid proteins. As we were unable to detect any homologs of proteins involved in signalling pathways where other cadherin families are involved, we present a conceptual hypothesis on the function of nonagonal cadherin based around the presence of putative carbohydrate binding domains. Copyright © 2016. Published by Elsevier B.V.

Centromeres Off the Hook: Massive Changes in Centromere Size and Structure Following Duplication of CenH3 Gene in Fabeae Species

PubMed Central

Neumann, Pavel; Pavlíková, Zuzana; Koblížková, Andrea; Fuková, Iva; Jedličková, Veronika; Novák, Petr; Macas, Jiří

2015-01-01

In most eukaryotes, centromere is determined by the presence of the centromere-specific histone variant CenH3. Two types of chromosome morphology are generally recognized with respect to centromere organization. Monocentric chromosomes possess a single CenH3-containing domain in primary constriction, whereas holocentric chromosomes lack the primary constriction and display dispersed distribution of CenH3. Recently, metapolycentric chromosomes have been reported in Pisum sativum, representing an intermediate type of centromere organization characterized by multiple CenH3-containing domains distributed across large parts of chromosomes that still form a single constriction. In this work, we show that this type of centromere is also found in other Pisum and closely related Lathyrus species, whereas Vicia and Lens genera, which belong to the same legume tribe Fabeae, possess only monocentric chromosomes. We observed extensive variability in the size of primary constriction and the arrangement of CenH3 domains both between and within individual Pisum and Lathyrus species, with no obvious correlation to genome or chromosome size. Search for CenH3 gene sequences revealed two paralogous variants, CenH3-1 and CenH3-2, which originated from a duplication event in the common ancestor of Fabeae species. The CenH3-1 gene was subsequently lost or silenced in the lineage leading to Vicia and Lens, whereas both genes are retained in Pisum and Lathyrus. Both of these genes appear to have evolved under purifying selection and produce functional CenH3 proteins which are fully colocalized. The findings described here provide the first evidence for a highly dynamic centromere structure within a group of closely related species, challenging previous concepts of centromere evolution. PMID:25771197

Cognitive Tests and Determining Fitness to Drive in Dementia: A Systematic Review.

PubMed

Bennett, Joanne M; Chekaluk, Eugene; Batchelor, Jennifer

2016-09-01

Evidence has shown that although all individuals with dementia will eventually need to stop driving, most can continue to drive safely early in the disease. Fitness to drive needs to be monitored, and the use of cognitive testing to determine driver safety has been suggested. This review is the first to examine cognitive test results pertaining only to individuals with dementia. The aim was to examine the relationship between cognitive tests and driving to determine whether a cognitive assessment can be implemented as a tool to examine driver safety. A systematic review of 28 studies investigating the relationship between cognitive functioning and driving in individuals with dementia was conducted. The results of this review demonstrated a lack of consistency in the findings, with some studies showing a relationship between cognitive testing and driving performance for individuals with dementia, whereas others did not. Results relating to individual cognitive tests and measures confined to a single cognitive domain were variable and not consistently associated with driving performance. Studies consistently found that composite batteries predicted driving performance. The findings from this review support the use of composite batteries comprising multiple individual tests from different cognitive domains in predicting driving performance for individuals with dementia. Scores on individual tests or tests of a single cognitive domain did not predict driver safety. The composite batteries that researchers have examined are not clinically usable because they lack the ability to discriminate sufficiently between safe and unsafe drivers. Researchers need to develop a reliable, valid composite battery that can correctly determine driver safety in individuals with dementia. © 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society.

Electromagnetic induction heating for single crystal graphene growth: morphology control by rapid heating and quenching

NASA Astrophysics Data System (ADS)

Wu, Chaoxing; Li, Fushan; Chen, Wei; Veeramalai, Chandrasekar Perumal; Ooi, Poh Choon; Guo, Tailiang

2015-03-01

The direct observation of single crystal graphene growth and its shape evolution is of fundamental importance to the understanding of graphene growth physicochemical mechanisms and the achievement of wafer-scale single crystalline graphene. Here we demonstrate the controlled formation of single crystal graphene with varying shapes, and directly observe the shape evolution of single crystal graphene by developing a localized-heating and rapid-quenching chemical vapor deposition (CVD) system based on electromagnetic induction heating. Importantly, rational control of circular, hexagonal, and dendritic single crystalline graphene domains can be readily obtained for the first time by changing the growth condition. Systematic studies suggest that the graphene nucleation only occurs during the initial stage, while the domain density is independent of the growth temperatures due to the surface-limiting effect. In addition, the direct observation of graphene domain shape evolution is employed for the identification of competing growth mechanisms including diffusion-limited, attachment-limited, and detachment-limited processes. Our study not only provides a novel method for morphology-controlled graphene synthesis, but also offers fundamental insights into the kinetics of single crystal graphene growth.

Life satisfaction of women of working age shortly after breast cancer surgery.

PubMed

Olsson, Mariann; Nilsson, Marie; Fugl-Meyer, Kerstin; Petersson, Lena-Marie; Wennman-Larsen, Agneta; Kjeldgård, Linnea; Alexanderson, Kristina

2017-03-01

To explore, among women of working age, satisfaction with life as a whole and with different life domains, and its associations with social and health variables, shortly after breast cancer surgery. This cross-sectional study included 605 women, aged 20-63 years, who had had breast cancer surgery with no distant metastasis, pre-surgical chemotherapy, or previous breast cancer. Associations between LiSat-11 and demographic and social factors as well as health- and treatment-related variables were analysed by multivariable logistic regression. Compared with Swedish reference levels, the women were, after breast cancer surgery, less satisfied with life, particularly sexual life. Women working shortly after breast cancer surgery were more often satisfied with life in provision domains compared with the reference population. Although most included variables showed associations with satisfaction, after adjustment for all significantly associated variables, only six variables-having children, being in work, having emotional and informational social support, and having good physical and emotional functioning-were positively associated with satisfaction with life as a whole. The odds ratios for satisfaction were higher in most life domains if the woman had social support and good emotional and cognitive functioning. One month after breast cancer surgery, satisfaction with different life domains was associated primarily with social support and health-related functioning. However, this soon after surgery, treatment-related variables showed no significant associations with life satisfaction. These results are useful for planning interventions to enhance e.g. social support and emotional as well as cognitive functioning.

C-Terminal Domain of Hemocyanin, a Major Antimicrobial Protein from Litopenaeus vannamei: Structural Homology with Immunoglobulins and Molecular Diversity

PubMed Central

Zhang, Yue-Ling; Peng, Bo; Li, Hui; Yan, Fang; Wu, Hong-Kai; Zhao, Xian-Liang; Lin, Xiang-Min; Min, Shao-Ying; Gao, Yuan-Yuan; Wang, San-Ying; Li, Yuan-You; Peng, Xuan-Xian

2017-01-01

Invertebrates rely heavily on immune-like molecules with highly diversified variability so as to counteract infections. However, the mechanisms and the relationship between this variability and functionalities are not well understood. Here, we showed that the C-terminal domain of hemocyanin (HMC) from shrimp Litopenaeus vannamei contained an evolutionary conserved domain with highly variable genetic sequence, which is structurally homologous to immunoglobulin (Ig). This domain is responsible for recognizing and binding to bacteria or red blood cells, initiating agglutination and hemolysis. Furthermore, when HMC is separated into three fractions using anti-human IgM, IgG, or IgA, the subpopulation, which reacted with anti-human IgM (HMC-M), showed the most significant antimicrobial activity. The high potency of HMC-M is a consequence of glycosylation, as it contains high abundance of α-d-mannose relative to α-d-glucose and N-acetyl-d-galactosamine. Thus, the removal of these glycans abolished the antimicrobial activity of HMC-M. Our results present a comprehensive investigation of the role of HMC in fighting against infections through genetic variability and epigenetic modification. PMID:28659912

Symmetry and defects in rhombohedral single-crystalline Na0.5Bi0.5TiO3

NASA Astrophysics Data System (ADS)

Beanland, Richard; Thomas, Pam A.

2014-05-01

Recent work has indicated that the symmetry of the lead-free piezoelectric perovskite Na0.5Bi0.5TiO3 can be changed from monoclinic to rhombohedral through the application of an electric field, which may have implications for the study and design of piezoelectric materials close to a morphotropic phase boundary. We have examined high-quality, single-crystal Na0.5Bi0.5TiO3 using transmission electron microscopy and have used digital electron diffraction to observe the symmetry of defect-free regions of material on length scales of a few nanometers. This unequivocally demonstrates that the material is rhombohedral with space group R3c on this length scale. We find that a model that allows disordered displacements of Bi atoms from their nominal sites in the R3c symmetry, while retaining this symmetry on average, gives a very significant improvement in fit to simulations. We use conventional transmission electron microscopy to enumerate the different types of defects that are observed in other regions of the crystal and find a complex microstructure of antiphase boundaries, domain walls, and tetragonal platelets. Their interaction leads to the formation of very high densities of nanotwins. We show that these are expected to have a variable monoclinic Cc symmetry that is driven by the constraint of continuity of the crystal across a domain wall.

Structural features and ligand binding properties of tandem WW domains from YAP and TAZ, nuclear effectors of the Hippo pathway.

PubMed

Webb, Claire; Upadhyay, Abhishek; Giuntini, Francesca; Eggleston, Ian; Furutani-Seiki, Makoto; Ishima, Rieko; Bagby, Stefan

2011-04-26

The paralogous multifunctional adaptor proteins YAP and TAZ are the nuclear effectors of the Hippo pathway, a central mechanism of organ size control and stem cell self-renewal. WW domains, mediators of protein-protein interactions, are essential for YAP and TAZ function, enabling interactions with PPxY motifs of numerous partner proteins. YAP has single and double WW domain isoforms (YAP1 and YAP2) whereas only a single WW domain isoform of TAZ has been described to date. Here we identify the first example of a double WW domain isoform of TAZ. Using NMR, we have characterized conformational features and peptide binding of YAP and TAZ tandem WW domains (WW1-WW2). The solution structure of YAP WW2 confirms that it has a canonical three-stranded antiparallel β-sheet WW domain fold. While chemical shift-based analysis indicates that the WW domains in the tandem WW pairs retain the characteristic WW domain fold, 15N relaxation data show that, within the respective WW pairs, YAP WW1 and both WW1 and WW2 of TAZ undergo conformational exchange. 15N relaxation data also indicate that the linker between the WW domains is flexible in both YAP and TAZ. Within both YAP and TAZ tandem WW pairs, WW1 and WW2 bind single PPxY-containing peptide ligand concurrently and noncooperatively with sub-mM affinity. YAP and TAZ WW1-WW2 bind a dual PPxY-containing peptide with approximately 6-fold higher affinity. Our results indicate that both WW domains in YAP and TAZ are functional and capable of enhanced affinity binding to multi-PPxY partner proteins such as LATS1, ErbB4, and AMOT.

Ferroelectric and multiferroic domain imaging by Laser-induced photoemission microscopy

NASA Astrophysics Data System (ADS)

Hoefer, Anke; Fechner, Michael; Duncker, Klaus; Mertig, Ingrid; Widdra, Wolf

2013-03-01

The ferroelectric as well as multiferroic surface domain structures of BaTiO3(001) and BiFeO3(001) are imaged based on photoemission electron microscopy (PEEM) by femtosecond laser threshold excitation under UHV conditions. For well-prepared BaTiO3(001), three ferroelectric domain types are clearly discriminable due to work function differences. At room temperature, the surface domains resemble the known ferroelectric domain structure of the bulk. Upon heating above the Curie point of 400 K, the specific surface domain pattern remains up to 500 K. Ab-initio calculations explain this observation by a remaining tetragonal distortion of the topmost unit cells stabilized by a surface relaxation. The (001) surface of the single-phase multiferroic BiFeO3 which is ferroelectric and antiferromagnetic, shows clear ferroelectric work function contrast in PEEM. Additionally, the multiferroic domains show significant linear dichroism. The observation of a varying dichroism for different ferroelectric domains can be explained based on the coupled ferroelectric-antiferromagnetic order in BiFeO3. It demonstrates multiferroic imaging of different domain types within a single, lab-based experiment.

Creation of a Ligand-Dependent Enzyme by Fusing Circularly Permuted Antibody Variable Region Domains.

PubMed

Iwai, Hiroto; Kojima-Misaizu, Miki; Dong, Jinhua; Ueda, Hiroshi

2016-04-20

Allosteric control of enzyme activity with exogenous substances has been hard to achieve, especially using antibody domains that potentially allow control by any antigens of choice. Here, in order to attain this goal, we developed a novel antibody variable region format introduced with circular permutations, called Clampbody. The two variable-region domains of the antibone Gla protein (BGP) antibody were each circularly permutated to have novel termini at the loops near their domain interface. Through their attachment to the N- and C-termini of a circularly permutated TEM-1 β-lactamase (cpBLA), we created a molecular switch that responds to the antigen peptide. The fusion protein specifically recognized the antigen, and in the presence of some detergent or denaturant, its catalytic activity was enhanced up to 4.7-fold in an antigen-dependent manner, due to increased resistance to these reagents. Hence, Clampbody will be a powerful tool for the allosteric regulation of enzyme and other protein activities and especially useful to design robust biosensors.

Thermal Sensitivity of MD Hematite: Implication for Magnetic Anomalies

NASA Technical Reports Server (NTRS)

Kletetschka, Gunther; Wasilewski, Peter J.; Taylor, Patrick T.

1999-01-01

Magnetic remanence of crustal rocks can reside in three common rock-forming magnetic minerals: magnetite, pyrrhotite, and hematite. Thermoremanent magnetization (TRM) of magnetite and pyrrhotite is carried mostly by single domain (SD) grains. The TRM of hematite grains, however, is carried mostly by multidomain (NM) grains. This characteristic is illustrated by TRM acquisition curves for hematite of variable grainsizes. The transition between truly NM behavior and tendency towards SD behavior his been established between hematite grainsizes of 0. 1 and 0.05 mm. Coarse grainsize of lower crustal rocks and the large sensitivity of MD hematite grains to acquire TRM indicates that hematite could be a significant contributor to long-wavelength magnetic anomalies.

Generation of single domain antibody fragments derived from camelids and generation of manifold constructs.

PubMed

Vincke, Cécile; Gutiérrez, Carlos; Wernery, Ulrich; Devoogdt, Nick; Hassanzadeh-Ghassabeh, Gholamreza; Muyldermans, Serge

2012-01-01

Immunizing a camelid (camels and llamas) with soluble, properly folded proteins raises an affinity-matured immune response in the unique camelid heavy-chain only antibodies (HCAbs). The peripheral blood lymphocytes of the immunized animal are used to clone the antigen-binding antibody fragment from the HCAbs in a phage display vector. A representative aliquot of the library of these antigen-binding fragments is used to retrieve single domain antigen-specific binders by successive rounds of panning. These single domain antibody fragments are cloned in tandem to generate manifold constructs (bivalent, biparatopic or bispecific constructs) to increase their functional affinity, to increase specificity, or to connect two independent antigen molecules.

Generation of Potent T-cell Immunotherapy for Cancer using DAP12-based, Multichain, Chimeric Immunoreceptors

PubMed Central

Wang, Enxiu; Wang, Liang-Chuan; Tsai, Ching-Yi; Bhoj, Vijay; Gershenson, Zack; Moon, Edmund; Newick, Kheng; Sun, Jing; Lo, Albert; Baradet, Timothy; Feldman, Michael D.; Barrett, David; Puré, Ellen; Albelda, Steven; Milone, Michael C.

2015-01-01

Chimeric antigen receptors (CAR) bearing an antigen-binding domain linked in cis to the cytoplasmic domains of CD3ζ and costimulatory receptors have provided a potent method for engineering T-cell cytotoxicity towards B-cell leukemia and lymphoma. However, resistance to immunotherapy due to loss of T-cell effector function remains a significant barrier, especially in solid malignancies. We describe an alternative chimeric immunoreceptor design in which we have fused a single-chain variable fragment for antigen recognition to the transmembrane and cytoplasmic domains of KIR2DS2, a stimulatory killer immunoglobulin-like receptor (KIR). We show that this simple, KIR-based CAR (KIR-CAR) triggers robust antigen-specific proliferation and effector function in vitro when introduced into human T cells with DAP12, an immunotyrosine-based activation motifs (ITAM)-containing adaptor. T cells modified to express a KIR-CAR and DAP12 exhibit superior antitumor activity compared to standard first and second generation CD3ζ-based CARs in a xenograft model of mesothelioma highly resistant to immunotherapy. The enhanced antitumor activity is associated with improved retention of chimeric immunoreceptor expression and improved effector function of isolated tumor-infiltrating lymphocytes. These results support the exploration of KIR-CARs for adoptive T-cell immunotherapy, particularly in immunotherapy-resistant solid tumors. PMID:25941351

Monovalent IgG4 molecules

PubMed Central

Wilkinson, Ian C.; Fowler, Susan B.; Machiesky, LeeAnn; Miller, Kenneth; Hayes, David B.; Adib, Morshed; Her, Cheng; Borrok, M. Jack; Tsui, Ping; Burrell, Matthew; Corkill, Dominic J.; Witt, Susanne; Lowe, David C.; Webster, Carl I.

2013-01-01

Antibodies have become the fastest growing class of biological therapeutics, in part due to their exquisite specificity and ability to modulate protein-protein interactions with a high biological potency. The relatively large size and bivalency of antibodies, however, limits their use as therapeutics in certain circumstances. Antibody fragments, such as single-chain variable fragments and antigen binding-fragments, have emerged as viable alternatives, but without further modifications these monovalent formats have reduced terminal serum half-lives because of their small size and lack of an Fc domain, which is required for FcRn-mediated recycling. Using rational engineering of the IgG4 Fc domain to disrupt key interactions at the CH3-CH3 interface, we identified a number of point mutations that abolish Fc dimerization and created half-antibodies, a novel monovalent antibody format that retains a monomeric Fc domain. Introduction of these mutations into an IgG1 framework also led to the creation of half-antibodies. These half-antibodies were shown to be soluble, thermodynamically stable and monomeric, characteristics that are favorable for use as therapeutic proteins. Despite significantly reduced FcRn binding in vitro, which suggests that avidity gains in a dimeric Fc are critical to optimal FcRn binding, this format demonstrated an increased terminal serum half-life compared with that expected for most alternative antibody fragments. PMID:23567207

Associated and mediating variables related to quality of life among service users with mental disorders.

PubMed

Fleury, Marie-Josée; Grenier, Guy; Bamvita, Jean-Marie

2018-02-01

This study aimed to identify variables associated with quality of life (QoL) and mediating variables among 338 service users with mental disorders in Quebec (Canada). Data were collected using nine standardized questionnaires and participant medical records. Quality of life was assessed with the Satisfaction with Life Domains Scale. Independent variables were organized into a six-block conceptual framework. Using structural equation modeling, associated and mediating variables related to QoL were identified. Lower seriousness of needs was the strongest variable associated with QoL, followed by recovery, greater service continuity, gender (male), adequacy of help received, not living alone, absence of substance use or mood disorders, and higher functional status, in that order. Recovery was the single mediating variable linking lower seriousness of needs, higher service continuity, and reduced alcohol use with QoL. Findings suggest that greater service continuity creates favorable conditions for recovery, reducing seriousness of needs and increasing QoL among service users. Lack of recovery-oriented services may affect QoL among alcohol users, as substance use disorders were associated directly and negatively with QoL. Decision makers and mental health professionals should promote service continuity, and closer collaboration between primary care and specialized services, while supporting recovery-oriented services that encourage service user involvement in their treatment and follow-up. Community-based organizations should aim to reduce the seriousness of needs particularly for female service users and those living alone.

Analysis of hepatitis B virus preS1 variability and prevalence of the rs2296651 polymorphism in a Spanish population

PubMed Central

Casillas, Rosario; Tabernero, David; Gregori, Josep; Belmonte, Irene; Cortese, Maria Francesca; González, Carolina; Riveiro-Barciela, Mar; López, Rosa Maria; Quer, Josep; Esteban, Rafael; Buti, Maria; Rodríguez-Frías, Francisco

2018-01-01

AIM To determine the variability/conservation of the domain of hepatitis B virus (HBV) preS1 region that interacts with sodium-taurocholate cotransporting polypeptide (hereafter, NTCP-interacting domain) and the prevalence of the rs2296651 polymorphism (S267F, NTCP variant) in a Spanish population. METHODS Serum samples from 246 individuals were included and divided into 3 groups: patients with chronic HBV infection (CHB) (n = 41, 73% Caucasians), patients with resolved HBV infection (n = 100, 100% Caucasians) and an HBV-uninfected control group (n = 105, 100% Caucasians). Variability/conservation of the amino acid (aa) sequences of the NTCP-interacting domain, (aa 2-48 in viral genotype D) and a highly conserved preS1 domain associated with virion morphogenesis (aa 92-103 in viral genotype D) were analyzed by next-generation sequencing and compared in 18 CHB patients with viremia > 4 log IU/mL. The rs2296651 polymorphism was determined in all individuals in all 3 groups using an in-house real-time PCR melting curve analysis. RESULTS The HBV preS1 NTCP-interacting domain showed a high degree of conservation among the examined viral genomes especially between aa 9 and 21 (in the genotype D consensus sequence). As compared with the virion morphogenesis domain, the NTCP-interacting domain had a smaller proportion of HBV genotype-unrelated changes comprising > 1% of the quasispecies (25.5% vs 31.8%), but a larger proportion of genotype-associated viral polymorphisms (34% vs 27.3%), according to consensus sequences from GenBank patterns of HBV genotypes A to H. Variation/conservation in both domains depended on viral genotype, with genotype C being the most highly conserved and genotype E the most variable (limited finding, only 2 genotype E included). Of note, proline residues were highly conserved in both domains, and serine residues showed changes only to threonine or tyrosine in the virion morphogenesis domain. The rs2296651 polymorphism was not detected in any participant. CONCLUSION In our CHB population, the NTCP-interacting domain was highly conserved, particularly the proline residues and essential amino acids related with the NTCP interaction, and the prevalence of rs2296651 was low/null. PMID:29456407

Cognitive components of a mathematical processing network in 9-year-old children.

PubMed

Szűcs, Dénes; Devine, Amy; Soltesz, Fruzsina; Nobes, Alison; Gabriel, Florence

2014-07-01

We determined how various cognitive abilities, including several measures of a proposed domain-specific number sense, relate to mathematical competence in nearly 100 9-year-old children with normal reading skill. Results are consistent with an extended number processing network and suggest that important processing nodes of this network are phonological processing, verbal knowledge, visuo-spatial short-term and working memory, spatial ability and general executive functioning. The model was highly specific to predicting arithmetic performance. There were no strong relations between mathematical achievement and verbal short-term and working memory, sustained attention, response inhibition, finger knowledge and symbolic number comparison performance. Non-verbal intelligence measures were also non-significant predictors when added to our model. Number sense variables were non-significant predictors in the model and they were also non-significant predictors when entered into regression analysis with only a single visuo-spatial WM measure. Number sense variables were predicted by sustained attention. Results support a network theory of mathematical competence in primary school children and falsify the importance of a proposed modular 'number sense'. We suggest an 'executive memory function centric' model of mathematical processing. Mapping a complex processing network requires that studies consider the complex predictor space of mathematics rather than just focusing on a single or a few explanatory factors.

Cognitive components of a mathematical processing network in 9-year-old children

PubMed Central

Szűcs, Dénes; Devine, Amy; Soltesz, Fruzsina; Nobes, Alison; Gabriel, Florence

2014-01-01

We determined how various cognitive abilities, including several measures of a proposed domain-specific number sense, relate to mathematical competence in nearly 100 9-year-old children with normal reading skill. Results are consistent with an extended number processing network and suggest that important processing nodes of this network are phonological processing, verbal knowledge, visuo-spatial short-term and working memory, spatial ability and general executive functioning. The model was highly specific to predicting arithmetic performance. There were no strong relations between mathematical achievement and verbal short-term and working memory, sustained attention, response inhibition, finger knowledge and symbolic number comparison performance. Non-verbal intelligence measures were also non-significant predictors when added to our model. Number sense variables were non-significant predictors in the model and they were also non-significant predictors when entered into regression analysis with only a single visuo-spatial WM measure. Number sense variables were predicted by sustained attention. Results support a network theory of mathematical competence in primary school children and falsify the importance of a proposed modular ‘number sense’. We suggest an ‘executive memory function centric’ model of mathematical processing. Mapping a complex processing network requires that studies consider the complex predictor space of mathematics rather than just focusing on a single or a few explanatory factors. PMID:25089322

Medication adherence among patients in a chronic disease clinic.

PubMed

Tourkmani, Ayla M; Al Khashan, Hisham I; Albabtain, Monirah A; Al Harbi, Turki J; Al Qahatani, Hala B; Bakhiet, Ahmed H

2012-12-01

To assess motivation and knowledge domains of medication adherence intention, and to determine their predictors in an ambulatory setting. We conducted a cross-sectional survey study among patients attending a chronic disease clinic at the Family and Community Medicine Department, Prince Sultan Military Medical City, Riyadh, Kingdom of Saudi Arabia between June and September 2010. Adherence intention was assessed using Modified Morisky Scale. Predictors of low motivation and/or knowledge were determined using logistic regression models. A total of 347 patients were interviewed during the study duration. Most patients (75.5%) had 2 or more chronic diseases with an average of 6.3 +/- 2.3 medications, and 6.5 +/- 2.9 pills per prescription. The frequency of adherence intention was low (4.6%), variable (37.2%), and high (58.2%). In multivariate logistic regression analysis, younger age and having asthma were significantly associated with low motivation, while male gender, single status, and not having hypertension were significantly associated with low knowledge. Single status was the only independent predictor of low adherence intention. In a population with multiple chronic diseases and high illiteracy rate, more than 40% had low/variable intention to adhere to prescribed medications. Identifying predictors of this group may help in providing group-specific interventional programs.

Phase coexistence and domain configuration in Pb(Mg1/3Nb2/3)O3-0.34PbTiO3 single crystal revealed by synchrotron-based X-ray diffractive three-dimensional reciprocal space mapping and piezoresponse force microscopy

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

Wang, Ruixue; Xu, Han; Yang, Bin

The crystalline phases and domain configuration in the morphotropic phase boundary composition Pb(Mg1/3Nb2/3)O3-0.34PbTiO3 (PMN-0.34PT) single crystal have been investigated by synchrotronbased X-ray 3D Reciprocal Space Mapping (3D-RSM) and Piezoresponse Force Microscopy. The coexistence of tetragonal (T) and monoclinic MC phases in this PMN-0.34PT single crystal is confirmed. The affiliation of each diffraction spot in the 3D-RSM was identified with the assistance of qualitative simulation. Most importantly, the twinning structure between different domains in such a mixed phase PMN-PT crystal is firmly clarified, and the spatial distribution of different twin domains is demonstrated. In addition, the lattice parameters of T andmore » MC phases in PMN-0.34PT single crystal as well as the tilting angles of crystal lattices caused by the interfacial lattice mismatch are determined.« less

Large-Area WS2 Film with Big Single Domains Grown by Chemical Vapor Deposition

NASA Astrophysics Data System (ADS)

Liu, Pengyu; Luo, Tao; Xing, Jie; Xu, Hong; Hao, Huiying; Liu, Hao; Dong, Jingjing

2017-10-01

High-quality WS2 film with the single domain size up to 400 μm was grown on Si/SiO2 wafer by atmospheric pressure chemical vapor deposition. The effects of some important fabrication parameters on the controlled growth of WS2 film have been investigated in detail, including the choice of precursors, tube pressure, growing temperature, holding time, the amount of sulfur powder, and gas flow rate. By optimizing the growth conditions at one atmospheric pressure, we obtained tungsten disulfide single domains with an average size over 100 μm. Raman spectra, atomic force microscopy, and transmission electron microscopy provided direct evidence that the WS2 film had an atomic layer thickness and a single-domain hexagonal structure with a high crystal quality. And the photoluminescence spectra indicated that the tungsten disulfide films showed an evident layer-number-dependent fluorescence efficiency, depending on their energy band structure. Our study provides an important experimental basis for large-area, controllable preparation of atom-thick tungsten disulfide thin film and can also expedite the development of scalable high-performance optoelectronic devices based on WS2 film.

New method for introducing nanometer flux pinning centers into single domain YBCO bulk superconductors

NASA Astrophysics Data System (ADS)

Yang, W. M.; Wang, Miao

2013-10-01

Single domain YBCO superconductors with different additions of Bi2O3 have been fabricated by top seeded infiltration and growth process (TSIG). The effect of Bi2O3 additions on the growth morphology, microstructure and levitation force of the YBCO bulk superconductor has been investigated. The results indicate that single domain YBCO superconductors can be fabricated with the additions of Bi2O3 less than 2 wt%; Bi2O3 can be reacted with Y2BaCuO5 and liquid phase and finally form Y2Ba4CuBiOx(YBi2411) nanoscale particles; the size of the YBi2411 particles is about 100 nm, which can act as effective flux pinning centers. It is also found that the levitation force of single domain YBCO bulks is increasing from 13 N to 34 N and decreasing to 11 N with the increasing of Bi2O3 addition from 0.1 wt% to 0.7 wt% and 2 wt%. This result is helpful for us to improve the physical properties of REBCO bulk superconductors.

Grasping the nettle: A bacterial invasin that targets immunoglobulin variable domains.

PubMed

Barlow, Paul

2018-06-01

In a new paper, the protein InvD from Yersinia pseudotuberculosis , a zoonotic pathogen, is shown to assist late-stage invasion of intestinal epithelia. Remarkably, InvD acts by binding the Fab region of IgG or IgA. It straddles adjacent light-chain and heavy-chain variable domains, but its binding is different from that of antigens in that complementarity-determining regions do not participate. Structure determination revealed that its Fab-interacting domain adopts an immunoglobulin-like fold, fused to the preceding immunoglobulin-like domain and carried on a long stalk anchored to the bacterial outer membrane. Possible roles of this unusual host-pathogen interaction include avoidance of clearance from the intestine by secretory IgA. © 2018 Barlow.

Electron backscatter diffraction as a domain analysis technique in BiFeO(3)-PbTiO(3) single crystals.

PubMed

Burnett, T L; Comyn, T P; Merson, E; Bell, A J; Mingard, K; Hegarty, T; Cain, M

2008-05-01

xBiFeO(3)-(1-x)PbTiO(3) single crystals were grown via a flux method for a range of compositions. Presented here is a study of the domain configuration in the 0.5BiFeO(3)-0.5PbTiO(3) composition using electron backscatter diffraction to demonstrate the ability of the technique to map ferroelastic domain structures at the micron and submicron scale. The micron-scale domains exhibit an angle of approximately 85 degrees between each variant, indicative of a ferroelastic domain wall in a tetragonal system with a spontaneous strain, c/a - 1 of 0.10, in excellent agreement with the lattice parameters derived from x-ray diffraction. Contrast seen in forescatter images is attributed to variations in the direction of the electrical polarization vector, providing images of ferroelectric domain patterns.

Unconventional Magnetic Domain Structure in the Ferromagnetic Phase of MnP Single Crystals

NASA Astrophysics Data System (ADS)

Koyama, Tsukasa; Yano, Shin-ichiro; Togawa, Yoshihiko; Kousaka, Yusuke; Mori, Shigeo; Inoue, Katsuya; Kishine, Jun-ichiro; Akimitsu, Jun

2012-04-01

We have studied ferromagnetic (FM) structures in the FM phase of MnP single crystals by low-temperature Lorentz transmission electron microscopy and small-angle electron diffraction analysis. In Lorentz Fresnel micrographs, striped FM domain structures were observed at an external magnetic field less than 10 Oe in specimens with the ab-plane in their plane. From real- and reciprocal-space analyses, it was clearly identified that striped FM domains oriented to the c-axis appear with Bloch-type domain walls in the b-direction and order regularly along the a-axis with a constant separation less than 100 nm. Moreover, the magnetic chirality reverses in alternate FM domain walls. These specific spin configuration of striped FM domains will affect the magnetic phase transition from the FM phase to the proper screw spiral phase at low temperature or to the FAN phase in magnetic fields in MnP.

Polarization-resolved second-harmonic generation microscopy as a method to visualize protein-crystal domains

PubMed Central

DeWalt, Emma L.; Begue, Victoria J.; Ronau, Judith A.; Sullivan, Shane Z.; Das, Chittaranjan; Simpson, Garth J.

2013-01-01

Polarization-resolved second-harmonic generation (PR-SHG) microscopy is described and applied to identify the presence of multiple crystallographic domains within protein-crystal conglomerates, which was confirmed by synchrotron X-ray diffraction. Principal component analysis (PCA) of PR-SHG images resulted in principal component 2 (PC2) images with areas of contrasting negative and positive values for conglomerated crystals and PC2 images exhibiting uniformly positive or uniformly negative values for single crystals. Qualitative assessment of PC2 images allowed the identification of domains of different internal ordering within protein-crystal samples as well as differentiation between multi-domain conglomerated crystals and single crystals. PR-SHG assessments of crystalline domains were in good agreement with spatially resolved synchrotron X-ray diffraction measurements. These results have implications for improving the productive throughput of protein structure determination through early identification of multi-domain crystals. PMID:23275165

Dynamics and Adaptive Benefits of Protein Domain Emergence and Arrangements during Plant Genome Evolution

PubMed Central

Kersting, Anna R.; Bornberg-Bauer, Erich; Moore, Andrew D.; Grath, Sonja

2012-01-01

Plant genomes are generally very large, mostly paleopolyploid, and have numerous gene duplicates and complex genomic features such as repeats and transposable elements. Many of these features have been hypothesized to enable plants, which cannot easily escape environmental challenges, to rapidly adapt. Another mechanism, which has recently been well described as a major facilitator of rapid adaptation in bacteria, animals, and fungi but not yet for plants, is modular rearrangement of protein-coding genes. Due to the high precision of profile-based methods, rearrangements can be well captured at the protein level by characterizing the emergence, loss, and rearrangements of protein domains, their structural, functional, and evolutionary building blocks. Here, we study the dynamics of domain rearrangements and explore their adaptive benefit in 27 plant and 3 algal genomes. We use a phylogenomic approach by which we can explain the formation of 88% of all arrangements by single-step events, such as fusion, fission, and terminal loss of domains. We find many domains are lost along every lineage, but at least 500 domains are novel, that is, they are unique to green plants and emerged more or less recently. These novel domains duplicate and rearrange more readily within their genomes than ancient domains and are overproportionally involved in stress response and developmental innovations. Novel domains more often affect regulatory proteins and show a higher degree of structural disorder than ancient domains. Whereas a relatively large and well-conserved core set of single-domain proteins exists, long multi-domain arrangements tend to be species-specific. We find that duplicated genes are more often involved in rearrangements. Although fission events typically impact metabolic proteins, fusion events often create new signaling proteins essential for environmental sensing. Taken together, the high volatility of single domains and complex arrangements in plant genomes demonstrate the importance of modularity for environmental adaptability of plants. PMID:22250127

Multipoint to multipoint routing and wavelength assignment in multi-domain optical networks

NASA Astrophysics Data System (ADS)

Qin, Panke; Wu, Jingru; Li, Xudong; Tang, Yongli

2018-01-01

In multi-point to multi-point (MP2MP) routing and wavelength assignment (RWA) problems, researchers usually assume the optical networks to be a single domain. However, the optical networks develop toward to multi-domain and larger scale in practice. In this context, multi-core shared tree (MST)-based MP2MP RWA are introduced problems including optimal multicast domain sequence selection, core nodes belonging in which domains and so on. In this letter, we focus on MST-based MP2MP RWA problems in multi-domain optical networks, mixed integer linear programming (MILP) formulations to optimally construct MP2MP multicast trees is presented. A heuristic algorithm base on network virtualization and weighted clustering algorithm (NV-WCA) is proposed. Simulation results show that, under different traffic patterns, the proposed algorithm achieves significant improvement on network resources occupation and multicast trees setup latency in contrast with the conventional algorithms which were proposed base on a single domain network environment.

The Super Tuesday Outbreak: Forecast Sensitivities to Single-Moment Microphysics Schemes

NASA Technical Reports Server (NTRS)

Molthan, Andrew L.; Case, Jonathan L.; Dembek, Scott R.; Jedlovec, Gary J.; Lapenta, William M.

2008-01-01

Forecast precipitation and radar characteristics are used by operational centers to guide the issuance of advisory products. As operational numerical weather prediction is performed at increasingly finer spatial resolution, convective precipitation traditionally represented by sub-grid scale parameterization schemes is now being determined explicitly through single- or multi-moment bulk water microphysics routines. Gains in forecasting skill are expected through improved simulation of clouds and their microphysical processes. High resolution model grids and advanced parameterizations are now available through steady increases in computer resources. As with any parameterization, their reliability must be measured through performance metrics, with errors noted and targeted for improvement. Furthermore, the use of these schemes within an operational framework requires an understanding of limitations and an estimate of biases so that forecasters and model development teams can be aware of potential errors. The National Severe Storms Laboratory (NSSL) Spring Experiments have produced daily, high resolution forecasts used to evaluate forecast skill among an ensemble with varied physical parameterizations and data assimilation techniques. In this research, high resolution forecasts of the 5-6 February 2008 Super Tuesday Outbreak are replicated using the NSSL configuration in order to evaluate two components of simulated convection on a large domain: sensitivities of quantitative precipitation forecasts to assumptions within a single-moment bulk water microphysics scheme, and to determine if these schemes accurately depict the reflectivity characteristics of well-simulated, organized, cold frontal convection. As radar returns are sensitive to the amount of hydrometeor mass and the distribution of mass among variably sized targets, radar comparisons may guide potential improvements to a single-moment scheme. In addition, object-based verification metrics are evaluated for their utility in gauging model performance and QPF variability.

Using the domain identification model to study major and career decision-making processes

NASA Astrophysics Data System (ADS)

Tendhar, Chosang; Singh, Kusum; Jones, Brett D.

2018-03-01

The purpose of this study was to examine the extent to which (1) a domain identification model could be used to predict students' engineering major and career intentions and (2) the MUSIC Model of Motivation components could be used to predict domain identification. The data for this study were collected from first-year engineering students. We used a structural equation model to test the hypothesised relationship between variables in the partial domain identification model. The findings suggested that engineering identification significantly predicted engineering major intentions and career intentions and had the highest effect on those two variables compared to other motivational constructs. Furthermore, results suggested that success, interest, and caring are plausible contributors to students' engineering identification. Overall, there is strong evidence that the domain identification model can be used as a lens to study career decision-making processes in engineering, and potentially, in other fields as well.

Linguistic explanation and domain specialization: a case study in bound variable anaphora.

PubMed

Adger, David; Svenonius, Peter

2015-01-01

The core question behind this Frontiers research topic is whether explaining linguistic phenomena requires appeal to properties of human cognition that are specialized to language. We argue here that investigating this issue requires taking linguistic research results seriously, and evaluating these for domain-specificity. We present a particular empirical phenomenon, bound variable interpretations of pronouns dependent on a quantifier phrase, and argue for a particular theory of this empirical domain that is couched at a level of theoretical depth which allows its principles to be evaluated for domain-specialization. We argue that the relevant principles are specialized when they apply in the domain of language, even if analogs of them are plausibly at work elsewhere in cognition or the natural world more generally. So certain principles may be specialized to language, though not, ultimately, unique to it. Such specialization is underpinned by ultimately biological factors, hence part of UG.

Linguistic explanation and domain specialization: a case study in bound variable anaphora

PubMed Central

Adger, David; Svenonius, Peter

2015-01-01

The core question behind this Frontiers research topic is whether explaining linguistic phenomena requires appeal to properties of human cognition that are specialized to language. We argue here that investigating this issue requires taking linguistic research results seriously, and evaluating these for domain-specificity. We present a particular empirical phenomenon, bound variable interpretations of pronouns dependent on a quantifier phrase, and argue for a particular theory of this empirical domain that is couched at a level of theoretical depth which allows its principles to be evaluated for domain-specialization. We argue that the relevant principles are specialized when they apply in the domain of language, even if analogs of them are plausibly at work elsewhere in cognition or the natural world more generally. So certain principles may be specialized to language, though not, ultimately, unique to it. Such specialization is underpinned by ultimately biological factors, hence part of UG. PMID:26441791

Structure-based engineering to restore high affinity binding of an isoform-selective anti-TGFβ1 antibody

PubMed Central

Honey, Denise M.; Best, Annie; Qiu, Huawei

2018-01-01

ABSTRACT Metelimumab (CAT192) is a human IgG4 monoclonal antibody developed as a TGFβ1-specific antagonist. It was tested in clinical trials for the treatment of scleroderma but later terminated due to lack of efficacy. Subsequent characterization of CAT192 indicated that its TGFβ1 binding affinity was reduced by ∼50-fold upon conversion from the parental single-chain variable fragment (scFv) to IgG4. We hypothesized this result was due to decreased conformational flexibility of the IgG that could be altered via engineering. Therefore, we designed insertion mutants in the elbow region and screened for binding and potency. Our results indicated that increasing the elbow region linker length in each chain successfully restored the isoform-specific and high affinity binding of CAT192 to TGFβ1. The crystal structure of the high binding affinity mutant displays large conformational rearrangements of the variable domains compared to the wild-type antigen-binding fragment (Fab) and the low binding affinity mutants. Insertion of two glycines in both the heavy and light chain elbow regions provided sufficient flexibility for the variable domains to extend further apart than the wild-type Fab, and allow the CDR3s to make additional interactions not seen in the wild-type Fab structure. These interactions coupled with the dramatic conformational changes provide a possible explanation of how the scFv and elbow-engineered Fabs bind TGFβ1 with high affinity. This study demonstrates the benefits of re-examining both structure and function when converting scFv to IgG molecules, and highlights the potential of structure-based engineering to produce fully functional antibodies. PMID:29333938

Flexibility and adaptability in binding of E. coli cytidine repressor to different operators suggests a role in differential gene regulation.

PubMed

Tretyachenko-Ladokhina, Vira; Cocco, Melanie J; Senear, Donald F

2006-09-15

Interactions between DNA-bound transcription factors CytR and CRP regulate the promoters of the Escherichia coli CytR regulon. A distinctive feature of the palindromic CytR operators is highly variable length central spacers (0-9 bp). Previously we demonstrated distinct modes of CytR binding to operators that differ in spacer length. These different modes are characterized by opposite enthalpic and entropic contributions at 25 degrees C. Of particular note were radically different negative DeltaCp values suggesting variable contribution from coupled protein folding and/or DNA structural transitions. We proposed that the CytR DNA binding-domain adopts either a more rigid or flexible DNA-bound conformation in response to the different spacer lengths. More recently, similar effects were shown to contribute to discrimination between operator and non-specific DNA binding by LacR, a CytR homolog. Here we have extended the thermodynamic analysis to the remaining natural CytR operators plus a set of synthetic operators designed to isolate spacing as the single variable. The thermodynamic results show a broad and monotonic range of effects that are primarily dependent on spacer length. The magnitude of effects suggests participation by more than the DNA-binding domain. 15N HSQC NMR and CD spectral analyses were employed to characterize the structural basis for these effects. The results indicate that while CytR forms a well-ordered structure in solution, it is highly dynamic. We propose a model in which a large ensemble of native state conformations narrows upon binding, to an extent governed by operator spacing. This in turn is expected to constrain intermolecular interactions in the CytR-CRP-DNA complex, thus generating operator-specific effects on repression and induction of transcription.

Single TRAM domain RNA-binding proteins in Archaea: functional insight from Ctr3 from the Antarctic methanogen Methanococcoides burtonii.

PubMed

Taha; Siddiqui, K S; Campanaro, S; Najnin, T; Deshpande, N; Williams, T J; Aldrich-Wright, J; Wilkins, M; Curmi, P M G; Cavicchioli, R

2016-09-01

TRAM domain proteins present in Archaea and Bacteria have a β-barrel shape with anti-parallel β-sheets that form a nucleic acid binding surface; a structure also present in cold shock proteins (Csps). Aside from protein structures, experimental data defining the function of TRAM domains is lacking. Here, we explore the possible functional properties of a single TRAM domain protein, Ctr3 (cold-responsive TRAM domain protein 3) from the Antarctic archaeon Methanococcoides burtonii that has increased abundance during low temperature growth. Ribonucleic acid (RNA) bound by Ctr3 in vitro was determined using RNA-seq. Ctr3-bound M. burtonii RNA with a preference for transfer (t)RNA and 5S ribosomal RNA, and a potential binding motif was identified. In tRNA, the motif represented the C loop; a region that is conserved in tRNA from all domains of life and appears to be solvent exposed, potentially providing access for Ctr3 to bind. Ctr3 and Csps are structurally similar and are both inferred to function in low temperature translation. The broad representation of single TRAM domain proteins within Archaea compared with their apparent absence in Bacteria, and scarcity of Csps in Archaea but prevalence in Bacteria, suggests they represent distinct evolutionary lineages of functionally equivalent RNA-binding proteins. © 2016 Society for Applied Microbiology and John Wiley & Sons Ltd.

Insensitivity of single particle time domain measurements to laser velocimeter 'Doppler ambiguity.'

NASA Technical Reports Server (NTRS)

Johnson, D. A.

1973-01-01

It is shown that single particle time domain measurements in high speed gas flows obtained by a laser velocimeter technique developed for use in wind tunnels are not affected by the so-called 'Doppler ambiguity.' A comparison of hot-wire anemometer and laser velocimeter measurements taken under similar flow conditions is used for the demonstration.

Large single domain 123 material produced by seeding with single crystal rare earth barium copper oxide single crystals

DOEpatents

Todt, V.; Miller, D.J.; Shi, D.; Sengupta, S.

1998-07-07

A method of fabricating bulk YBa{sub 2}Cu{sub 3}O{sub x} where compressed powder oxides and/or carbonates of Y and Ba and Cu present in mole ratios to form YBa{sub 2}Cu{sub 3}O{sub x} are heated in the presence of a Nd{sub 1+x}Ba{sub 2{minus}x}Cu{sub 3}O{sub y} seed crystal to a temperature sufficient to form a liquid phase in the YBa{sub 2}Cu{sub 3}O{sub x} while maintaining the seed crystal solid. The materials are slowly cooled to provide a YBa{sub 2}Cu{sub 3}O{sub x} material having a predetermined number of domains between 1 and 5. Crack-free single domain materials can be formed using either plate shaped seed crystals or cube shaped seed crystals with a pedestal of preferential orientation material. 7 figs.

Large single domain 123 material produced by seeding with single crystal rare earth barium copper oxide single crystals

DOEpatents

Todt, Volker; Miller, Dean J.; Shi, Donglu; Sengupta, Suvankar

1998-01-01

A method of fabricating bulk YBa.sub.2 Cu.sub.3 O.sub.x where compressed powder oxides and/or carbonates of Y and Ba and Cu present in mole ratios to form YBa.sub.2 Cu.sub.3 O.sub.x are heated in the presence of a Nd.sub.1+x Ba.sub.2-x Cu.sub.3 O.sub.y seed crystal to a temperature sufficient to form a liquid phase in the YBa.sub.2 Cu.sub.3 O.sub.x while maintaining the seed crystal solid. The materials are slowly cooled to provide a YBa.sub.2 Cu.sub.3 O.sub.x material having a predetermined number of domains between 1 and 5. Crack-free single domain materials can be formed using either plate shaped seed crystals or cube shaped seed crystals with a pedestal of preferential orientation material.

Structure analysis of the single-domain Si(111)4 × 1-In surface by μ-probe Auger electron diffraction and μ-probe reflection high energy electron diffraction

NASA Astrophysics Data System (ADS)

Nakamura, N.; Anno, K.; Kono, S.

1991-10-01

A single-domain Si(111)4 × 1-In surface has been studied by μ-probe reflection high-energy electron diffraction (RHEED) to elucidate the symmetry of the 4 × 1 surface. Azimuthal diffraction patterns of In MNN Auger electron have been obtained by a μ-probe Auger electron diffraction (AED) apparatus from the single-domain Si(111)4 × 1-In surface. On the basis of information from scanning tunneling microscopy [J. Microsc. 152 (1988) 727] and under the assumption that the 4 × 1 surface is composed of In-overlayers, the μ-probe AED patterns were kinematically analyzed to reach a concrete model of indium arrangement.

Single-pixel imaging based on compressive sensing with spectral-domain optical mixing

NASA Astrophysics Data System (ADS)

Zhu, Zhijing; Chi, Hao; Jin, Tao; Zheng, Shilie; Jin, Xiaofeng; Zhang, Xianmin

2017-11-01

In this letter a single-pixel imaging structure is proposed based on compressive sensing using a spatial light modulator (SLM)-based spectrum shaper. In the approach, an SLM-based spectrum shaper, the pattern of which is a predetermined pseudorandom bit sequence (PRBS), spectrally codes the optical pulse carrying image information. The energy of the spectrally mixed pulse is detected by a single-pixel photodiode and the measurement results are used to reconstruct the image via a sparse recovery algorithm. As the mixing of the image signal and the PRBS is performed in the spectral domain, optical pulse stretching, modulation, compression and synchronization in the time domain are avoided. Experiments are implemented to verify the feasibility of the approach.

Direct Growth of Graphene on Silicon by Metal-Free Chemical Vapor Deposition

NASA Astrophysics Data System (ADS)

Tai, Lixuan; Zhu, Daming; Liu, Xing; Yang, Tieying; Wang, Lei; Wang, Rui; Jiang, Sheng; Chen, Zhenhua; Xu, Zhongmin; Li, Xiaolong

2018-06-01

The metal-free synthesis of graphene on single-crystal silicon substrates, the most common commercial semiconductor, is of paramount significance for many technological applications. In this work, we report the growth of graphene directly on an upside-down placed, single-crystal silicon substrate using metal-free, ambient-pressure chemical vapor deposition. By controlling the growth temperature, in-plane propagation, edge-propagation, and core-propagation, the process of graphene growth on silicon can be identified. This process produces atomically flat monolayer or bilayer graphene domains, concave bilayer graphene domains, and bulging few-layer graphene domains. This work would be a significant step toward the synthesis of large-area and layer-controlled, high-quality graphene on single-crystal silicon substrates. [Figure not available: see fulltext.

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

Calvo, Eric; Mans, Ben J.; Ribeiro, José M.C.

The mosquito D7 salivary proteins are encoded by a multigene family related to the arthropod odorant-binding protein (OBP) superfamily. Forms having either one or two OBP domains are found in mosquito saliva. Four single-domain and one two-domain D7 proteins from Anopheles gambiae and Aedes aegypti (AeD7), respectively, were shown to bind biogenic amines with high affinity and with a stoichiometry of one ligand per protein molecule. Sequence comparisons indicated that only the C-terminal domain of AeD7 is homologous to the single-domain proteins from A. gambiae, suggesting that the N-terminal domain may bind a different class of ligands. Here, we describemore » the 3D structure of AeD7 and examine the ligand-binding characteristics of the N- and C-terminal domains. Isothermal titration calorimetry and ligand complex crystal structures show that the N-terminal domain binds cysteinyl leukotrienes (cysLTs) with high affinities (50-60 nM) whereas the C-terminal domain binds biogenic amines. The lipid chain of the cysLT binds in a hydrophobic pocket of the N-terminal domain, whereas binding of norepinephrine leads to an ordering of the C-terminal portion of the C-terminal domain into an alpha-helix that, along with rotations of Arg-176 and Glu-268 side chains, acts to bury the bound ligand.« less

How culture shapes the body: cultural consonance and body mass in urban Brazil.

PubMed

Dressler, William W; Oths, Kathryn S; Balieiro, Mauro C; Ribeiro, Rosane P; Dos Santos, José Ernesto

2012-01-01

The aim of this article is to develop a model of how culture shapes the body, based on two studies conducted in urban Brazil. Research was conducted in 1991 and 2001 in four socioeconomically distinct neighborhoods. First, cultural domain analyses were conducted with samples of key informants. The cultural domains investigated included lifestyle, social support, family life, national identity, and food. Cultural consensus analysis was used to confirm shared knowledge in each domain and to derive measures of cultural consonance. Cultural consonance assesses how closely an individual matches the cultural consensus model for each domain. Second, body composition, cultural consonance, and related variables were assessed in community surveys. Multiple regression analysis was used to examine the association of cultural consonance and body composition, controlling for standard covariates and competing explanatory variables. In 1991, in a survey of 260 individuals, cultural consonance had a curvilinear association with the body mass index that differed for men and women, controlling for sociodemographic and dietary variables. In 2001, in a survey of 267 individuals, cultural consonance had a linear association with abdominal circumference that differed for men and women, controlling for sociodemographic and dietary variables. In general, as cultural consonance increases, body mass index and abdominal circumference decline, more strongly for women than men. As individuals, in their own beliefs and behaviors, more closely approximate shared cultural models in socially salient domains, body composition also more closely approximates the cultural prototype of the body. Copyright © 2012 Wiley Periodicals, Inc.

Beating the confusion limit: the necessity of high angular resolution for probing the physics of Sagittarius A* and its environment: opportunities for LINC-NIRVANA (LBT), GRAVITY (VLTI) and and METIS (E-ELT)

NASA Astrophysics Data System (ADS)

Eckart, A.; Sabha, N.; Witzel, G.; Straubmeier, C.; Shahzamanian, B.; Valencia-S., M.; García-Marín, Macarena; Horrobin, M.; Moser, L.; Zuther, J.; Fischer, S.; Rauch, C.; Rost, S.; Iserlohe, C.; Yazici, S.; Smajic, S.; Wiest, M.; Araujo-Hauck, C.; Wank, I.

2012-07-01

The super-massive 4 million solar mass black hole (SMBH) SgrA* shows variable emission from the millimeter to the X-ray domain. A detailed analysis of the infrared light curves allows us to address the accretion phenomenon in a statistical way. The analysis shows that the near-infrared flux density excursions are dominated by a single state power law, with the low states of SgrA* are limited by confusion through the unresolved stellar background. We show that for 8-10m class telescopes blending effects along the line of sight will result in artificial compact star-like objects of 0.5-1 mJy that last for about 3-4 years. We discuss how the imaging capabilities of GRAVITY at the VLTI, LINC-NIRVANA at the LBT and METIS at the E-ELT will contribute to the investigation of the low variability states of SgrA*.

Tethered lives: A couple-based perspective on the consequences of parenthood for time use, occupation, and wages.

PubMed

Killewald, Alexandra; García-Manglano, Javier

2016-11-01

Prior research on parenthood effects has typically used single-sex models and estimated average effects. By contrast, we estimate population-level variability in partners' changes in housework hours, paid work hours, occupation traits, and wages after becoming parents, and we explore whether one partner's adjustment offsets or supplements the other's. We find tradeoffs between spouses on paid work adjustments to parenthood, but complementarity in adjustments to housework hours, occupation traits, and wages. The effect of parenthood on wives' behaviors is larger and more variable than on husbands' behaviors in every domain. The modest variation between husbands in work responses to parenthood explains little of the variation in the motherhood penalty, while variation in wives' own behaviors plays a larger role. We refer to this pattern as tethered autonomy: variation across American couples in work responses to parenthood is shaped primarily by variation in wives' adjustments, while husbands' work acts largely as a fixed point. Copyright © 2016 Elsevier Inc. All rights reserved.

Variable-Domain Functional Regression for Modeling ICU Data.

PubMed

Gellar, Jonathan E; Colantuoni, Elizabeth; Needham, Dale M; Crainiceanu, Ciprian M

2014-12-01

We introduce a class of scalar-on-function regression models with subject-specific functional predictor domains. The fundamental idea is to consider a bivariate functional parameter that depends both on the functional argument and on the width of the functional predictor domain. Both parametric and nonparametric models are introduced to fit the functional coefficient. The nonparametric model is theoretically and practically invariant to functional support transformation, or support registration. Methods were motivated by and applied to a study of association between daily measures of the Intensive Care Unit (ICU) Sequential Organ Failure Assessment (SOFA) score and two outcomes: in-hospital mortality, and physical impairment at hospital discharge among survivors. Methods are generally applicable to a large number of new studies that record a continuous variables over unequal domains.

Biogeographic patterns in below-ground diversity in New York City's Central Park are similar to those observed globally.

PubMed

Ramirez, Kelly S; Leff, Jonathan W; Barberán, Albert; Bates, Scott Thomas; Betley, Jason; Crowther, Thomas W; Kelly, Eugene F; Oldfield, Emily E; Shaw, E Ashley; Steenbock, Christopher; Bradford, Mark A; Wall, Diana H; Fierer, Noah

2014-11-22

Soil biota play key roles in the functioning of terrestrial ecosystems, however, compared to our knowledge of above-ground plant and animal diversity, the biodiversity found in soils remains largely uncharacterized. Here, we present an assessment of soil biodiversity and biogeographic patterns across Central Park in New York City that spanned all three domains of life, demonstrating that even an urban, managed system harbours large amounts of undescribed soil biodiversity. Despite high variability across the Park, below-ground diversity patterns were predictable based on soil characteristics, with prokaryotic and eukaryotic communities exhibiting overlapping biogeographic patterns. Further, Central Park soils harboured nearly as many distinct soil microbial phylotypes and types of soil communities as we found in biomes across the globe (including arctic, tropical and desert soils). This integrated cross-domain investigation highlights that the amount and patterning of novel and uncharacterized diversity at a single urban location matches that observed across natural ecosystems spanning multiple biomes and continents. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

Trajectories of change in self-esteem in older adults: exercise intervention effects.

PubMed

Gothe, Neha P; Mullen, Sean P; Wójcicki, Thomas R; Mailey, Emily L; White, Siobhan M; Olson, Erin A; Szabo, Amanda N; Kramer, Arthur F; McAuley, Edward

2011-08-01

This 12-month, 2 arm, single blind randomized controlled exercise trial examined relationships among changes in multidimensional self-esteem as a function of intervention mode (i.e., walking vs. flexibility-toning-balance). Data were collected on three equidistant occasions (baseline, 6 and 12 months). One-hundred seventy-nine older adults (M(age) = 66.38) began the study and 145 completed assessments at all time points. Participants completed measures of physical and global self-esteem as well as demographic information. There were no significant group differences at baseline on these demographic indicators or esteem variables. Data were analyzed using linear and parallel process growth modeling procedures. Results supported the position that across both groups, domain-level (i.e., physical self-worth) was dependent upon sub-domain-level (i.e., perceived attractiveness, strength, and condition) esteem change. Furthermore, greater improvements were observed in the flexibility-toning-balance group, in terms of perceived strength and attractiveness esteem, compared to the walking group. Our findings support theoretically-based predictions and extend the literature showing unique psychological responses conditional on specific types of physical activities.

Correlates of male cohabiting partner's involvement in child-rearing tasks in low-income urban Black stepfamilies.

PubMed

Forehand, Rex; Parent, Justin; Golub, Andrew; Reid, Megan

2014-06-01

Cohabitation is a family structure experienced by many Black children. This study examines the link between family relationships (child relationship with mother and the cohabiting partner; parent and cohabiting partner relationship) and involvement of biologically unrelated male cohabiting partners (MCP) in child rearing. The participants were 121 low-income urban Black families consisting of a single mother, MCP, and an adolescent (56% female, M age = 13.7). Assessments were conducted individually with mothers, MCPs, and adolescents via measures administered by interview. MCPs were involved in both domains of child rearing assessed (daily child-related tasks and setting limits) and those identified as coparents by the mother were more involved in child-rearing tasks than those not identified as coparents. Using structural equation modeling (SEM), the mother-MCP relationship (both support and conflict) and the adolescent-MCP relationship were related to MCP's involvement in both domains of child rearing. The findings indicate that MCPs are actively involved in child rearing and family relationship variables are associated with their involvement in these tasks. PsycINFO Database Record (c) 2014 APA, all rights reserved.

Retroviral transduction of fluonanobody and the variable domain of camelid heavy-chain antibodies to chicken embryonic cells.

PubMed

Rajabibazl, Masoumeh; Rasaee, Mohammad Javad; Forouzandeh, Mehdi; Rahimpour, Azam

2013-12-01

Single domain antibodies from camel heavy chain antibodies (VHH or nanobody), are advantages due to higher solubility, stability, high homology with human antibody, lower immunogenicity and low molecular weight. These criteria make them candidates for production of engineered antibody fragments particularly in transgenic animals. To study the development of transgenic chicken using a recombinant retrovirus containing fluonanobody. The retrovirus constructs containing nanobody genes along with secretory signals and GFP gene were established and packed. The virus particle containing the obtained fusion gene was injected into the eggs in stage X. Molecular detection and protein analysis was done in the G0 chickens. The rate of hatched chicken after gene manipulation was estimated to be about 33%. Real-Time PCR assay showed that the nanobody along with GFP gene were integrated in cells of 1.2% of chickens. We conclude that although the rate of gene transfer by recombinant viruses in chickens is low, it would be possible to transfect the target camel immunoglobulin gene into chicken genome.

Trajectories of change in self-esteem in older adults: exercise intervention effects

PubMed Central

Gothe, Neha P.; Mullen, Sean P.; Wójcicki, Thomas R.; Mailey, Emily L.; White, Siobhan M.; Olson, Erin A.; Szabo, Amanda N.; Kramer, Arthur F.

2011-01-01

This 12-month, 2 arm, single blind randomized controlled exercise trial examined relationships among changes in multidimensional self-esteem as a function of intervention mode (i.e., walking vs. flexibility-toning-balance). Data were collected on three equidistant occasions (baseline, 6 and 12 months). One-hundred seventy-nine older adults (Mage = 66.38) began the study and 145 completed assessments at all time points. Participants completed measures of physical and global self-esteem as well as demographic information. There were no significant group differences at baseline on these demographic indicators or esteem variables. Data were analyzed using linear and parallel process growth modeling procedures. Results supported the position that across both groups, domain-level (i.e., physical self-worth) was dependent upon sub-domain-level (i.e., perceived attractiveness, strength, and condition) esteem change. Furthermore, greater improvements were observed in the flexibility-toning-balance group, in terms of perceived strength and attractiveness esteem, compared to the walking group. Our findings support theoretically-based predictions and extend the literature showing unique psychological responses conditional on specific types of physical activities. PMID:21222223

Holistic measurement of well-being: psychometric properties of the physical, mental and social well-being scale (PMSW-21) for adults.

PubMed

Supranowicz, Piotr; Paź, Małgorzata

2014-01-01

A holistic approach to health requires the development of tools that would allow to measure the inner world of individuals within its physical, mental and social dimensions. To create the Physical, Mental and Social Well-being scale (PMSW-21) that allows a holistic representation of various dimensions of well-being in such a way as they are perceived by the individuals and how affected their health. The study was conducted on the sample of 406 inhabitants of Warsaw involving in the Social Participation in Health Reform project. The PMSW-21 scale included: headache, tiredness, abdominal pain, palpitation, joint pain, backache, sleep disturbance (physical domain), anxiety, guiltiness, helplessness, hopelessness, sadness, self-dissatisfaction, hostility (mental domain), security, communicability, protection, loneliness, rejection, sociability and appreciation (social domain). The five criterial variables of health and seven of life experiences were adopted to assess the discriminative power of the PMSW-21 scale. The total well-being scale as well as its physical, mental and social domains showed high reliability (Cronbach a 0.81, 0.77, 0.90, 0.72, respectively). The analysis confirmed the construct validity. All the items stronger correlated with their own domain than with the others (ranges for physical: 0.41 - 0.55, mental: 0.49 - 0.80 and social: 0.31 - 0.50). The total scale demonstrate high sensitivity; it significantly differentiated almost all criterial variables. Physical domain showed high sensitivity for health as well as for negative life events variables, while the mental and social domains were more sensitive for life events. The analysis confirmed the usefulness of PMSW-21 scale for measure the holistic well-being. The reliability of the total scale and its domains, construct validity and sensitivity for health and life determinants were at acceptable level.

A comprehensive assessment of memory, delay aversion, timing, inhibition, decision making and variability in attention deficit hyperactivity disorder: advancing beyond the three-pathway models.

PubMed

Coghill, D R; Seth, S; Matthews, K

2014-07-01

Although attention deficit hyperactivity disorder (ADHD) has been associated with a broad range of deficits across various neuropsychological domains, most studies have assessed only a narrow range of neuropsychological functions. Direct cross-domain comparisons are rare, with almost all studies restricted to less than four domains. Therefore, the relationships between these various domains remain undefined. In addition, almost all studies included previously medicated participants, limiting the conclusions that can be drawn. We present the first study to compare a large cohort of medication-naive boys with ADHD with healthy controls on a broad battery of neuropsychological tasks, assessing six key domains of neuropsychological functioning. The neuropsychological functioning of 83 medication-naive boys with well-characterized ADHD (mean age 8.9 years) was compared with that of 66 typically developing (TYP) boys (mean age 9.0 years) on a broad battery of validated neuropsychological tasks. Data reduction using complementary factor analysis (CFA) confirmed six distinct neuropsychological domains: working memory, inhibition, delay aversion, decision making, timing and response variability. Boys with ADHD performed less well across all six domains although, for each domain, only a minority of boys with ADHD had a deficit [effect size (% with deficit) ADHD versus TYP: working memory 0.95 (30.1), inhibition 0.61 (22.9), delay aversion 0.82 (36.1), decision making 0.55 (20.5), timing 0.71 (31.3), response variability 0.37 (18.1)]. The clinical syndrome of ADHD is neuropsychologically heterogeneous. These data highlight the complexity of the relationships between the different neuropsychological profiles associated with ADHD and the clinical symptoms and functional impairment.

Structural diversity of domain superfamilies in the CATH database.

PubMed

Reeves, Gabrielle A; Dallman, Timothy J; Redfern, Oliver C; Akpor, Adrian; Orengo, Christine A

2006-07-14

The CATH database of domain structures has been used to explore the structural variation of homologous domains in 294 well populated domain structure superfamilies, each containing at least three sequence diverse relatives. Our analyses confirm some previously detected trends relating sequence divergence to structural variation but for a much larger dataset and in some superfamilies the new data reveal exceptional structural variation. Use of a new algorithm (2DSEC) to analyse variability in secondary structure compositions across a superfamily sheds new light on how structures evolve. 2DSEC detects inserted secondary structures that embellish the core of conserved secondary structures found throughout the superfamily. Analysis showed that for 56% of highly populated superfamilies (>9 sequence diverse relatives), there are twofold or more increases in the numbers of secondary structures in some relatives. In some families fivefold increases occur, sometimes modifying the fold of the domain. Manual inspection of secondary structure insertions or embellishments in 48 particularly variable superfamilies revealed that although these insertions were usually discontiguous in the sequence they were often co-located in 3D resulting in a larger structural motif that often modified the geometry of the active site or the surface conformation promoting diverse domain partnerships and protein interactions. These observations, supported by automatic analysis of all well populated CATH families, suggest that accretion of small secondary structure insertions may provide a simple mechanism for evolving new functions in diverse relatives. Some layered domain architectures (e.g. mainly-beta and alpha-beta sandwiches) that recur highly in the genomes more frequently exploit these types of embellishments to modify function. In these architectures, aggregation occurs most often at the edges, top or bottom of the beta-sheets. Information on structural variability across domain superfamilies has been made available through the CATH Dictionary of Homologous Structures (DHS).

Production of a novel camel single-domain antibody specific for the type III mutant EGFR.

PubMed

Omidfar, K; Rasaee, M J; Modjtahedi, H; Forouzandeh, M; Taghikhani, M; Golmakani, N

2004-01-01

Camelids have a unique immune system capable of producing single-domain heavy-chain antibodies. The antigen-specific domain of these heavy-chain IgGs (VHH) are the smallest binding units produced by the immune system. In this study, we report the isolation and characterization of several binders against the epidermal growth factor receptor (EGFR) vIII retrieved from immune library of camels (Camelus bactrianus and Camelus dromedarius). The EGFRvIII is a ligand-independent, constitutively active, mutated form of the wild-type EGFR. The expression of EGFRvIII has been demonstrated in a wide range of human malignancies, including gliomas, and breast, prostate, ovarian and lung cancer. Camels were immunized with a synthetic peptide corresponding to a mutated sequence and tissue homogenates. Single-domain antibodies (VHH) were directly selected by panning a phage display library on successively decreasing amounts of synthetic peptide immobilized on magnetic beads. The anti-EGFRvIII camel single-domain antibodies selectively bound to the EGFRvIII peptide and reacted specifically with the immunoaffinity-purified antigen from a non-small cell lung cancer patient. These antibodies with affinities in the nanomolar range recognized the EGFRvIII peptide and affinity-purified mutated receptor. We concluded that using the phage display technique, antigen-specific VHH antibody fragments are readily accessible from the camelids. These antibodies may be good candidates for tumor-diagnostic and therapeutic applications. Copyright 2004 S. Karger AG, Basel.

Spectroscopic Study of the Variability of Three Northern Of+ Supergiants

NASA Astrophysics Data System (ADS)

De Becker, M.; Rauw, G.; Linder, N.

2009-10-01

The transition from early Of stars to WN-type objects is poorly understood. O-type supergiants with emission lines (OIf+) are considered to be intermediate between these two classes. The scope of this paper is to investigate the spectral variability of three Of+ supergiants. We constituted spectral time series of unprecedented quality for our targets (~200 spectra in total), essentially in the blue domain, covering timescales from a few hours up to a few years. Temporal Variance Spectrum and Fourier analyses were performed in order to characterize their spectral variability. We report on a correlated significant line profile variability in the prominent He II λ4686 and Hβ lines most likely related to the strong stellar winds. The variability pattern is similar for the three stars investigated (HD 14947, HD 15570, and HD 16691), and the main differences are more quantitative than qualitative. However, the reported timescales are somewhat different, and the most striking variability pattern is reported for HD 16691. We did not find any clear evidence for binarity, and we focus mainly on an interpretation based on a single-star scenario. We show that the behavior of the three stars investigated in this study present strong similarities, pointing to a putative common scenario, even though a few differences should be noted. Our preferred interpretation scheme is that of Large-Scale Corotating Structures modulating the profile of the lines that are produced in the strong stellar wind. Based on observations collected at the Observatoire de Haute-Provence (France).

Comparisons of estimates of annual exceedance-probability discharges for small drainage basins in Iowa, based on data through water year 2013

USGS Publications Warehouse

Eash, David A.

2015-01-01

An examination was conducted to understand why the 1987 single-variable RREs seem to provide better accuracy and less bias than either of the 2013 multi- or single-variable RREs. A comparison of 1-percent annual exceedance-probability regression lines for hydrologic regions 1-4 from the 1987 single-variable RREs and for flood regions 1-3 from the 2013 single-variable RREs indicates that the 1987 single-variable regional-regression lines generally have steeper slopes and lower discharges when compared to 2013 single-variable regional-regression lines for corresponding areas of Iowa. The combination of the definition of hydrologic regions, the lower discharges, and the steeper slopes of regression lines associated with the 1987 single-variable RREs seem to provide better accuracy and less bias when compared to the 2013 multi- or single-variable RREs; better accuracy and less bias was determined particularly for drainage areas less than 2 mi2, and also for some drainage areas between 2 and 20 mi2. The 2013 multi- and single-variable RREs are considered to provide better accuracy and less bias for larger drainage areas. Results of this study indicate that additional research is needed to address the curvilinear relation between drainage area and AEPDs for areas of Iowa.

Classification of intrinsic variables. IX - The Cepheid domain

NASA Astrophysics Data System (ADS)

Eggen, O. J.

1983-03-01

Intermediate band, Hβ and RI observations have been obtained throughout the cycle of variation for 135 high mass, long-period and short-period cepheids (LPC and SPC). This material, together with the observations previously discussed for some 100 ultrashort periods cepheids (USPC), is used to delineate the cepheid domain in the (β,[C1]) and (MBol,log Te) planes. The independently derived luminosity calibrations for bright giants and supergiants previously published are found to closely reproduce the luminosities derived from the Sandage-Tammann PL relation for most variables. The theoretical "fundamental blue edge," computed by Iben and Tuggle with Y = 0.38, closely represents the blue edge of the cepheid domain.

Preferentially oriented, High temperature superconductors by seeding and a method for their preparation

DOEpatents

Lee, Dominic F.; Kroeger, Donald M.; Goyal, Amit

2001-01-01

A multi-domained bulk REBa.sub.2 Cu.sub.3 O.sub.x with low-angle domain boundaries which resembles a quasi-single domained material and a method for producing the same comprising arranging multiple seeds, which can be small single crystals, single domained melt-textured REBa.sub.2 Cu.sub.3 O.sub.x pieces, textured substrates comprised of grains with low misorientation angles, or thick film REBa.sub.2 Cu.sub.3 O.sub.x deposited on such textured substrate, such seeds being tailored for various REBa.sub.2 Cu.sub.3 O.sub.x compounds, in specific pattern and relative seed orientations on a superconductor precursor material which may be placed in contact with a porous substrate so as to reduce the amount of liquid phase in the melt. Because seeds can be arranged in virtually any pattern, high quality REBa.sub.2 Cu.sub.3 O.sub.x elements of virtually unlimited size and complex geometry can be fabricated.

Method for preparing preferentially oriented, high temperature superconductors using solution reagents

DOEpatents

Lee, Dominic F.; Kroeger, Donald M.; Goyal, Amit

2002-01-01

A multi-domained bulk REBa.sub.2 CU.sub.3 O.sub.x with low-angle domain boundaries which resemble a quasi-single domained material and a method for producing the same comprising arranging multiple seeds, which can be small single crystals, single domained melt-textured REBa.sub.2 CU.sub.3 O.sub.x pieces, textured substrates comprises of grains with low misorientation angles, or thick film REBa.sub.2 CU.sub.3 O.sub.x deposited on such textured substrate, such seeds being tailored for various REBa.sub.2 CU.sub.3 O.sub.x compounds, in specific pattern and relative seed orientations on a superconductor precursor material which may be placed in contact with a porous substrate so as to reduce the amount of liquid phase in the melt. Because seeds can be arranged in virtually any pattern, high quality REBa.sub.2 CU.sub.3 O.sub.x elements of virtually unlimited size and complex geometry can be fabricated.

Comment on 'Detecting uniaxial single domain grains with a modified IRM technique' by R. Mitra, L. Tauxe and J. S. Gee

NASA Astrophysics Data System (ADS)

Fabian, K.

2012-10-01

In a recent article, Mitra et al. (2011) propose a modified IRM technique to identify the symmetry of magnetic anisotropy in single domain particle ensembles. They apply this technique to support an earlier suggestion that single domain grains in young mid-ocean ridge basalts (MORB) exhibit multiaxial anisotropy. Here it is shown that the design of their measurement is flawed, in that they do not take into account that the outcome essentially depends on the initial demagnetization state of the sample before the experiment, and on the coercivity distribution of the sample. Because all MORB specimens measured by Mitra et al. (2011) carried their original NRM, which closely resembles a thermally demagnetized state, their measurements first of all reflect the coercivity distributions and domain states of the samples, and contain little or no information about the symmetry of the magnetic anisotropy. All arguments previously put forward in favour of a dominant uniaxial anisotropy in MORB are therefore still valid.

The work of titin protein folding as a major driver in muscle contraction

PubMed Central

Eckels, Edward C.; Tapia-Rojo, Rafael; Rivas-Pardo, Jamie Andrés; Fernández, Julio M.

2018-01-01

Single molecule atomic force microscopy and magnetic tweezers experiments have demonstrated that titin Ig domains are capable of folding against a pulling force, generating mechanical work which exceeds that produced by a myosin motor. We hypothesize that upon muscle activation, formation of actomyosin crossbridges reduces the force on titin causing entropic recoil of the titin polymer and triggering the folding of the titin Ig domains. In the physiological force range of 4–15 pN under which titin operates in muscle, the folding contraction of a single Ig domain can generate 200% of the work of entropic recoil, and occurs at forces which exceed the maximum stalling force of single myosin motors. Thus titin operates like a mechanical battery storing elastic energy efficiently by unfolding Ig domains, and delivering the charge back by folding when the motors are activated during a contraction. We advance the hypothesis that titin folding and myosin activation act as inextricable partners during muscle contraction. PMID:29433413

Mechanism of SOS PR-domain autoinhibition revealed by single-molecule assays on native protein from lysate

PubMed Central

Lee, Young Kwang; Low-Nam, Shalini T.; Chung, Jean K.; Hansen, Scott D.; Lam, Hiu Yue Monatrice; Alvarez, Steven; Groves, Jay T.

2017-01-01

The guanine nucleotide exchange factor (GEF) Son of Sevenless (SOS) plays a critical role in signal transduction by activating Ras. Here we introduce a single-molecule assay in which individual SOS molecules are captured from raw cell lysate using Ras-functionalized supported membrane microarrays. This enables characterization of the full-length SOS protein, which has not previously been studied in reconstitution due to difficulties in purification. Our measurements on the full-length protein reveal a distinct role of the C-terminal proline-rich (PR) domain to obstruct the engagement of allosteric Ras independently of the well-known N-terminal domain autoinhibition. This inhibitory role of the PR domain limits Grb2-independent recruitment of SOS to the membrane through binding of Ras·GTP in the SOS allosteric binding site. More generally, this assay strategy enables characterization of the functional behaviour of GEFs with single-molecule precision but without the need for purification. PMID:28452363

Mechanism of SOS PR-domain autoinhibition revealed by single-molecule assays on native protein from lysate.

PubMed

Lee, Young Kwang; Low-Nam, Shalini T; Chung, Jean K; Hansen, Scott D; Lam, Hiu Yue Monatrice; Alvarez, Steven; Groves, Jay T

2017-04-28

The guanine nucleotide exchange factor (GEF) Son of Sevenless (SOS) plays a critical role in signal transduction by activating Ras. Here we introduce a single-molecule assay in which individual SOS molecules are captured from raw cell lysate using Ras-functionalized supported membrane microarrays. This enables characterization of the full-length SOS protein, which has not previously been studied in reconstitution due to difficulties in purification. Our measurements on the full-length protein reveal a distinct role of the C-terminal proline-rich (PR) domain to obstruct the engagement of allosteric Ras independently of the well-known N-terminal domain autoinhibition. This inhibitory role of the PR domain limits Grb2-independent recruitment of SOS to the membrane through binding of Ras·GTP in the SOS allosteric binding site. More generally, this assay strategy enables characterization of the functional behaviour of GEFs with single-molecule precision but without the need for purification.

Single Molecule Effects of Osteogenesis Imperfecta Mutations in Tropocollagen Protein Domains

DTIC Science & Technology

2008-12-02

Single molecule effects of osteogenesis imperfecta mutations in tropocollagen protein domains Alfonso Gautieri,1,2 Simone Vesentini,2 Alberto...2008 proteinscience.org Abstract: Osteogenesis imperfecta (OI) is a genetic disease characterized by fragile bones, skeletal deformities and, in severe...diagnosis and treatment, an effort referred to as materiomics. Keywords: steered molecular dynamics; osteogenesis imperfecta ; Young’s modulus; collagen

Structural Biology of Non-Ribosomal Peptide Synthetases

PubMed Central

Miller, Bradley R.; Gulick, Andrew M.

2016-01-01

Summary The non-ribosomal peptide synthetases are modular enzymes that catalyze synthesis of important peptide products from a variety of standard and non-proteinogenic amino acid substrates. Within a single module are multiple catalytic domains that are responsible for incorporation of a single residue. After the amino acid is activated and covalently attached to an integrated carrier protein domain, the substrates and intermediates are delivered to neighboring catalytic domains for peptide bond formation or, in some modules, chemical modification. In the final module, the peptide is delivered to a terminal thioesterase domain that catalyzes release of the peptide product. This multi-domain modular architecture raises questions about the structural features that enable this assembly line synthesis in an efficient manner. The structures of the core component domains have been determined and demonstrate insights into the catalytic activity. More recently, multi-domain structures have been determined and are providing clues to the features of these enzyme systems that govern the functional interaction between multiple domains. This chapter describes the structures of NRPS proteins and the strategies that are being used to assist structural studies of these dynamic proteins, including careful consideration of domain boundaries for generation of truncated proteins and the use of mechanism-based inhibitors that trap interactions between the catalytic and carrier protein domains. PMID:26831698

Phase coexistence and domain configuration in Pb(Mg{sub 1/3}Nb{sub 2/3})O{sub 3}-0.34PbTiO{sub 3} single crystal revealed by synchrotron-based X-ray diffractive three-dimensional reciprocal space mapping and piezoresponse force microscopy

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

Wang, Ruixue; Yang, Bin, E-mail: binyang@hit.edu.cn; Sun, Enwei

The crystalline phases and domain configuration in the morphotropic phase boundary composition Pb(Mg{sub 1/3}Nb{sub 2/3})O{sub 3}-0.34PbTiO{sub 3} (PMN-0.34PT) single crystal have been investigated by synchrotron-based X-ray 3D Reciprocal Space Mapping (3D-RSM) and Piezoresponse Force Microscopy. The coexistence of tetragonal (T) and monoclinic M{sub C} phases in this PMN-0.34PT single crystal is confirmed. The affiliation of each diffraction spot in the 3D-RSM was identified with the assistance of qualitative simulation. Most importantly, the twinning structure between different domains in such a mixed phase PMN-PT crystal is firmly clarified, and the spatial distribution of different twin domains is demonstrated. In addition, themore » lattice parameters of T and M{sub C} phases in PMN-0.34PT single crystal as well as the tilting angles of crystal lattices caused by the interfacial lattice mismatch are determined.« less

Visualization of evolving laser-generated structures by frequency domain tomography

NASA Astrophysics Data System (ADS)

Chang, Yenyu; Li, Zhengyan; Wang, Xiaoming; Zgadzaj, Rafal; Downer, Michael

2011-10-01

We introduce frequency domain tomography (FDT) for single-shot visualization of time-evolving refractive index structures (e.g. laser wakefields, nonlinear index structures) moving at light-speed. Previous researchers demonstrated single-shot frequency domain holography (FDH), in which a probe-reference pulse pair co- propagates with the laser-generated structure, to obtain snapshot-like images. However, in FDH, information about the structure's evolution is averaged. To visualize an evolving structure, we use several frequency domain streak cameras (FDSCs), in each of which a probe-reference pulse pair propagates at an angle to the propagation direction of the laser-generated structure. The combination of several FDSCs constitutes the FDT system. We will present experimental results for a 4-probe FDT system that has imaged the whole-beam self-focusing of a pump pulse propagating through glass in a single laser shot. Combining temporal and angle multiplexing methods, we successfully processed data from four probe pulses in one spectrometer in a single-shot. The output of data processing is a multi-frame movie of the self- focusing pulse. Our results promise the possibility of visualizing evolving laser wakefield structures that underlie laser-plasma accelerators used for multi-GeV electron acceleration.

Single item measures of emotional exhaustion and depersonalization are useful for assessing burnout in medical professionals.

PubMed

West, Colin P; Dyrbye, Liselotte N; Sloan, Jeff A; Shanafelt, Tait D

2009-12-01

Burnout has negative effects on work performance and patient care. The current standard for burnout assessment is the Maslach Burnout Inventory (MBI), a well-validated instrument consisting of 22 items answered on a 7-point Likert scale. However, the length of the MBI can limit its utility in physician surveys. To evaluate the performance of two questions relative to the full MBI for measuring burnout. Cross-sectional data from 2,248 medical students, 333 internal medicine residents, 465 internal medicine faculty, and 7,905 practicing surgeons. The single questions with the highest factor loading on the emotional exhaustion (EE) ("I feel burned out from my work") and depersonalization (DP) ("I have become more callous toward people since I took this job") domains of burnout were evaluated in four large samples of medical students, internal medicine residents, internal medicine faculty, and practicing surgeons. Spearman correlations between the single EE question and the full EE domain score minus that question ranged from 0.76-0.83. Spearman correlations between the single DP question and the full DP domain score minus that question ranged from 0.61-0.72. Responses to the single item measures of emotional exhaustion and depersonalization stratified risk of high burnout in the relevant domain on the full MBI, with consistent patterns across the four sampled groups. Single item measures of emotional exhaustion and depersonalization provide meaningful information on burnout in medical professionals.

Soil conservation service curve number: How to take into account spatial and temporal variability

NASA Astrophysics Data System (ADS)

Rianna, M.; Orlando, D.; Montesarchio, V.; Russo, F.; Napolitano, F.

2012-09-01

The most commonly used method to evaluate rainfall excess, is the Soil Conservation Service (SCS) runoff curve number model. This method is based on the determination of the CN valuethat is linked with a hydrological soil group, cover type, treatment, hydrologic condition and antecedent runoff condition. To calculate the antecedent runoff condition the standard procedure needs to calculate the rainfall over the entire basin during the five days previous to the beginning of the event in order to simulate and then to use that volume of rainfall to calculate the antecedent moisture condition (AMC). This is necessary in order to obtain the correct curve number value. The value of the modified parameter is then kept constant throughout the whole event. The aim of this work is to evaluate the possibility of improving the curve number method. The various assumptions are focused on modifying those related to rainfall and the determination of an AMC condition and their role in the determination of the value of the curve number parameter. In order to consider the spatial variability we assumed that the rainfall which influences the AMC and the CN value does not account for the rainfall over the entire basin, but for the rainfall within a single cell where the basin domain is discretized. Furthermore, in order to consider the temporal variability of rainfall we assumed that the value of the CN of the single cell is not maintained constant during the whole event, but instead varies throughout it according to the time interval used to define the AMC conditions.

What helps and hinders midwives in engaging with pregnant women about stopping smoking? A cross-sectional survey of perceived implementation difficulties among midwives in the North East of England.

PubMed

Beenstock, Jane; Sniehotta, Falko F; White, Martin; Bell, Ruth; Milne, Eugene Mg; Araujo-Soares, Vera

2012-04-24

Around 5,000 miscarriages and 300 perinatal deaths per year result from maternal smoking in the United Kingdom. In the northeast of England, 22% of women smoke at delivery compared to 14% nationally. Midwives have designated responsibilities to help pregnant women stop smoking. We aimed to assess perceived implementation difficulties regarding midwives' roles in smoking cessation in pregnancy. A self-completed, anonymous survey was sent to all midwives in northeast England (n = 1,358) that explores the theoretical explanations for implementation difficulties of four behaviours recommended in the National Institute for Health and Clinical Excellence (NICE) guidance: (a) asking a pregnant woman about her smoking behaviour, (b) referring to the stop-smoking service, (c) giving advice about smoking behaviour, and (d) using a carbon monoxide monitor. Questions covering Michie et al.'s theoretical domain framework (TDF), describing 11 domains of hypothesised behavioural determinants (i.e., 'knowledge', 'skills', 'social/professional role/identity', 'beliefs about capabilities', 'beliefs about consequences', 'motivation and goals', 'memory', 'attention and decision processes', 'environmental context and resources', 'social influences', 'emotion', and 'self-regulation/action planning'), were used to describe perceived implementation difficulties, predict self-reported implementation behaviours, and explore relationships with demographic and professional variables. The overall response rate was 43% (n = 589). The number of questionnaires analysed was 364, following removal of the delivery-unit midwives, who are not directly involved in providing smoking-cessation services. Participants reported few implementation difficulties, high levels of motivation for all four behaviours and identified smoking-cessation work with their role. Midwives were less certain about the consequences of, and the environmental context and resources available for, engaging in this work relative to other TDF domains. All domains were highly correlated. A principal component analysis showed that a single factor ('propensity to act'), derived from all domains, explained 66% of variance in theoretical domain measures. The 'propensity to act' was predictive of the self-reported behaviour 'Refer all women who smoke……to NHS Stop Smoking Services' and mediated the relationship between demographic variables, such as midwives' main place of work, and behaviour. Our findings advance understanding of what facilitates and inhibits midwives' guideline implementation behaviours in relation to smoking cessation and will inform the development of current practice and new interventions. Using the TDF as a self-completion questionnaire is innovative, and this study supports previous research that the TDF is an appropriate tool to understand the behaviour of healthcare professionals.

Interaction of von Willebrand factor domains with collagen investigated by single molecule force spectroscopy

NASA Astrophysics Data System (ADS)

Posch, Sandra; Obser, Tobias; König, Gesa; Schneppenheim, Reinhard; Tampé, Robert; Hinterdorfer, Peter

2018-03-01

von Willebrand factor (VWF) is a huge multimeric protein that plays a key role in primary hemostasis. Sites for collagen binding, an initial event of hemostasis, are located in the VWF-domains A1 and A3. In this study, we investigated single molecule interactions between collagen surfaces and wild type VWF A1A2A3 domain constructs, as well as clinically relevant VWF A3 domain point mutations, such as p.Ser1731Thr, p.Gln1734His, and p.His1786Arg. For this, we utilized atomic force microscopy based single molecular force spectroscopy. The p.Ser1731Thr mutant had no impact on the VWF-collagen type III and VI interactions, while the p.Gln1734His and p.His1786Arg mutants showed a slight increase in bond stability to collagen type III. This effect probably arises from additional hydrogen bonds that come along with the introduction of these mutations. Using the same mutants, but collagen type VI as a binding partner, resulted in a significant increase in bond stability. VWF domain A1 was reported to be essential for the interaction with collagen type VI and thus our findings strengthen the hypothesis that the VWF A1 domain can compensate for mutations in the VWF A3 domain. Additionally, our data suggest that the mutations could even stabilize the interaction between VWF and collagen without shear. VWF-collagen interactions seem to be an important system in which defective interactions between one VWF domain and one type of collagen can be compensated by alternative binding events.

Latent class analysis derived subgroups of low back pain patients - do they have prognostic capacity?

PubMed

Molgaard Nielsen, Anne; Hestbaek, Lise; Vach, Werner; Kent, Peter; Kongsted, Alice

2017-08-09

Heterogeneity in patients with low back pain is well recognised and different approaches to subgrouping have been proposed. One statistical technique that is increasingly being used is Latent Class Analysis as it performs subgrouping based on pattern recognition with high accuracy. Previously, we developed two novel suggestions for subgrouping patients with low back pain based on Latent Class Analysis of patient baseline characteristics (patient history and physical examination), which resulted in 7 subgroups when using a single-stage analysis, and 9 subgroups when using a two-stage approach. However, their prognostic capacity was unexplored. This study (i) determined whether the subgrouping approaches were associated with the future outcomes of pain intensity, pain frequency and disability, (ii) assessed whether one of these two approaches was more strongly or more consistently associated with these outcomes, and (iii) assessed the performance of the novel subgroupings as compared to the following variables: two existing subgrouping tools (STarT Back Tool and Quebec Task Force classification), four baseline characteristics and a group of previously identified domain-specific patient categorisations (collectively, the 'comparator variables'). This was a longitudinal cohort study of 928 patients consulting for low back pain in primary care. The associations between each subgroup approach and outcomes at 2 weeks, 3 and 12 months, and with weekly SMS responses were tested in linear regression models, and their prognostic capacity (variance explained) was compared to that of the comparator variables listed above. The two previously identified subgroupings were similarly associated with all outcomes. The prognostic capacity of both subgroupings was better than that of the comparator variables, except for participants' recovery beliefs and the domain-specific categorisations, but was still limited. The explained variance ranged from 4.3%-6.9% for pain intensity and from 6.8%-20.3% for disability, and highest at the 2 weeks follow-up. Latent Class-derived subgroups provided additional prognostic information when compared to a range of variables, but the improvements were not substantial enough to warrant further development into a new prognostic tool. Further research could investigate if these novel subgrouping approaches may help to improve existing tools that subgroup low back pain patients.

Imaging workflow and calibration for CT-guided time-domain fluorescence tomography

PubMed Central

Tichauer, Kenneth M.; Holt, Robert W.; El-Ghussein, Fadi; Zhu, Qun; Dehghani, Hamid; Leblond, Frederic; Pogue, Brian W.

2011-01-01

In this study, several key optimization steps are outlined for a non-contact, time-correlated single photon counting small animal optical tomography system, using simultaneous collection of both fluorescence and transmittance data. The system is presented for time-domain image reconstruction in vivo, illustrating the sensitivity from single photon counting and the calibration steps needed to accurately process the data. In particular, laser time- and amplitude-referencing, detector and filter calibrations, and collection of a suitable instrument response function are all presented in the context of time-domain fluorescence tomography and a fully automated workflow is described. Preliminary phantom time-domain reconstructed images demonstrate the fidelity of the workflow for fluorescence tomography based on signal from multiple time gates. PMID:22076264

Raman tensor elements for tetragonal BaTiO3 and their use for in-plane domain texture assessments

NASA Astrophysics Data System (ADS)

Deluca, Marco; Higashino, Masayuki; Pezzotti, Giuseppe

2007-08-01

A quantitative assessment of c-axis oriented domains in a textured BaTiO3 (BT) single crystal has been carried out by polarized Raman microprobe spectroscopy. The relative intensity modulation of the Raman phonon modes has been theoretically modeled as a function of crystal rotation and linked to the volume fraction of c-axis oriented domains. Raman tensor elements have also been experimentally determined for the Ag and B1 vibrational modes. As an application, the internal in-plane texture and the volume fraction of c-oriented domains in the BT single crystal have been nondestructively visualized by monitoring the relative intensity of Ag and B1 Raman modes.

A new scaling approach for the mesoscale simulation of magnetic domain structures using Monte Carlo simulations

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

Radhakrishnan, B.; Eisenbach, M.; Burress, Timothy A.

2017-01-24

A new scaling approach has been proposed for the spin exchange and the dipole–dipole interaction energy as a function of the system size. The computed scaling laws are used in atomistic Monte Carlo simulations of magnetic moment evolution to predict the transition from single domain to a vortex structure as the system size increases. The width of a 180° – domain wall extracted from the simulated structures is in close agreement with experimentally values for an F–Si alloy. In conclusion, the transition size from a single domain to a vortex structure is also in close agreement with theoretically predicted andmore » experimentally measured values for Fe.« less

Cognitive training in Parkinson disease: cognition-specific vs nonspecific computer training.

PubMed

Zimmermann, Ronan; Gschwandtner, Ute; Benz, Nina; Hatz, Florian; Schindler, Christian; Taub, Ethan; Fuhr, Peter

2014-04-08

In this study, we compared a cognition-specific computer-based cognitive training program with a motion-controlled computer sports game that is not cognition-specific for their ability to enhance cognitive performance in various cognitive domains in patients with Parkinson disease (PD). Patients with PD were trained with either a computer program designed to enhance cognition (CogniPlus, 19 patients) or a computer sports game with motion-capturing controllers (Nintendo Wii, 20 patients). The effect of training in 5 cognitive domains was measured by neuropsychological testing at baseline and after training. Group differences over all variables were assessed with multivariate analysis of variance, and group differences in single variables were assessed with 95% confidence intervals of mean difference. The groups were similar regarding age, sex, and educational level. Patients with PD who were trained with Wii for 4 weeks performed better in attention (95% confidence interval: -1.49 to -0.11) than patients trained with CogniPlus. In our study, patients with PD derived at least the same degree of cognitive benefit from non-cognition-specific training involving movement as from cognition-specific computerized training. For patients with PD, game consoles may be a less expensive and more entertaining alternative to computer programs specifically designed for cognitive training. This study provides Class III evidence that, in patients with PD, cognition-specific computer-based training is not superior to a motion-controlled computer game in improving cognitive performance.

Single-shot terahertz time-domain spectroscopy in pulsed high magnetic fields.

PubMed

Noe, G Timothy; Katayama, Ikufumi; Katsutani, Fumiya; Allred, James J; Horowitz, Jeffrey A; Sullivan, David M; Zhang, Qi; Sekiguchi, Fumiya; Woods, Gary L; Hoffmann, Matthias C; Nojiri, Hiroyuki; Takeda, Jun; Kono, Junichiro

2016-12-26

We have developed a single-shot terahertz time-domain spectrometer to perform optical-pump/terahertz-probe experiments in pulsed, high magnetic fields up to 30 T. The single-shot detection scheme for measuring a terahertz waveform incorporates a reflective echelon to create time-delayed beamlets across the intensity profile of the optical gate beam before it spatially and temporally overlaps with the terahertz radiation in a ZnTe detection crystal. After imaging the gate beam onto a camera, we can retrieve the terahertz time-domain waveform by analyzing the resulting image. To demonstrate the utility of our technique, we measured cyclotron resonance absorption of optically excited carriers in the terahertz frequency range in intrinsic silicon at high magnetic fields, with results that agree well with published values.

Impairment in proverb interpretation as an executive function deficit in patients with amnestic mild cognitive impairment and early Alzheimer's disease.

PubMed

Leyhe, Thomas; Saur, Ralf; Eschweiler, Gerhard W; Milian, Monika

2011-01-01

Proverb interpretation is assumed to reflect executive functions. We hypothesized that proverb interpretation is impaired in patients with amnestic mild cognitive impairment (aMCI) diagnosed as single-domain impairment by common neuropsychological testing. We compared performance in a proverb interpretation test in single-domain aMCI patients and patients with early Alzheimer's disease (EAD). The groups with aMCI and EAD performed significantly worse than healthy controls. Both patient groups gave concrete answers with a similar frequency. However, patients with EAD tended to give senseless answers more frequently. Our data suggest that in patients diagnosed as single-domain aMCI, deterioration of executive functions is detectable with subtle and appropriate neuropsychological testing. Implementation of these procedures may improve the early prediction of AD.

Chicken immunoglobulin gamma-heavy chains: limited VH gene repertoire, combinatorial diversification by D gene segments and evolution of the heavy chain locus.

PubMed

Parvari, R; Avivi, A; Lentner, F; Ziv, E; Tel-Or, S; Burstein, Y; Schechter, I

1988-03-01

cDNA clones encoding the variable and constant regions of chicken immunoglobulin (Ig) gamma-chains were obtained from spleen cDNA libraries. Southern blots of kidney DNA show that the variable region sequences of eight cDNA clones reveal the same set of bands corresponding to approximately 30 cross-hybridizing VH genes of one subgroup. Since the VH clones were randomly selected, it is likely that the bulk of chicken H-chains are encoded by a single VH subgroup. Nucleotide sequence determinations of two cDNA clones reveal VH, D, JH and the constant region. The VH segments are closely related to each other (83% homology) as expected for VH or the same subgroup. The JHs are 15 residues long and differ by one amino acid. The Ds differ markedly in sequence (20% homology) and size (10 and 20 residues). These findings strongly indicate multiple (at least two) D genes which by a combinatorial joining mechanism diversify the H-chains, a mechanism which is not operative in the chicken L-chain locus. The most notable among the chicken Igs is the so-called 7S IgG because its H-chain differs in many important aspects from any mammalian IgG. The sequence of the C gamma cDNA reported here resolves this issue. The chicken C gamma is 426 residues long with four CH domains (unlike mammalian C gamma which has three CH domains) and it shows 25% homology to the chicken C mu. The chicken C gamma is most related to the mammalian C epsilon in length, the presence of four CH domains and the distribution of cysteines in the CH1 and CH2 domains. We propose that the unique chicken C gamma is the ancestor of the mammalian C epsilon and C gamma subclasses, and discuss the evolution of the H-chain locus from that of chicken with presumably three genes (mu, gamma, alpha) to the mammalian loci with 8-10 H-chain genes.

How does a newly encountered face become familiar? The effect of within-person variability on adults' and children's perception of identity.

PubMed

Baker, Kristen A; Laurence, Sarah; Mondloch, Catherine J

2017-04-01

Adults and children aged 6years and older easily recognize multiple images of a familiar face, but often perceive two images of an unfamiliar face as belonging to different identities. Here we examined the process by which a newly encountered face becomes familiar, defined as accurate recognition of multiple images that capture natural within-person variability in appearance. In Experiment 1 we examined whether exposure to within-person variability in appearance helps children learn a new face. Children aged 6-13years watched a 10-min video of a woman reading a story; she was filmed on a single day (low variability) or over three days, across which her appearance and filming conditions (e.g., camera, lighting) varied (high variability). After familiarization, participants sorted a set of images comprising novel images of the target identity intermixed with distractors. Compared to participants who received no familiarization, children showed evidence of learning only in the high-variability condition, in contrast to adults who showed evidence of learning in both the low- and high-variability conditions. Experiment 2 highlighted the efficiency with which adults learn a new face; their accuracy was comparable across training conditions despite variability in duration (1 vs. 10min) and type (video vs. static images) of training. Collectively, our findings show that exposure to variability leads to the formation of a robust representation of facial identity, consistent with perceptual learning in other domains (e.g., language), and that the development of face learning is protracted throughout childhood. We discuss possible underlying mechanisms. Copyright © 2016. Published by Elsevier B.V.

Computer simulation of multiple pilots flying a modern high performance helicopter

NASA Technical Reports Server (NTRS)

Zipf, Mark E.; Vogt, William G.; Mickle, Marlin H.; Hoelzeman, Ronald G.; Kai, Fei; Mihaloew, James R.

1988-01-01

A computer simulation of a human response pilot mechanism within the flight control loop of a high-performance modern helicopter is presented. A human response mechanism, implemented by a low order, linear transfer function, is used in a decoupled single variable configuration that exploits the dominant vehicle characteristics by associating cockpit controls and instrumentation with specific vehicle dynamics. Low order helicopter models obtained from evaluations of the time and frequency domain responses of a nonlinear simulation model, provided by NASA Lewis Research Center, are presented and considered in the discussion of the pilot development. Pilot responses and reactions to test maneuvers are presented and discussed. Higher level implementation, using the pilot mechanisms, are discussed and considered for their use in a comprehensive control structure.

Jammed Limit of Bijel Structure Formation

DOE PAGES

Welch, P. M.; Lee, M. N.; Parra-Vasquez, A. N. G.; ...

2017-11-02

Over the past decade, methods to control microstructure in heterogeneous mixtures by arresting spinodal decomposition via the addition of colloidal particles have led to an entirely new class of bicontinuous materials known as bijels. We present a new model for the development of these materials that yields to both numerical and analytical evaluation. This model reveals that a single dimensionless parameter that captures both chemical and environmental variables dictates the dynamics and ultimate structure formed in bijels. We also demonstrate that this parameter must fall within a fixed range in order for jamming to occur during spinodal decomposition, as wellmore » as show that known experimental trends for the characteristic domain sizes and time scales for formation are recovered by this model.« less

Modeling optical transmissivity of graphene grate in on-chip silicon photonic device

NASA Astrophysics Data System (ADS)

Amiri, Iraj S.; Ariannejad, M. M.; Jalil, M. A.; Ali, J.; Yupapin, P.

2018-06-01

A three-dimensional (3-D) finite-difference-time-domain (FDTD) analysis was used to simulate a silicon photonic waveguide. We have calculated power and transmission of the graphene used as single or multilayers to study the light transmission behavior. A new technique has been developed to define the straight silicon waveguide integrated with grate graphene layer. The waveguide has a variable grate spacing to be filled by the graphene layer. The number of graphene atomic layers varies between 100 and 1000 (or 380 nm and 3800 nm), the transmitted power obtained varies as ∼30% and ∼80%. The ∼99%, blocking of the light was occurred in 10,000 (or 38,000 nm) atomic layers of the graphene grate.

Flexible CRISPR library construction using parallel oligonucleotide retrieval

PubMed Central

Read, Abigail; Gao, Shaojian; Batchelor, Eric

2017-01-01

Abstract CRISPR/Cas9-based gene knockout libraries have emerged as a powerful tool for functional screens. We present here a set of pre-designed human and mouse sgRNA sequences that are optimized for both high on-target potency and low off-target effect. To maximize the chance of target gene inactivation, sgRNAs were curated to target both 5΄ constitutive exons and exons that encode conserved protein domains. We describe here a robust and cost-effective method to construct multiple small sized CRISPR library from a single oligo pool generated by array synthesis using parallel oligonucleotide retrieval. Together, these resources provide a convenient means for individual labs to generate customized CRISPR libraries of variable size and coverage depth for functional genomics application. PMID:28334828

LONG-TERM RETROSPECTIVE ANALYSIS OF VISUAL ACUITY AND OPTICAL COHERENCE TOPOGRAPHIC CHANGES AFTER SINGLE VERSUS DOUBLE PEELING DURING VITRECTOMY FOR MACULAR EPIRETINAL MEMBRANES.

PubMed

Jung, Jesse J; Hoang, Quan V; Ridley-Lane, Megan L; Sebrow, Dov B; Dhrami-Gavazi, Elona; Chang, Stanley

2016-11-01

To determine the long-term effect of internal limiting membrane with associated epiretinal membrane (ERM) peeling versus single peeling alone in terms of best-corrected visual acuity and anatomical outcomes on spectral-domain optical coherence tomography. This retrospective comparative cohort study of patients who had follow-up of >1 year and underwent surgery for ERM by a single surgeon (S.C.) from January 1, 2008 to December 31, 2012 compared cases in which the internal limiting membrane was stained with brilliant blue G to facilitate double peeling (n = 42) and single peeling (n = 43) of the ERM alone for up to 3 years of follow-up. For continuous variables, an independent two-tailed t-test was performed. For binary variables, the Fisher's exact test was performed. Statistical significance was defined as P < 0.05. Eighty-five of 142 patients fit the inclusion criteria. At the last follow-up, the single-peeling group were more likely to have ERM remaining in the central fovea postoperatively (P = 0.0020, becoming significant by postoperative Year 1, P = 0.022) and less likely to develop inner retinal dimpling (P = 0.000, becoming significant by postoperative Month 3, P = 0.015). At 3 years, central foveal thickness had decreased in the single-peeling group by -136.9 µm and by -84.1 μm in the double-peeling group, which was not significantly different (P = 0.08). Mean best-corrected visual acuity improved in both the groups at all time points. There was no statistically significant difference between the 2 groups at 3 years (P = 0.44; single-peeling group, 0.32 ± 0.42, Snellen 20/42; double-peeling group, 0.23 ± 0.27, Snellen 20/34). Brilliant blue G-assisted internal limiting membrane peeling for ERM results in a more thorough removal of residual ERM around the paracentral fovea. However, there is no difference in long-term best-corrected visual acuity at 3 years and a greater likelihood of inner retinal dimpling.

Tip-induced domain growth on the non-polar cuts of lithium niobate single-crystals

DOE PAGES

Alikin, Denis O.; Ievlev, Anton; Turigin, Anton P.; ...

2015-05-05

Currently ferroelectric materials with designed domain structures are considered as a perspective material for new generation of photonic, data storage and data processing devices. Application of external electric field is the most convenient way of the domain structure formation. Lots of papers are devoted to investigation of the domain kinetics on polar surface of crystals while the forward growth remains one of the most mysterious stages due to lack of experimental methods allowing to study it. Here we performed tip-induced polarization reversal on X- and Y-non-polar cuts in single-crystal of congruent lithium niobate allows us to study the forward growthmore » with high spatial resolution. The revealed difference in the shape and length of domains induced on X- and Y-cuts is beyond previously developed theoretical approaches used for the theoretical consideration of the domains growth at non-polar ferroelectric surfaces. Lastly, to explain experimental results we used kinetic approach with anisotropy of screening efficiency along different crystallographic directions.« less

Aircraft Measurements for Understanding Air-Sea Coupling and Improving Coupled Model Predictions

DTIC Science & Technology

2014-09-30

layer thermodynamic properties across the DYNAMO domain during the suppressed and active phase of MJO; and 3) variability and distribution of upper ocean...structure during suppressed, active and restoring phase of MJO. One of the unique aspects of LASP/ DYNAMO WP-3D project was to supplement the point...observations by probing the atmospheric and oceanic variability across the DYNAMO domain. Adhering to this aspect, vertical cross section of lower

Comparison and correlation of binding mode of ATP in the kinase domains of Hexokinase family

PubMed Central

Kumar, Yellapu Nanda; Kumar, Pasupuleti Santhosh; Sowjenya, Gopal; Rao, Valasani Koteswara; Yeswanth, Sthanikam; Prasad, Uppu Venkateswara; Pradeepkiran, Jangampalli Adi; Sarma, PVGK; Bhaskar, Matcha

2012-01-01

Hexokinases (HKs) are the enzymes that catalyses the ATP dependent phosphorylation of Hexose sugars to Hexose-6-Phosphate (Hex-6-P). There exist four different forms of HKs namely HK-I, HK-II, HK-III and HK-IV and all of them share a common ATP binding site core surrounded by more variable sequence that determine substrate affinities. Although they share a common binding site but they differ in their kinetic functions, hence the present study is aimed to analyze the binding mode of ATP. The analysis revealed that the four ATP binding domains are showing 13 identical, 7 similar and 6 dissimilar residues with similar structural conformation. Molecular docking of ATP into the kinase domains using Molecular Operating Environment (MOE) soft ware tool clearly showed the variation in the binding mode of ATP with variable docking scores. This probably explains the variable phosphorylation rates among hexokinases family. PMID:22829728

Intraindividual variability in cognitive performance in three groups of older adults: cross-domain links to physical status and self-perceived affect and beliefs.

PubMed

Strauss, Esther; MacDonald, Stuart W S; Hunter, Michael; Moll, Alex; Hultsch, David F

2002-11-01

Intraindividual variability of physical status and affect/beliefs as well as their relations with cognition were examined in 3 groups of older adults: healthy elderly, individuals with a nonneurological health-related disturbance (arthritis) and people with neurological compromise (dementia). The findings showed that greater inconsistency in physical performance was observed in groups characterized by central nervous system dysfunction. By contrast, fluctuations in affect appeared to reflect other more transient sources, such as pain. In general, increased inconsistency in non-cognitive domains was associated with poorer cognitive function. There were cross-domain links between inconsistency in physical functioning and fluctuations in cognitive performance, although the nature of the links depended largely upon the neurological status of the individuals. Considered together, the result indicated that measures of cognitive as well as physical variability are important behavioral markers of neurological integrity.

Time-response shaping using output to input saturation transformation

NASA Astrophysics Data System (ADS)

Chambon, E.; Burlion, L.; Apkarian, P.

2018-03-01

For linear systems, the control law design is often performed so that the resulting closed loop meets specific frequency-domain requirements. However, in many cases, it may be observed that the obtained controller does not enforce time-domain requirements amongst which the objective of keeping a scalar output variable in a given interval. In this article, a transformation is proposed to convert prescribed bounds on an output variable into time-varying saturations on the synthesised linear scalar control law. This transformation uses some well-chosen time-varying coefficients so that the resulting time-varying saturation bounds do not overlap in the presence of disturbances. Using an anti-windup approach, it is obtained that the origin of the resulting closed loop is globally asymptotically stable and that the constrained output variable satisfies the time-domain constraints in the presence of an unknown finite-energy-bounded disturbance. An application to a linear ball and beam model is presented.

Component Provider’s and Tool Developer’s Handbook. Central Archive for Reusable Defense Software (CARDS)

DTIC Science & Technology

1994-03-25

metrics [DISA93b]. " The Software Engineering Institute (SET) has developed a domain analysis process (Feature-Oriented Domain Analysis - FODA ) and is...and expresses the range of variability of these decisions. 3.2.2.3 Feature Oriented Domain Analysis Feature Oriented Domain Analysis ( FODA ) is a domain...documents created in this phase. From a purely profit-oriented business point of view, a company may develop its own analysis of a government or commercial

Evaluating the effect of internal aperture variability on transport in kilometer scale discrete fracture networks

DOE PAGES

Makedonska, Nataliia; Hyman, Jeffrey D.; Karra, Satish; ...

2016-08-01

The apertures of natural fractures in fractured rock are highly heterogeneous. However, in-fracture aperture variability is often neglected in flow and transport modeling and individual fractures are assumed to have uniform aperture distribution. The relative importance of in-fracture variability in flow and transport modeling within kilometer-scale fracture networks has been under debate for a long time, since the flow in each single fracture is controlled not only by in-fracture variability but also by boundary conditions. Computational limitations have previously prohibited researchers from investigating the relative importance of in-fracture variability in flow and transport modeling within large-scale fracture networks. We addressmore » this question by incorporating internal heterogeneity of individual fractures into flow simulations within kilometer scale three-dimensional fracture networks, where fracture intensity, P 32 (ratio between total fracture area and domain volume) is between 0.027 and 0.031 [1/m]. The recently developed discrete fracture network (DFN) simulation capability, dfnWorks, is used to generate kilometer scale DFNs that include in-fracture aperture variability represented by a stationary log-normal stochastic field with various correlation lengths and variances. The Lagrangian transport parameters, non-reacting travel time, , and cumulative retention, , are calculated along particles streamlines. As a result, it is observed that due to local flow channeling early particle travel times are more sensitive to in-fracture aperture variability than the tails of travel time distributions, where no significant effect of the in-fracture aperture variations and spatial correlation length is observed.« less

Evaluating the effect of internal aperture variability on transport in kilometer scale discrete fracture networks

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

Makedonska, Nataliia; Hyman, Jeffrey D.; Karra, Satish

The apertures of natural fractures in fractured rock are highly heterogeneous. However, in-fracture aperture variability is often neglected in flow and transport modeling and individual fractures are assumed to have uniform aperture distribution. The relative importance of in-fracture variability in flow and transport modeling within kilometer-scale fracture networks has been under debate for a long time, since the flow in each single fracture is controlled not only by in-fracture variability but also by boundary conditions. Computational limitations have previously prohibited researchers from investigating the relative importance of in-fracture variability in flow and transport modeling within large-scale fracture networks. We addressmore » this question by incorporating internal heterogeneity of individual fractures into flow simulations within kilometer scale three-dimensional fracture networks, where fracture intensity, P 32 (ratio between total fracture area and domain volume) is between 0.027 and 0.031 [1/m]. The recently developed discrete fracture network (DFN) simulation capability, dfnWorks, is used to generate kilometer scale DFNs that include in-fracture aperture variability represented by a stationary log-normal stochastic field with various correlation lengths and variances. The Lagrangian transport parameters, non-reacting travel time, , and cumulative retention, , are calculated along particles streamlines. As a result, it is observed that due to local flow channeling early particle travel times are more sensitive to in-fracture aperture variability than the tails of travel time distributions, where no significant effect of the in-fracture aperture variations and spatial correlation length is observed.« less

Anti-tumor necrosis factor VNAR single domains reduce lethality and regulate underlying inflammatory response in a murine model of endotoxic shock

PubMed Central

2013-01-01

Background In sepsis, tumor necrosis factor (TNF) is the key factor triggering respiratory burst, tissue injury and disseminated coagulation. Anti-TNF strategies based on monoclonal antibodies or F(ab’)2 fragments have been used in sepsis with contradictory results. Immunoglobulin new antigen receptors (IgNAR) are a unique subset of antibodies consisting of five constant (CNAR) and one variable domains (VNAR). VNAR domains are the smallest, naturally occurring, antibody-based immune recognition units, having potential use as therapy. Our aim was to explore the impact of an anti-TNF VNAR on survival in an experimental model of endotoxic shock. Also, mRNA expression and serum protein of several inflammatory molecules were measured. Results Endotoxic shock was induced by lipopolysaccharide (LPS) in male Balb/c mice. Animals were treated with anti-TNF VNAR domains, F(ab’)2 antibody fragments, or saline solution 15 minutes before, 2 h and 24 h after lethal dose100 (LD100) LPS administration. TNF blockade with either VNAR domains or F(ab’)2 fragments were associated with lower mortality (60% and 75%, respectively) compared to LD100. Challenge with LPS induced significant production of serum TNF and interleukins -10 and -6 at 3 h. After that, significant reduction of IL-6 at 24 h (vs 3 h) was shown only in the VNAR group. Nitrites level also increased in response to LPS. In liver, TNF and IL-10 mRNA expression showed a pro-inflammatory imbalance in response to LPS. Blocking TNF was associated with a shift towards an anti-inflammatory status; however, polarization was more pronounced in animals receiving F(ab’)2 fragments than in those with VNAR therapy. With regard to IL-6, gene expression was increased at 3 h in all groups. TNF blockade was associated with rapid and sustained suppression of IL-6 expression, even more evident in the VNAR group. Finally, expression of inducible-nitric oxide synthase (iNOS) increased in response to LPS at 3 h, but this was decreased at 24 h only in the anti-TNF VNAR group. Conclusions Anti-TNF VNAR single domains improved survival in a murine model of endotoxic shock. Protection was associated with regulation in the TNF/IL-10 balance, attenuation of IL-6 and iNOS gene expression in the liver as well as decreased serum IL-6 concentration. PMID:23548047

Frequency-domain-independent vector analysis for mode-division multiplexed transmission

NASA Astrophysics Data System (ADS)

Liu, Yunhe; Hu, Guijun; Li, Jiao

2018-04-01

In this paper, we propose a demultiplexing method based on frequency-domain independent vector analysis (FD-IVA) algorithm for mode-division multiplexing (MDM) system. FD-IVA extends frequency-domain independent component analysis (FD-ICA) from unitary variable to multivariate variables, and provides an efficient method to eliminate the permutation ambiguity. In order to verify the performance of FD-IVA algorithm, a 6 ×6 MDM system is simulated. The simulation results show that the FD-IVA algorithm has basically the same bit-error-rate(BER) performance with the FD-ICA algorithm and frequency-domain least mean squares (FD-LMS) algorithm. Meanwhile, the convergence speed of FD-IVA algorithm is the same as that of FD-ICA. However, compared with the FD-ICA and the FD-LMS, the FD-IVA has an obviously lower computational complexity.

Cognitive correlates of white matter lesion load and brain atrophy

PubMed Central

Dong, Chuanhui; Nabizadeh, Nooshin; Caunca, Michelle; Cheung, Ying Kuen; Rundek, Tatjana; Elkind, Mitchell S.V.; DeCarli, Charles; Sacco, Ralph L.; Stern, Yaakov

2015-01-01

Objective: We investigated white matter lesion load and global and regional brain volumes in relation to domain-specific cognitive performance in the stroke-free Northern Manhattan Study (NOMAS) population. Methods: We quantified white matter hyperintensity volume (WMHV), total cerebral volume (TCV), and total lateral ventricular (TLV) volume, as well as hippocampal and cortical gray matter (GM) lobar volumes in a subgroup. We used general linear models to examine MRI markers in relation to domain-specific cognitive performance, adjusting for key covariates. Results: MRI and cognitive data were available for 1,163 participants (mean age 70 ± 9 years; 60% women; 66% Hispanic, 17% black, 15% white). Across the entire sample, those with greater WMHV had worse processing speed. Those with larger TLV volume did worse on episodic memory, processing speed, and semantic memory tasks, and TCV did not explain domain-specific variability in cognitive performance independent of other measures. Age was an effect modifier, and stratified analysis showed that TCV and WMHV explained variability in some domains above age 70. Smaller hippocampal volume was associated with worse performance across domains, even after adjusting for APOE ε4 and vascular risk factors, whereas smaller frontal lobe volumes were only associated with worse executive function. Conclusions: In this racially/ethnically diverse, community-based sample, white matter lesion load was inversely associated with cognitive performance, independent of brain atrophy. Lateral ventricular, hippocampal, and lobar GM volumes explained domain-specific variability in cognitive performance. PMID:26156514

Stabilization of an immunoglobulin fold domain by an engineered disulfide bond at the buried hydrophobic region.

PubMed

Hagihara, Yoshihisa; Mine, Shouhei; Uegaki, Koichi

2007-12-14

We report for the first time the stabilization of an immunoglobulin fold domain by an engineered disulfide bond. In the llama single-domain antibody, which has human chorionic gonadotropin as its specific antigen, Ala49 and Ile70 are buried in the structure. A mutant with an artificial disulfide bond at this position showed a 10 degrees C higher midpoint temperature of thermal unfolding than that without the extra disulfide bond. The modified domains exhibited an antigen binding affinity comparable with that of the wild-type domain. Ala49 and Ile70 are conserved in camel and llama single-domain antibody frameworks. Therefore, domains against different antigens are expected to be stabilized by the engineered disulfide bond examined here. In addition to the effect of the loop constraints in the unfolded state, thermodynamic analysis indicated that internal interaction and hydration also control the stability of domains with disulfide bonds. The change in physical properties resulting from mutation often causes unpredictable and destabilizing effects on these interactions. The introduction of a hydrophobic cystine into the hydrophobic region maintains the hydrophobicity of the protein and is expected to minimize the unfavorable mutational effects.

Quantifying Effects of Pharmacological Blockers of Cardiac Autonomous Control Using Variability Parameters.

PubMed

Miyabara, Renata; Berg, Karsten; Kraemer, Jan F; Baltatu, Ovidiu C; Wessel, Niels; Campos, Luciana A

2017-01-01

Objective: The aim of this study was to identify the most sensitive heart rate and blood pressure variability (HRV and BPV) parameters from a given set of well-known methods for the quantification of cardiovascular autonomic function after several autonomic blockades. Methods: Cardiovascular sympathetic and parasympathetic functions were studied in freely moving rats following peripheral muscarinic (methylatropine), β1-adrenergic (metoprolol), muscarinic + β1-adrenergic, α1-adrenergic (prazosin), and ganglionic (hexamethonium) blockades. Time domain, frequency domain and symbolic dynamics measures for each of HRV and BPV were classified through paired Wilcoxon test for all autonomic drugs separately. In order to select those variables that have a high relevance to, and stable influence on our target measurements (HRV, BPV) we used Fisher's Method to combine the p -value of multiple tests. Results: This analysis led to the following best set of cardiovascular variability parameters: The mean normal beat-to-beat-interval/value (HRV/BPV: meanNN), the coefficient of variation (cvNN = standard deviation over meanNN) and the root mean square differences of successive (RMSSD) of the time domain analysis. In frequency domain analysis the very-low-frequency (VLF) component was selected. From symbolic dynamics Shannon entropy of the word distribution (FWSHANNON) as well as POLVAR3, the non-linear parameter to detect intermittently decreased variability, showed the best ability to discriminate between the different autonomic blockades. Conclusion: Throughout a complex comparative analysis of HRV and BPV measures altered by a set of autonomic drugs, we identified the most sensitive set of informative cardiovascular variability indexes able to pick up the modifications imposed by the autonomic challenges. These indexes may help to increase our understanding of cardiovascular sympathetic and parasympathetic functions in translational studies of experimental diseases.

Geophysical characterization of Range-Front Faults, Snake Valley, Nevada

USGS Publications Warehouse

Asch, Theodore H.; Sweetkind, Donald S.

2010-01-01

In September 2009, the U.S. Geological Survey, in cooperation with the National Park Service, collected audiomagnetotelluric (AMT) data along two profiles on the eastern flank of the Snake Range near Great Basin National Park to refine understanding of the subsurface geology. Line 1 was collected along Baker Creek, was approximately 6.7-km long, and recorded subsurface geologic conditions to approximately 800-m deep. Line 2, collected farther to the southeast in the vicinity of Kious Spring, was 2.8-km long, and imaged to depths of approximately 600 m. The two AMT lines are similar in their electrical response and are interpreted to show generally similar subsurface geologic conditions. The geophysical response seen on both lines may be described by three general domains of electrical response: (1) a shallow (mostly less than 100-200-m deep) domain of highly variable resistivity, (2) a deep domain characterized by generally high resistivity that gradually declines eastward to lower resistivity with a steeply dipping grain or fabric, and (3) an eastern domain in which the resistivity character changes abruptly at all depths from that in the western domain. The shallow, highly variable domain is interpreted to be the result of a heterogeneous assemblage of Miocene conglomerate and incorporated megabreccia blocks overlying a shallowly eastward-dipping southern Snake Range detachment fault. The deep domain of generally higher resistivity is interpreted as Paleozoic sedimentary rocks (Pole Canyon limestone and Prospect Mountain Quartzite) and Mesozoic and Cenozoic plutonic rocks occurring beneath the detachment surface. The range of resistivity values within this deep domain may result from fracturing adjacent to the detachment, the presence of Paleozoic rock units of variable resistivities that do not crop out in the vicinity of the lines, or both. The eastern geophysical domain is interpreted to be a section of Miocene strata at depth, overlain by Quaternary alluvial fill. These deposits lie east of a steeply east-dipping normal fault that cuts all units and has about 100 m of east-side-down offset.

Streamlined method for parallel identification of single domain antibodies to membrane receptors on whole cells

PubMed Central

Rossotti, Martín; Tabares, Sofía; Alfaya, Lucía; Leizagoyen, Carmen; Moron, Gabriel; González-Sapienza, Gualberto

2015-01-01

BACKGROUND Owing to their minimal size, high production yield, versatility and robustness, the recombinant variable domain (nanobody) of camelid single chain antibodies are valued affinity reagents for research, diagnostic, and therapeutic applications. While their preparation against purified antigens is straightforward, the generation of nanobodies to difficult targets such as multi-pass or complex membrane cell receptors remains challenging. Here we devised a platform for high throughput identification of nanobodies to cell receptor based on the use of a biotin handle. METHODS Using a biotin-acceptor peptide tag, the in vivo biotinylation of nanobodies in 96 well culture blocks was optimized allowing their parallel analysis by flow cytometry and ELISA, and their direct used for pull-down/MS target identification. RESULTS The potential of this strategy was demonstrated by the selection and characterization of panels of nanobodies to Mac-1 (CD11b/CD18), MHC II and the mouse Ly-5 leukocyte common antigen (CD45) receptors, from a VHH library obtained from a llama immunized with mouse bone marrow derived dendritic cells. By on and off switching of the addition of biotin, the method also allowed the epitope binning of the selected Nbs directly on cells. CONCLUSIONS This strategy streamline the selection of potent nanobodies to complex antigens, and the selected nanobodies constitute ready-to-use biotinylated reagents. GENERAL SIGNIFICANCE This method will accelerate the discovery of nanobodies to cell membrane receptors which comprise the largest group of drug and analytical targets. PMID:25819371

Bioinformatic flowchart and database to investigate the origins and diversity of Clan AA peptidases

PubMed Central

Llorens, Carlos; Futami, Ricardo; Renaud, Gabriel; Moya, Andrés

2009-01-01

Background Clan AA of aspartic peptidases relates the family of pepsin monomers evolutionarily with all dimeric peptidases encoded by eukaryotic LTR retroelements. Recent findings describing various pools of single-domain nonviral host peptidases, in prokaryotes and eukaryotes, indicate that the diversity of clan AA is larger than previously thought. The ensuing approach to investigate this enzyme group is by studying its phylogeny. However, clan AA is a difficult case to study due to the low similarity and different rates of evolution. This work is an ongoing attempt to investigate the different clan AA families to understand the cause of their diversity. Results In this paper, we describe in-progress database and bioinformatic flowchart designed to characterize the clan AA protein domain based on all possible protein families through ancestral reconstructions, sequence logos, and hidden markov models (HMMs). The flowchart includes the characterization of a major consensus sequence based on 6 amino acid patterns with correspondence with Andreeva's model, the structural template describing the clan AA peptidase fold. The set of tools is work in progress we have organized in a database within the GyDB project, referred to as Clan AA Reference Database . Conclusion The pre-existing classification combined with the evolutionary history of LTR retroelements permits a consistent taxonomical collection of sequence logos and HMMs. This set is useful for gene annotation but also a reference to evaluate the diversity of, and the relationships among, the different families. Comparisons among HMMs suggest a common ancestor for all dimeric clan AA peptidases that is halfway between single-domain nonviral peptidases and those coded by Ty3/Gypsy LTR retroelements. Sequence logos reveal how all clan AA families follow similar protein domain architecture related to the peptidase fold. In particular, each family nucleates a particular consensus motif in the sequence position related to the flap. The different motifs constitute a network where an alanine-asparagine-like variable motif predominates, instead of the canonical flap of the HIV-1 peptidase and closer relatives. Reviewers This article was reviewed by Daniel H. Haft, Vladimir Kapitonov (nominated by Jerry Jurka), and Ben M. Dunn (nominated by Claus Wilke). PMID:19173708

Stability-Diversity Tradeoffs Impose Fundamental Constraints on Selection of Synthetic Human VH/VL Single-Domain Antibodies from In Vitro Display Libraries

PubMed Central

Henry, Kevin A.; Kim, Dae Young; Kandalaft, Hiba; Lowden, Michael J.; Yang, Qingling; Schrag, Joseph D.; Hussack, Greg; MacKenzie, C. Roger; Tanha, Jamshid

2017-01-01

Human autonomous VH/VL single-domain antibodies (sdAbs) are attractive therapeutic molecules, but often suffer from suboptimal stability, solubility and affinity for cognate antigens. Most commonly, human sdAbs have been isolated from in vitro display libraries constructed via synthetic randomization of rearranged VH/VL domains. Here, we describe the design and characterization of three novel human VH/VL sdAb libraries through a process of: (i) exhaustive biophysical characterization of 20 potential VH/VL sdAb library scaffolds, including assessment of expression yield, aggregation resistance, thermostability and tolerance to complementarity-determining region (CDR) substitutions; (ii) in vitro randomization of the CDRs of three VH/VL sdAb scaffolds, with tailored amino acid representation designed to promote solubility and expressibility; and (iii) systematic benchmarking of the three VH/VL libraries by panning against five model antigens. We isolated ≥1 antigen-specific human sdAb against four of five targets (13 VHs and 7 VLs in total); these were predominantly monomeric, had antigen-binding affinities ranging from 5 nM to 12 µM (average: 2–3 µM), but had highly variable expression yields (range: 0.1–19 mg/L). Despite our efforts to identify the most stable VH/VL scaffolds, selection of antigen-specific binders from these libraries was unpredictable (overall success rate for all library-target screens: ~53%) with a high attrition rate of sdAbs exhibiting false positive binding by ELISA. By analyzing VH/VL sdAb library sequence composition following selection for monomeric antibody expression (binding to protein A/L followed by amplification in bacterial cells), we found that some VH/VL sdAbs had marked growth advantages over others, and that the amino acid composition of the CDRs of this set of sdAbs was dramatically restricted (bias toward Asp and His and away from aromatic and hydrophobic residues). Thus, CDR sequence clearly dramatically impacts the stability of human autonomous VH/VL immunoglobulin domain folds, and sequence-stability tradeoffs must be taken into account during the design of such libraries. PMID:29375542

Quality of life in a large cohort of adult Brazilian patients with 46,XX and 46,XY disorders of sex development from a single tertiary centre.

PubMed

Cassia Amaral, Rita; Inacio, Marlene; Brito, Vinicius N; Bachega, Tania A S S; Oliveira, Ari A; Domenice, Sorahia; Denes, Francisco T; Sircili, Maria Helena; Arnhold, Ivo J P; Madureira, Guiomar; Gomes, Larissa; Costa, Elaine M F; Mendonca, Berenice B

2015-02-01

Few studies have focused on the quality of life (QoL) of patients with disorders of sex development (DSD). Our aim was to evaluate QoL in DSD patients with defined diagnoses followed until adulthood in a single tertiary centre. Adult patients with DSD (56 patients with 46,XX DSD - 49 with female social sex and 7 with male social sex as well as 88 patients with 46,XY DSD - 54 with female social sex and 34 with male social sex). QoL using WHOQOL-Bref questionnaire. Both patients with 46,XX DSD and patients with 46,XY DSD had similar QoL scores on the WHOQOL-Bref, comparable to the scores of the Brazilian general population. The chronological age at the start of treatment was negatively and significantly associated with general QoL score. Patients with male social sex DSD had better scores on the psychological domain than patients with female social sex DSD, as found in the Brazilian general population. In addition, among the 46,XY DSD group, the male social sex patients had better QoL compared with the female social sex patients. There was a positive and significant correlation between sexual performance and general QoL, although it explained only 4% of the variability of the general QoL score. The most influencing variables were general health, positive feelings and spirituality, religion and personal beliefs, each of them contributing with 18% of the variability of the general QoL score. Our large cohort of adult patients with DSD, which was followed by a multidisciplinary team in a single tertiary centre, had good QoL in adulthood; in addition, late treatment compromised the QoL of patients with DSD, whereas sexual performance has little influence on QoL. © 2014 John Wiley & Sons Ltd.

What does it mean to be pseudo single domain? Demystifying the PSD state

NASA Astrophysics Data System (ADS)

Lascu, I.; Harrison, R. J.; Einsle, J. F.; Ball, M.

2016-12-01

Until recently, non-interacting stable single domain grains were thought to be the sole reliable paleomagnetic recorders. However most natural samples contain so-called "non-ideal" paleomagnetic recorders, which are either interacting single domain particles, or magnetic grains larger than single domain grains, but smaller than proper multi domain grains, which are poor paleomagnetic recorders. The grain size range for these recorders, which for magnetite comprises grains from 100 nm to a few μm in size, is known as the pseudo single domain (PSD) state. Natural samples containing abundant PSD grains have been shown time and again to reliably record thermomagnetic remanent magnetizations that are stable over billions of years. Here we attempt to shed new light on the PSD state by investigating obsidian varieties found at Glass Butte, Oregon, which present the opportunity to study simple cases of magnetic grains encapsulated in volcanic glass. We do this by combining rock magnetism, scanning electron microscopy (SEM) nanotomography, and finite-element micromagnetic modeling. Using rock magnetism we have identified PSD signatures in these samples via their fingerprint in first-order reversal curve (FORC) diagrams. Tomographic reconstructions obtained by stacking SEM images acquired via sequential milling through sample volumes of a few tens of cubic μm reveal the presence of abundant grains that span the PSD grain size interval. These grains have a variety of shapes, from simple ellipsoidal particles, to more complex morphologies attained through the coalescence of neighboring grains during crystallization, to intricate "rolling snowball" morphologies in larger grains that contain appendices formed as a result of particle growth in a dynamic environment as the flowing lava cooled. Micromagnetic modeling of the simplest morphologies reveals that these grains are in single vortex states, with the remanence controlled by irregularities in grain morphology. Coalesced grains present extreme cases of shape anisotropy, which will control the remanence. The remanence of the largest grains is controlled by the collection of PSD states from areas of the grain with pronounced shape anisotropy. Finally, micromagnetic modeling of realistic grain shapes allows the understanding of PSD signatures in FORC diagrams.

Factors in Patient Empowerment: A Survey of an Online Patient Research Network.

PubMed

Chiauzzi, Emil; DasMahapatra, Pronabesh; Cochin, Elisenda; Bunce, Mikele; Khoury, Raya; Dave, Purav

2016-12-01

Providers and healthcare organizations have begun recognizing the importance of patient empowerment as a driver of patient-centered care. Unfortunately, most studies have investigated empowerment with single diseases. Identifying factors of empowerment across conditions and populations would enable a greater understanding of this construct. The purpose of this study was to understand empowerment in relation to health information-seeking, interactions with providers and peers, and healthcare access in chronic disease patients. This study also sought to identify key empowerment factors and their association with patient characteristics. Participants were recruited through PatientsLikeMe, an online research platform where patients share their personal and medical history data. Patients completed an online survey that assessed self-reported health behavior (e.g. knowledge-seeking, experiences with healthcare providers, and peer interactions) and healthcare access. An exploratory factor analysis identified key empowerment domains. Domain level sum scores and sum of all domains (total score) were compared across patient characteristics and diseases. Overall, 3988 participants were included in the study, with the majority actively involved in their healthcare, but many cited difficulties with matching their treatment goals with those of their physician (34 %) and spending sufficient time with the physician (36 %). Factor analysis identified two domains-Positive Patient-Provider Interaction, and Knowledge and Personal Control-that explained >60 % of the overall variance in the observed variables. Mean total empowerment scores for patients with a primary complaint of Parkinson's disease (61.8) and multiple sclerosis (60.3) were significantly greater than fibromyalgia (55.3) and chronic fatigue syndrome (54.8). Patients who were older, male, more educated, and insured also reported significantly greater levels of empowerment. The two domains of empowerment identified in this study are consistent with previous studies, but the differences in empowerment levels across diseases suggest a need for further studies on disease-related attributes of empowerment. Future research should examine the pathways for empowerment, as well as the relationship between empowerment domains and clinical outcomes.

Reciprocal Influence of Protein Domains in the Cold-Adapted Acyl Aminoacyl Peptidase from Sporosarcina psychrophila

PubMed Central

Parravicini, Federica; Natalello, Antonino; Papaleo, Elena; De Gioia, Luca; Doglia, Silvia Maria; Lotti, Marina; Brocca, Stefania

2013-01-01

Acyl aminoacyl peptidases are two-domain proteins composed by a C-terminal catalytic α/β-hydrolase domain and by an N-terminal β-propeller domain connected through a structural element that is at the N-terminus in sequence but participates in the 3D structure of the C-domain. We investigated about the structural and functional interplay between the two domains and the bridge structure (in this case a single helix named α1-helix) in the cold-adapted enzyme from Sporosarcina psychrophila (SpAAP) using both protein variants in which entire domains were deleted and proteins carrying substitutions in the α1-helix. We found that in this enzyme the inter-domain connection dramatically affects the stability of both the whole enzyme and the β-propeller. The α1-helix is required for the stability of the intact protein, as in other enzymes of the same family; however in this psychrophilic enzyme only, it destabilizes the isolated β-propeller. A single charged residue (E10) in the α1-helix plays a major role for the stability of the whole structure. Overall, a strict interaction of the SpAAP domains seems to be mandatory for the preservation of their reciprocal structural integrity and may witness their co-evolution. PMID:23457536

Reciprocal influence of protein domains in the cold-adapted acyl aminoacyl peptidase from Sporosarcina psychrophila.

PubMed

Parravicini, Federica; Natalello, Antonino; Papaleo, Elena; De Gioia, Luca; Doglia, Silvia Maria; Lotti, Marina; Brocca, Stefania

2013-01-01

Acyl aminoacyl peptidases are two-domain proteins composed by a C-terminal catalytic α/β-hydrolase domain and by an N-terminal β-propeller domain connected through a structural element that is at the N-terminus in sequence but participates in the 3D structure of the C-domain. We investigated about the structural and functional interplay between the two domains and the bridge structure (in this case a single helix named α1-helix) in the cold-adapted enzyme from Sporosarcina psychrophila (SpAAP) using both protein variants in which entire domains were deleted and proteins carrying substitutions in the α1-helix. We found that in this enzyme the inter-domain connection dramatically affects the stability of both the whole enzyme and the β-propeller. The α1-helix is required for the stability of the intact protein, as in other enzymes of the same family; however in this psychrophilic enzyme only, it destabilizes the isolated β-propeller. A single charged residue (E10) in the α1-helix plays a major role for the stability of the whole structure. Overall, a strict interaction of the SpAAP domains seems to be mandatory for the preservation of their reciprocal structural integrity and may witness their co-evolution.

Use of Model-Based Design Methods for Enhancing Resiliency Analysis of Unmanned Aerial Vehicles

NASA Astrophysics Data System (ADS)

Knox, Lenora A.

The most common traditional non-functional requirement analysis is reliability. With systems becoming more complex, networked, and adaptive to environmental uncertainties, system resiliency has recently become the non-functional requirement analysis of choice. Analysis of system resiliency has challenges; which include, defining resilience for domain areas, identifying resilience metrics, determining resilience modeling strategies, and understanding how to best integrate the concepts of risk and reliability into resiliency. Formal methods that integrate all of these concepts do not currently exist in specific domain areas. Leveraging RAMSoS, a model-based reliability analysis methodology for Systems of Systems (SoS), we propose an extension that accounts for resiliency analysis through evaluation of mission performance, risk, and cost using multi-criteria decision-making (MCDM) modeling and design trade study variability modeling evaluation techniques. This proposed methodology, coined RAMSoS-RESIL, is applied to a case study in the multi-agent unmanned aerial vehicle (UAV) domain to investigate the potential benefits of a mission architecture where functionality to complete a mission is disseminated across multiple UAVs (distributed) opposed to being contained in a single UAV (monolithic). The case study based research demonstrates proof of concept for the proposed model-based technique and provides sufficient preliminary evidence to conclude which architectural design (distributed vs. monolithic) is most resilient based on insight into mission resilience performance, risk, and cost in addition to the traditional analysis of reliability.

The Fanconi anemia associated protein FAAP24 uses two substrate specific binding surfaces for DNA recognition

PubMed Central

Wienk, Hans; Slootweg, Jack C.; Speerstra, Sietske; Kaptein, Robert; Boelens, Rolf; Folkers, Gert E.

2013-01-01

To maintain the integrity of the genome, multiple DNA repair systems exist to repair damaged DNA. Recognition of altered DNA, including bulky adducts, pyrimidine dimers and interstrand crosslinks (ICL), partially depends on proteins containing helix-hairpin-helix (HhH) domains. To understand how ICL is specifically recognized by the Fanconi anemia proteins FANCM and FAAP24, we determined the structure of the HhH domain of FAAP24. Although it resembles other HhH domains, the FAAP24 domain contains a canonical hairpin motif followed by distorted motif. The HhH domain can bind various DNA substrates; using nuclear magnetic resonance titration experiments, we demonstrate that the canonical HhH motif is required for double-stranded DNA (dsDNA) binding, whereas the unstructured N-terminus can interact with single-stranded DNA. Both DNA binding surfaces are used for binding to ICL-like single/double-strand junction-containing DNA substrates. A structural model for FAAP24 bound to dsDNA has been made based on homology with the translesion polymerase iota. Site-directed mutagenesis, sequence conservation and charge distribution support the dsDNA-binding model. Analogous to other HhH domain-containing proteins, we suggest that multiple FAAP24 regions together contribute to binding to single/double-strand junction, which could contribute to specificity in ICL DNA recognition. PMID:23661679

The CRM domain: an RNA binding module derived from an ancient ribosome-associated protein.

PubMed

Barkan, Alice; Klipcan, Larik; Ostersetzer, Oren; Kawamura, Tetsuya; Asakura, Yukari; Watkins, Kenneth P

2007-01-01

The CRS1-YhbY domain (also called the CRM domain) is represented as a stand-alone protein in Archaea and Bacteria, and in a family of single- and multidomain proteins in plants. The function of this domain is unknown, but structural data and the presence of the domain in several proteins known to interact with RNA have led to the proposal that it binds RNA. Here we describe a phylogenetic analysis of the domain, its incorporation into diverse proteins in plants, and biochemical properties of a prokaryotic and eukaryotic representative of the domain family. We show that a bacterial member of the family, Escherichia coli YhbY, is associated with pre-50S ribosomal subunits, suggesting that YhbY functions in ribosome assembly. GFP fused to a single-domain CRM protein from maize localizes to the nucleolus, suggesting that an analogous activity may have been retained in plants. We show further that an isolated maize CRM domain has RNA binding activity in vitro, and that a small motif shared with KH RNA binding domains, a conserved "GxxG" loop, contributes to its RNA binding activity. These and other results suggest that the CRM domain evolved in the context of ribosome function prior to the divergence of Archaea and Bacteria, that this function has been maintained in extant prokaryotes, and that the domain was recruited to serve as an RNA binding module during the evolution of plant genomes.

An intact SAM-dependent methyltransferase fold is encoded by the human endothelin-converting enzyme-2 gene

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

Tempel, W.; Wu, H.; Dombrovsky, L.

2010-08-17

A recent survey of protein expression patterns in patients with Alzheimer's disease (AD) has identified ece2 (chromosome: 3; Locations: 3q27.1) as the most significantly downregulated gene within the tested group. ece2 encodes endothelin-converting enzyme ECE2, a metalloprotease with a role in neuropeptide processing. Deficiency in the highly homologous ECE1 has earlier been linked to increased levels of AD-related {beta}-amyloid peptide in mice, consistent with a role for ECE in the degradation of that peptide. Initially, ECE2 was presumed to resemble ECE1, in that it comprises a single transmembrane region of {approx}20 residues flanked by a small amino-terminal cytosolic segment andmore » a carboxy-terminal lumenar peptidase domain. The carboxy-terminal domain has significant sequence similarity to both neutral endopeptidase, for which an X-ray structure has been determined, and Kell blood group protein. After their initial discovery, multiple isoforms of ECE1 and ECE2 were discovered, generated by alternative splicing of multiple exons. The originally described ece2 transcript, RefSeq NM{_}174046, contains the amino-terminal cytosolic portion followed by the transmembrane region and peptidase domain (Fig. 1, isoform B). Another ece2 transcript, available from the Mammalian Gene Collection under MGC2408 (Fig. 1, isoform C), RefSeq accession NM{_}032331, is predicted to be translated into a 255 residue peptide with low but detectable sequence similarity to known S-adenosyl-L-methionine (SAM)-dependent methyltransferases (SAM-MTs), such as the hypothetical protein TT1324 from Thermus thermophilis, PDB code 2GS9, which shares 30% amino acid sequence identity with ECE2 over 138 residues of the sequence. Intriguingly, another 'elongated' ece2 transcript (Fig. 1, isoform A) (RefSeq NM{_}014693) contains an amino-terminal portion of the putative SAM-MT domain, the transmembrane domain, and the protease domain. This suggests the possibility for coexistence of the putative SAM-MT and protease domains in a single polypeptide and their transmembrane interplay. Although sequence conservation across the SAM-MT family is weak, the structural fold is highly conserved. The most conserved part of this fold is the SAM-binding subdomain, which is shared between MGC2408 and hypothetical protein TT1324. Typically, the SAM-binding subdomain is flanked by a variable Nterminal extension and, at the C-terminus, by a substrate- binding subdomain, which varies enormously in size but preserves a conserved topology with three antiparallel b-strands. The 'elongated' transcript of ece2 lacks this substrate-binding subdomain. To test the hypothesis that the 255 residue ece2 gene product MGC2408 represents a complete SAM-MT fold, we have determined a crystal structure of this protein in the presence of SAH.« less

Fabrication of single domain GdBCO bulk superconductors by a new modified TSIG technique

NASA Astrophysics Data System (ADS)

Yang, W. M.; Zhi, X.; Chen, S. L.; Wang, M.; Li, J. W.; Ma, J.; Chao, X. X.

2014-01-01

Single domain GdBCO bulk superconductors have been fabricated with new and traditional solid phases by a top seeded infiltration and growth (TSIG) process technique. In the conventional TSIG process, three types of powders, such as Gd2BaCuO5, GdBa2Cu3O7-x and Ba3Cu5O8, must be prepared, but in our new modified TSIG technique, only BaCuO2 powders are required during the fabrication of the single domain GdBCO bulk superconductors. The solid phase used in the conventional process is Gd2BaCuO5 instead of the solid phase (Gd2O3 + BaCuO2) utilized in the new process. The liquid phase used in the conventional process is a mixture of (GdBa2Cu3O7-x + Ba3Cu5O8), and the liquid phase in the new process is a mixture of (Gd2O3 + 10BaCuO2 + 6CuO). Single domain GdBCO bulk superconductors have been fabricated with the new solid and liquid phases. The levitation force of the GdBCO bulk samples fabricated by the new solid phase is 28 N, which is slightly higher than that of the samples fabricated using the conventional solid phases (26 N). The microstructure and the levitation force of the samples indicate that this new method can greatly simplify the fabrication process, introduce nanometer-sized flux centers, improve the levitation force and working efficiency, and greatly reduce the cost of fabrication of single domain GdBCO bulk superconductors by the TSIG process.

Numerical solution of the wave equation with variable wave speed on nonconforming domains by high-order difference potentials

NASA Astrophysics Data System (ADS)

Britt, S.; Tsynkov, S.; Turkel, E.

2018-02-01

We solve the wave equation with variable wave speed on nonconforming domains with fourth order accuracy in both space and time. This is accomplished using an implicit finite difference (FD) scheme for the wave equation and solving an elliptic (modified Helmholtz) equation at each time step with fourth order spatial accuracy by the method of difference potentials (MDP). High-order MDP utilizes compact FD schemes on regular structured grids to efficiently solve problems on nonconforming domains while maintaining the design convergence rate of the underlying FD scheme. Asymptotically, the computational complexity of high-order MDP scales the same as that for FD.

Topology and weights in a protein domain interaction network--a novel way to predict protein interactions.

PubMed

Wuchty, Stefan

2006-05-23

While the analysis of unweighted biological webs as diverse as genetic, protein and metabolic networks allowed spectacular insights in the inner workings of a cell, biological networks are not only determined by their static grid of links. In fact, we expect that the heterogeneity in the utilization of connections has a major impact on the organization of cellular activities as well. We consider a web of interactions between protein domains of the Protein Family database (PFAM), which are weighted by a probability score. We apply metrics that combine the static layout and the weights of the underlying interactions. We observe that unweighted measures as well as their weighted counterparts largely share the same trends in the underlying domain interaction network. However, we only find weak signals that weights and the static grid of interactions are connected entities. Therefore assuming that a protein interaction is governed by a single domain interaction, we observe strong and significant correlations of the highest scoring domain interaction and the confidence of protein interactions in the underlying interactions of yeast and fly. Modeling an interaction between proteins if we find a high scoring protein domain interaction we obtain 1, 428 protein interactions among 361 proteins in the human malaria parasite Plasmodium falciparum. Assessing their quality by a logistic regression method we observe that increasing confidence of predicted interactions is accompanied by high scoring domain interactions and elevated levels of functional similarity and evolutionary conservation. Our results indicate that probability scores are randomly distributed, allowing to treat static grid and weights of domain interactions as separate entities. In particular, these finding confirms earlier observations that a protein interaction is a matter of a single interaction event on domain level. As an immediate application, we show a simple way to predict potential protein interactions by utilizing expectation scores of single domain interactions.

Domain Specificity and the Limits of Creativity Theory

ERIC Educational Resources Information Center

Baer, John

2012-01-01

A growing body of research evidence suggests that creativity is very domain-specific and that domain-general skills or traits contribute little to creative performance. The term "creativity" is a convenient term for collecting many interesting artifacts, processes, and people into a single category, and the term "creative thinking…

Single-shot terahertz time-domain spectroscopy in pulsed high magnetic fields

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

Noe, II, G. Timothy; Katayama, Ikufumi; Katsutani, Fumiya

Here, we have developed a single-shot terahertz time-domain spectrometer to perform optical-pump/terahertz-probe experiments in pulsed, high magnetic fields up to 30 T. The single-shot detection scheme for measuring a terahertz waveform incorporates a reflective echelon to create time-delayed beamlets across the intensity profile of the optical gate beam before it spatially and temporally overlaps with the terahertz radiation in a ZnTe detection crystal. After imaging the gate beam onto a camera, we can retrieve the terahertz time-domain waveform by analyzing the resulting image. To demonstrate the utility of our technique, we measured cyclotron resonance absorption of optically excited carriers inmore » the terahertz frequency range in intrinsic silicon at high magnetic fields, with results that agree well with published values.« less

Single-shot terahertz time-domain spectroscopy in pulsed high magnetic fields

DOE PAGES

Noe, II, G. Timothy; Katayama, Ikufumi; Katsutani, Fumiya; ...

2016-12-22

Here, we have developed a single-shot terahertz time-domain spectrometer to perform optical-pump/terahertz-probe experiments in pulsed, high magnetic fields up to 30 T. The single-shot detection scheme for measuring a terahertz waveform incorporates a reflective echelon to create time-delayed beamlets across the intensity profile of the optical gate beam before it spatially and temporally overlaps with the terahertz radiation in a ZnTe detection crystal. After imaging the gate beam onto a camera, we can retrieve the terahertz time-domain waveform by analyzing the resulting image. To demonstrate the utility of our technique, we measured cyclotron resonance absorption of optically excited carriers inmore » the terahertz frequency range in intrinsic silicon at high magnetic fields, with results that agree well with published values.« less

Impairment in Proverb Interpretation as an Executive Function Deficit in Patients with Amnestic Mild Cognitive Impairment and Early Alzheimer's Disease

PubMed Central

Leyhe, Thomas; Saur, Ralf; Eschweiler, Gerhard W.; Milian, Monika

2011-01-01

Background/Aims Proverb interpretation is assumed to reflect executive functions. We hypothesized that proverb interpretation is impaired in patients with amnestic mild cognitive impairment (aMCI) diagnosed as single-domain impairment by common neuropsychological testing. Methods We compared performance in a proverb interpretation test in single-domain aMCI patients and patients with early Alzheimer's disease (EAD). Results The groups with aMCI and EAD performed significantly worse than healthy controls. Both patient groups gave concrete answers with a similar frequency. However, patients with EAD tended to give senseless answers more frequently. Conclusions Our data suggest that in patients diagnosed as single-domain aMCI, deterioration of executive functions is detectable with subtle and appropriate neuropsychological testing. Implementation of these procedures may improve the early prediction of AD. PMID:22163233

Contributions of physical and cognitive impairments to self-reported driving difficulty in chronic whiplash-associated disorders.

PubMed

Takasaki, Hiroshi; Treleaven, Julia; Johnston, Venerina; Jull, Gwendolen

2013-08-15

Cross-sectional. To conduct a preliminary analysis of the physical, cognitive, and psychological domains contributing to self-reported driving difficulty after adjusting for neck pain, dizziness, and relevant demographics in chronic whiplash-associated disorders (WAD) using hierarchical regression modeling. Pain is a risk factor for car crashes, and dizziness may affect fitness to drive. Both symptoms are common in chronic WAD and difficulty driving is a common complaint in this group. Chronic WAD is often accompanied by physical, cognitive, and psychological impairments. These impairments may contribute to self-reported driving difficulty beyond neck pain, dizziness, and relevant demographics. Forty individuals with chronic WAD participated. Dependent variables were the magnitude of self-reported driving difficulty assessed in the strategic, tactical, and operational levels of the Neck Pain Driving Index. Three models were developed to assess the contributions of independent variables (physical, cognitive, and psychological domains) to each of the 3 dependent variables after adjusting for neck pain intensity, dizziness, and driving demographics. The measures included were: physical domain-range and maximum speed of head rotation, performances during gaze stability, eye-head coordination, and visual dependency tests; cognitive domain-self-reported cognitive symptoms including fatigue and the trail making tests; and psychological domain-general stress, traumatic stress, depression, and fear of neck movements and driving. Symptom duration was relevant to driving difficulty in the strategic and tactical levels. The cognitive domain increased statistical power to estimate the strategic and operational levels (P < 0.1) beyond other contributors. The physical domain increased statistical power to estimate the tactical level (P < 0.1) beyond other contributors. Physical and cognitive impairments independently contributed to self-reported driving difficulty in chronic WAD beyond neck pain, dizziness, and symptom duration. 3.

Multiple graph regularized protein domain ranking.

PubMed

Wang, Jim Jing-Yan; Bensmail, Halima; Gao, Xin

2012-11-19

Protein domain ranking is a fundamental task in structural biology. Most protein domain ranking methods rely on the pairwise comparison of protein domains while neglecting the global manifold structure of the protein domain database. Recently, graph regularized ranking that exploits the global structure of the graph defined by the pairwise similarities has been proposed. However, the existing graph regularized ranking methods are very sensitive to the choice of the graph model and parameters, and this remains a difficult problem for most of the protein domain ranking methods. To tackle this problem, we have developed the Multiple Graph regularized Ranking algorithm, MultiG-Rank. Instead of using a single graph to regularize the ranking scores, MultiG-Rank approximates the intrinsic manifold of protein domain distribution by combining multiple initial graphs for the regularization. Graph weights are learned with ranking scores jointly and automatically, by alternately minimizing an objective function in an iterative algorithm. Experimental results on a subset of the ASTRAL SCOP protein domain database demonstrate that MultiG-Rank achieves a better ranking performance than single graph regularized ranking methods and pairwise similarity based ranking methods. The problem of graph model and parameter selection in graph regularized protein domain ranking can be solved effectively by combining multiple graphs. This aspect of generalization introduces a new frontier in applying multiple graphs to solving protein domain ranking applications.

Multiple graph regularized protein domain ranking

PubMed Central

2012-01-01

Background Protein domain ranking is a fundamental task in structural biology. Most protein domain ranking methods rely on the pairwise comparison of protein domains while neglecting the global manifold structure of the protein domain database. Recently, graph regularized ranking that exploits the global structure of the graph defined by the pairwise similarities has been proposed. However, the existing graph regularized ranking methods are very sensitive to the choice of the graph model and parameters, and this remains a difficult problem for most of the protein domain ranking methods. Results To tackle this problem, we have developed the Multiple Graph regularized Ranking algorithm, MultiG-Rank. Instead of using a single graph to regularize the ranking scores, MultiG-Rank approximates the intrinsic manifold of protein domain distribution by combining multiple initial graphs for the regularization. Graph weights are learned with ranking scores jointly and automatically, by alternately minimizing an objective function in an iterative algorithm. Experimental results on a subset of the ASTRAL SCOP protein domain database demonstrate that MultiG-Rank achieves a better ranking performance than single graph regularized ranking methods and pairwise similarity based ranking methods. Conclusion The problem of graph model and parameter selection in graph regularized protein domain ranking can be solved effectively by combining multiple graphs. This aspect of generalization introduces a new frontier in applying multiple graphs to solving protein domain ranking applications. PMID:23157331

Single-Molecule Fluorescence Reveals the Oligomerization and Folding Steps Driving the Prion-like Behavior of ASC.

PubMed

Gambin, Yann; Giles, Nichole; O'Carroll, Ailís; Polinkovsky, Mark; Hunter, Dominic; Sierecki, Emma

2018-02-16

Single-molecule fluorescence has the unique ability to quantify small oligomers and track conformational changes at a single-protein level. Here we tackled one of the most extreme protein behaviors, found recently in an inflammation pathway. Upon danger recognition in the cytosol, NLRP3 recruits its signaling adaptor, ASC. ASC start polymerizing in a prion-like manner and the system goes in "overdrive" by producing a single micron-sized "speck." By precisely controlling protein expression levels in an in vitro translation system, we could trigger the polymerization of ASC and mimic formation of specks in the absence of inflammasome nucleators. We utilized single-molecule spectroscopy to fully characterize prion-like behaviors and self-propagation of ASC fibrils. We next used our controlled system to monitor the conformational changes of ASC upon fibrillation. Indeed, ASC consists of a PYD and CARD domains, separated by a flexible linker. Individually, both domains have been found to form fibrils, but the structure of the polymers formed by the full-length ASC proteins remains elusive. For the first time, using single-molecule Förster resonance energy transfer, we studied the relative positions of the CARD and PYD domains of full-length ASC. An unexpectedly large conformational change occurred upon ASC fibrillation, suggesting that the CARD domain folds back onto the PYD domain. However, contradicting current models, the "prion-like" conformer was not initiated by binding of ASC to the NLRP3 platform. Rather, using a new method, hybrid between Photon Counting Histogram and Number and Brightness analysis, we showed that NLRP3 forms hexamers with self-binding affinities around 300nM. Overall our data suggest a new mechanism, where NLRP3 can initiate ASC polymerization simply by increasing the local concentration of ASC above a supercritical level. Copyright © 2017. Published by Elsevier Ltd.

Design and Testing of a Thermostable Platform for Multimerization of Single Domain Antibodies

DTIC Science & Technology

2012-08-01

1 DESIGN AND TESTING OF A THERMOSTABLE PLATFORM FOR MULTIMERIZATION OF SINGLE DOMAIN ANTIBODIES ECBC-TR...Army position unless so designated by other authorizing documents. REPORT DOCUMENTATION PAGE Form Approved OMB No. 0704-0188 Public...ADDRESS. 1. REPORT DATE (DD-MM-YYYY) XX-08-2012 2. REPORT TYPE Final 3. DATES COVERED (From - To) Oct 2008 - Sep 2010 4. TITLE AND SUBTITLE Design

The time dependent magnetization of fine-grained iron in lunar breccias

NASA Technical Reports Server (NTRS)

Gose, W. A.; Carnes, J. G.

1973-01-01

Lunar breccias of low metamorphic grade offer a unique opportunity to investigate the magnetic properties of dispersed fine-grained iron. These rocks exhibit a pronounced time-dependent magnetization whose acquisition and decay are well explained by Neel's single-domain theory. The effect is due to iron grains in the range from 120 to 150 A in diameter, which covers the transition from superparamagnetic to stable single-domain behavior.

Direct observation of magnetic domains by Kerr microscopy in a Ni-Mn-Ga magnetic shape-memory alloy

NASA Astrophysics Data System (ADS)

Perevertov, O.; Heczko, O.; Schäfer, R.

2017-04-01

The magnetic domains in a magnetic shape-memory Ni-Mn-Ga alloy were observed by magneto-optical Kerr microscopy using monochromatic blue LED light. The domains were observed for both single- and multivariant ferroelastic states of modulated martensite. The multivariant state with very fine twins was spontaneously formed after transformation from high-temperature austenite. For both cases, bar domains separated by 180∘ domain walls were found and their dynamics was studied. A quasidomain model was applied to explain the domains in the multivariant state.

Continuum analysis of the nucleus growth of reverse domains in large ferroelectric crystals

NASA Astrophysics Data System (ADS)

Neumeister, Peter; Balke, Herbert; Lupascu, Doru C.

2009-04-01

Polarization reversal in ferroelectrics arises due to domain nucleation and domain wall motion. The nucleation of reverse domains at crystal boundaries is the fundamental initiation process observed in single crystals. The classical continuum approach by Landauer determines an insurmountable energy barrier to extrinsic domain nucleation. We rediscuss the continuum approach. Predetermined surface states are found to be a misleading concept. Alternate energy contributions, for example, due to a dead layer or due to charge injection as well as reduced domain wall energy and anisotropy of domain wall energy, have to be included into a convincing picture of domain nucleation.

A three-lead, programmable, and microcontroller-based electrocardiogram generator with frequency domain characteristics of heart rate variability.

PubMed

Wei, Ying-Chieh; Wei, Ying-Yu; Chang, Kai-Hsiung; Young, Ming-Shing

2012-04-01

The objective of this study is to design and develop a programmable electrocardiogram (ECG) generator with frequency domain characteristics of heart rate variability (HRV) which can be used to test the efficiency of ECG algorithms and to calibrate and maintain ECG equipment. We simplified and modified the three coupled ordinary differential equations in McSharry's model to a single differential equation to obtain the ECG signal. This system not only allows the signal amplitude, heart rate, QRS-complex slopes, and P- and T-wave position parameters to be adjusted, but can also be used to adjust the very low frequency, low frequency, and high frequency components of HRV frequency domain characteristics. The system can be tuned to function with HRV or not. When the HRV function is on, the average heart rate can be set to a value ranging from 20 to 122 beats per minute (BPM) with an adjustable variation of 1 BPM. When the HRV function is off, the heart rate can be set to a value ranging from 20 to 139 BPM with an adjustable variation of 1 BPM. The amplitude of the ECG signal can be set from 0.0 to 330 mV at a resolution of 0.005 mV. These parameters can be adjusted either via input through a keyboard or through a graphical user interface (GUI) control panel that was developed using LABVIEW. The GUI control panel depicts a preview of the ECG signal such that the user can adjust the parameters to establish a desired ECG morphology. A complete set of parameters can be stored in the flash memory of the system via a USB 2.0 interface. Our system can generate three different types of synthetic ECG signals for testing the efficiency of an ECG algorithm or calibrating and maintaining ECG equipment. © 2012 American Institute of Physics

A three-lead, programmable, and microcontroller-based electrocardiogram generator with frequency domain characteristics of heart rate variability

NASA Astrophysics Data System (ADS)

Wei, Ying-Chieh; Wei, Ying-Yu; Chang, Kai-Hsiung; Young, Ming-Shing

2012-04-01

The objective of this study is to design and develop a programmable electrocardiogram (ECG) generator with frequency domain characteristics of heart rate variability (HRV) which can be used to test the efficiency of ECG algorithms and to calibrate and maintain ECG equipment. We simplified and modified the three coupled ordinary differential equations in McSharry's model to a single differential equation to obtain the ECG signal. This system not only allows the signal amplitude, heart rate, QRS-complex slopes, and P- and T-wave position parameters to be adjusted, but can also be used to adjust the very low frequency, low frequency, and high frequency components of HRV frequency domain characteristics. The system can be tuned to function with HRV or not. When the HRV function is on, the average heart rate can be set to a value ranging from 20 to 122 beats per minute (BPM) with an adjustable variation of 1 BPM. When the HRV function is off, the heart rate can be set to a value ranging from 20 to 139 BPM with an adjustable variation of 1 BPM. The amplitude of the ECG signal can be set from 0.0 to 330 mV at a resolution of 0.005 mV. These parameters can be adjusted either via input through a keyboard or through a graphical user interface (GUI) control panel that was developed using LABVIEW. The GUI control panel depicts a preview of the ECG signal such that the user can adjust the parameters to establish a desired ECG morphology. A complete set of parameters can be stored in the flash memory of the system via a USB 2.0 interface. Our system can generate three different types of synthetic ECG signals for testing the efficiency of an ECG algorithm or calibrating and maintaining ECG equipment.

Cognitive Effects of Stimulant, Guanfacine, and Combined Treatment in Child and Adolescent Attention-Deficit/Hyperactivity Disorder.

PubMed

Bilder, Robert M; Loo, Sandra K; McGough, James J; Whelan, Fiona; Hellemann, Gerhard; Sugar, Catherine; Del'Homme, Melissa; Sturm, Alexandra; Cowen, Jennifer; Hanada, Grant; McCracken, James T

2016-08-01

Psychostimulants are partially effective in reducing cognitive dysfunction associated with attention-deficit/hyperactivity disorder (ADHD). Cognitive effects of guanfacine, an alternative treatment, are poorly understood. Given its distinct action on α2A receptors, guanfacine may have different or complementary effects relative to stimulants. This study tested stimulant and guanfacine monotherapies relative to combined treatment on cognitive functions important in ADHD. Children with ADHD (n = 182; aged 7-14 years) completed an 8-week, double blind, randomized, controlled trial with 3 arms: d-methylphenidate (DMPH), guanfacine (GUAN), or combination treatment with DMPH and GUAN (COMB). A nonclinical comparison group (n = 93) had baseline testing, and a subset was retested 8 weeks later (n = 38). Analyses examined treatment effects in 4 cognitive domains (working memory, response inhibition, reaction time, and reaction time variability) constructed from 20 variables. The ADHD group showed impaired working memory relative to the nonclinical comparison group (effect size = -0.53 SD unit). The treatments differed in effects on working memory but not other cognitive domains. Combination treatment improved working memory more than GUAN but was not significantly better than DMPH alone. Treatment did not fully normalize the initial deficit in ADHD relative to the comparison group. Combined treatment with DMPH and GUAN yielded greater improvements in working memory than placebo or GUAN alone, but the combined treatment was not superior to DMPH alone and did not extend to other cognitive domains. Although GUAN may be a useful add-on treatment to psychostimulants, additional strategies appear to be necessary to achieve normalization of cognitive function in ADHD. Single Versus Combination Medication Treatment for Children With Attention Deficit Hyperactivity Disorder; http://clinicaltrials.gov/; NCT00429273. Copyright © 2016 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

Computer program for single input-output, single-loop feedback systems

NASA Technical Reports Server (NTRS)

1976-01-01

Additional work is reported on a completely automatic computer program for the design of single input/output, single loop feedback systems with parameter uncertainly, to satisfy time domain bounds on the system response to step commands and disturbances. The inputs to the program are basically the specified time-domain response bounds, the form of the constrained plant transfer function and the ranges of the uncertain parameters of the plant. The program output consists of the transfer functions of the two free compensation networks, in the form of the coefficients of the numerator and denominator polynomials, and the data on the prescribed bounds and the extremes actually obtained for the system response to commands and disturbances.

Characterization of the molecular basis of group II intron RNA recognition by CRS1-CRM domains.

PubMed

Keren, Ido; Klipcan, Liron; Bezawork-Geleta, Ayenachew; Kolton, Max; Shaya, Felix; Ostersetzer-Biran, Oren

2008-08-22

CRM (chloroplast RNA splicing and ribosome maturation) is a recently recognized RNA-binding domain of ancient origin that has been retained in eukaryotic genomes only within the plant lineage. Whereas in bacteria CRM domains exist as single domain proteins involved in ribosome maturation, in plants they are found in a family of proteins that contain between one and four repeats. Several members of this family with multiple CRM domains have been shown to be required for the splicing of specific plastidic group II introns. Detailed biochemical analysis of one of these factors in maize, CRS1, demonstrated its high affinity and specific binding to the single group II intron whose splicing it facilitates, the plastid-encoded atpF intron RNA. Through its association with two intronic regions, CRS1 guides the folding of atpF intron RNA into its predicted "catalytically active" form. To understand how multiple CRM domains cooperate to achieve high affinity sequence-specific binding to RNA, we analyzed the RNA binding affinity and specificity associated with each individual CRM domain in CRS1; whereas CRM3 bound tightly to the RNA, CRM1 associated specifically with a unique region found within atpF intron domain I. CRM2, which demonstrated only low binding affinity, also seems to form specific interactions with regions localized to domains I, III, and IV. We further show that CRM domains share structural similarities and RNA binding characteristics with the well known RNA recognition motif domain.

Thermal phase transition behavior of lipid layers on a single human corneocyte cell.

PubMed

Imai, Tomohiro; Nakazawa, Hiromitsu; Kato, Satoru

2013-09-01

We have improved the selected area electron diffraction method to analyze the dynamic structural change in a single corneocyte cell non-invasively stripped off from human skin surface. The improved method made it possible to obtain reliable diffraction images to trace the structural change in the intercellular lipid layers on a single corneocyte cell during heating from 24°C to 100°C. Comparison of the results with those of synchrotron X-ray diffraction experiments on human stratum corneum sheets revealed that the intercellular lipid layers on a corneocyte cell exhibit essentially the same thermal phase transitions as those in a stratum corneum sheet. These results suggest that the structural features of the lipid layers are well preserved after the mechanical stripping of the corneocyte cell. Moreover, electron diffraction analyses of the thermal phase transition behaviors of the corneocyte cells that had the lipid layers with different distributions of orthorhombic and hexagonal domains at 24°C suggested that small orthorhombic domains interconnected with surrounding hexagonal domains transforms in a continuous manner into new hexagonal domains. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Single Carrier with Frequency Domain Equalization for Synthetic Aperture Underwater Acoustic Communications

PubMed Central

He, Chengbing; Xi, Rui; Wang, Han; Jing, Lianyou; Shi, Wentao; Zhang, Qunfei

2017-01-01

Phase-coherent underwater acoustic (UWA) communication systems typically employ multiple hydrophones in the receiver to achieve spatial diversity gain. However, small underwater platforms can only carry a single transducer which can not provide spatial diversity gain. In this paper, we propose single-carrier with frequency domain equalization (SC-FDE) for phase-coherent synthetic aperture acoustic communications in which a virtual array is generated by the relative motion between the transmitter and the receiver. This paper presents synthetic aperture acoustic communication results using SC-FDE through data collected during a lake experiment in January 2016. The performance of two receiver algorithms is analyzed and compared, including the frequency domain equalizer (FDE) and the hybrid time frequency domain equalizer (HTFDE). The distances between the transmitter and the receiver in the experiment were about 5 km. The bit error rate (BER) and output signal-to-noise ratio (SNR) performances with different receiver elements and transmission numbers were presented. After combining multiple transmissions, error-free reception using a convolution code with a data rate of 8 kbps was demonstrated. PMID:28684683

Adaptive frequency-domain equalization for the transmission of the fundamental mode in a few-mode fiber.

PubMed

Bai, Neng; Xia, Cen; Li, Guifang

2012-10-08

We propose and experimentally demonstrate single-carrier adaptive frequency-domain equalization (SC-FDE) to mitigate multipath interference (MPI) for the transmission of the fundamental mode in a few-mode fiber. The FDE approach reduces computational complexity significantly compared to the time-domain equalization (TDE) approach while maintaining the same performance. Both FDE and TDE methods are evaluated by simulating long-haul fundamental-mode transmission using a few-mode fiber. For the fundamental mode operation, the required tap length of the equalizer depends on the differential mode group delay (DMGD) of a single span rather than DMGD of the entire link.

Predicting Health Care Utilization in Marginalized Populations: Black, Female, Street-based Sex Workers

PubMed Central

Varga, Leah M.; Surratt, Hilary L.

2014-01-01

Background Patterns of social and structural factors experienced by vulnerable populations may negatively affect willingness and ability to seek out health care services, and ultimately, their health. Methods The outcome variable was utilization of health care services in the previous 12 months. Using Andersen’s Behavioral Model for Vulnerable Populations, we examined self-reported data on utilization of health care services among a sample of 546 Black, street-based female sex workers in Miami, Florida. To evaluate the impact of each domain of the model on predicting health care utilization, domains were included in the logistic regression analysis by blocks using the traditional variables first and then adding the vulnerable domain variables. Findings The most consistent variables predicting health care utilization were having a regular source of care and self-rated health. The model that included only enabling variables was the most efficient model in predicting health care utilization. Conclusions Any type of resource, link, or connection to or with an institution, or any consistent point of care contributes significantly to health care utilization behaviors. A consistent and reliable source for health care may increase health care utilization and subsequently decrease health disparities among vulnerable and marginalized populations, as well as contribute to public health efforts that encourage preventive health. PMID:24657047

Single Crystalline Film of Hexagonal Boron Nitride Atomic Monolayer by Controlling Nucleation Seeds and Domains

PubMed Central

Wu, Qinke; Park, Ji-Hoon; Park, Sangwoo; Jung, Seong Jun; Suh, Hwansoo; Park, Noejung; Wongwiriyapan, Winadda; Lee, Sungjoo; Lee, Young Hee; Song, Young Jae

2015-01-01

A monolayer hexagonal boron nitride (h-BN) film with controllable domain morphology and domain size (varying from less than 1 μm to more than 100 μm) with uniform crystalline orientation was successfully synthesized by chemical vapor deposition (CVD). The key for this extremely large single crystalline domain size of a h-BN monolayer is a decrease in the density of nucleation seeds by increasing the hydrogen gas flow during the h-BN growth. Moreover, the well-defined shape of h-BN flakes can be selectively grown by controlling Cu-annealing time under argon atmosphere prior to h-BN growth, which provides the h-BN shape varies in triangular, trapezoidal, hexagonal and complex shapes. The uniform crystalline orientation of h-BN from different nucleation seeds can be easily confirmed by polarized optical microscopy (POM) with a liquid crystal coating. Furthermore, seamlessly merged h-BN flakes without structural domain boundaries were evidence by a selective hydrogen etching after a full coverage of a h-BN film was achieved. This seamless large-area and atomic monolayer of single crystalline h-BN film can offer as an ideal and practical template of graphene-based devices or alternative two-dimensional materials for industrial applications with scalability. PMID:26537788

Complete stress-induced depolarization of relaxor ferroelectric crystals without transition through a non-polar phase

NASA Astrophysics Data System (ADS)

Shkuratov, Sergey I.; Baird, Jason; Antipov, Vladimir G.; Hackenberger, Wesley; Luo, Jun; Zhang, Shujun; Lynch, Christopher S.; Chase, Jay B.; Jo, Hwan R.; Roberts, Christopher C.

2018-03-01

The development of relaxor ferroelectric single crystal technology is driven by the ability to tailor ferroelectric properties through domain engineering not achievable in polycrystalline materials. In this study, three types of domain-engineered rhombohedral Pb(In1/2Nb1/2)O3-Pb(Mg1/3Nb2/3)O3-PbTiO3 crystals were subjected to transverse high strain rate loading. The experimental results indicate that the domain configuration has a significant effect on the stress-induced depolarization and the associated charge released. A complete depolarization of the single-domain crystals with 3m symmetry is observed, while multidomain crystals with 4mm and mm2 symmetries retain a fraction of their initial remanent polarization. The complete depolarization of single-domain crystals is unique without transition to a non-polar phase, with a stress-induced charge density of 0.48 C/m2. This is up to three times higher than that of the multidomain crystals and PbZrxTi1-xO3 ferroelectric ceramics that are critical for ultrahigh-power transducer applications. The main offering of this work is to propose a detailed mechanism for complete stress-induced depolarization in ferroelectric crystals which does not involve an intermediate transformation to a non-polar phase.

Single Crystalline Film of Hexagonal Boron Nitride Atomic Monolayer by Controlling Nucleation Seeds and Domains

NASA Astrophysics Data System (ADS)

Wu, Qinke; Park, Ji-Hoon; Park, Sangwoo; Jung, Seong Jun; Suh, Hwansoo; Park, Noejung; Wongwiriyapan, Winadda; Lee, Sungjoo; Lee, Young Hee; Song, Young Jae

2015-11-01

A monolayer hexagonal boron nitride (h-BN) film with controllable domain morphology and domain size (varying from less than 1 μm to more than 100 μm) with uniform crystalline orientation was successfully synthesized by chemical vapor deposition (CVD). The key for this extremely large single crystalline domain size of a h-BN monolayer is a decrease in the density of nucleation seeds by increasing the hydrogen gas flow during the h-BN growth. Moreover, the well-defined shape of h-BN flakes can be selectively grown by controlling Cu-annealing time under argon atmosphere prior to h-BN growth, which provides the h-BN shape varies in triangular, trapezoidal, hexagonal and complex shapes. The uniform crystalline orientation of h-BN from different nucleation seeds can be easily confirmed by polarized optical microscopy (POM) with a liquid crystal coating. Furthermore, seamlessly merged h-BN flakes without structural domain boundaries were evidence by a selective hydrogen etching after a full coverage of a h-BN film was achieved. This seamless large-area and atomic monolayer of single crystalline h-BN film can offer as an ideal and practical template of graphene-based devices or alternative two-dimensional materials for industrial applications with scalability.

Coordinated disintegration reactions mediated by Moloney murine leukemia virus integrase.

PubMed Central

Donzella, G A; Jonsson, C B; Roth, M J

1996-01-01

The protein-DNA and protein-protein interactions important for function of the integrase (IN) protein of Moloney murine leukemia virus (M-MuLV) were investigated by using a coordinated-disintegration assay. A panel of M-MuLV IN mutants and substrate alterations highlighted distinctions between the intermolecular and intramolecular reactions of coordinated disintegration. Mispairing of the crossbone single-strand region and altered long terminal repeat (LTR) positioning affected the intermolecular, but not the intramolecular, reactions of coordinated disintegration. Partial components of the crossbone substrate were coordinated by M-MuLV IN, indicating a reliance on both LTR and target DNA determinants for substrate assembly. The intramolecular reaction was dependent on the presence of either the HHCC domain or a crossbone LTR 5' single-stranded tail. An M-MuLV IN mutant without the HHCC domain (Ndelta105) catalyzed reduced levels of double disintegration but not single disintegration. A separately purified HHCC domain protein (Cdelta232) stimulated double disintegration mediated by Ndelta105, suggesting a role of the N-terminal HHCC domain in stable IN-IN and IN-DNA interactions. Significantly, crossbone substrates lacking the LTR 5' tails were not recognized by the fingerless Ndelta105 protein. Collectively, these data suggest similar roles of the HHCC domain and 5' LTR tail in substrate recognition and modulation of IN activity. PMID:8648728

Modelling Escherichia coli concentrations in the tidal Scheldt river and estuary.

PubMed

de Brauwere, Anouk; de Brye, Benjamin; Servais, Pierre; Passerat, Julien; Deleersnijder, Eric

2011-04-01

Recent observations in the tidal Scheldt River and Estuary revealed a poor microbiological water quality and substantial variability of this quality which can hardly be assigned to a single factor. To assess the importance of tides, river discharge, point sources, upstream concentrations, mortality and settling a new model (SLIM-EC) was built. This model was first validated by comparison with the available field measurements of Escherichia coli (E. coli, a common fecal bacterial indicator) concentrations. The model simulations agreed well with the observations, and in particular were able to reproduce the observed long-term median concentrations and variability. Next, the model was used to perform sensitivity runs in which one process/forcing was removed at a time. These simulations revealed that the tide, upstream concentrations and the mortality process are the primary factors controlling the long-term median E. coli concentrations and the observed variability. The tide is crucial to explain the increased concentrations upstream of important inputs, as well as a generally increased variability. Remarkably, the wastewater treatment plants discharging in the study domain do not seem to have a significant impact. This is due to a dilution effect, and to the fact that the concentrations coming from upstream (where large cities are located) are high. Overall, the settling process as it is presently described in the model does not significantly affect the simulated E. coli concentrations. Copyright © 2011 Elsevier Ltd. All rights reserved.

Phylogenetic analysis of the envelope protein (domain lll) of dengue 4 viruses

PubMed Central

Mota, Javier; Ramos-Castañeda, José; Rico-Hesse, Rebeca; Ramos, Celso

2011-01-01

Objective To evaluate the genetic variability of domain III of envelope (E) protein and to estimate phylogenetic relationships of dengue 4 (Den-4) viruses isolated in Mexico and from other endemic areas of the world. Material and Methods A phylogenetic study of domain III of envelope (E) protein of Den-4 viruses was conducted in 1998 using virus strains from Mexico and other parts of the world, isolated in different years. Specific primers were used to amplify by RT-PCR the domain III and to obtain nucleotide sequence. Based on nucleotide and deduced aminoacid sequence, genetic variability was estimated and a phylogenetic tree was generated. To make an easy genetic analysis of domain III region, a Restriction Fragment Length Polymorphism (RFLP) assay was performed, using six restriction enzymes. Results Study results demonstrate that nucleotide and aminoacid sequence analysis of domain III are similar to those reported from the complete E protein gene. Based on the RFLP analysis of domain III using the restriction enzymes Nla III, Dde I and Cfo I, Den-4 viruses included in this study were clustered into genotypes 1 and 2 previously reported. Conclusions Study results suggest that domain III may be used as a genetic marker for phylogenetic and molecular epidemiology studies of dengue viruses. The English version of this paper is available too at: http://www.insp.mx/salud/index.html PMID:12132320

Analysis of the relationship between community characteristics and depression using geographically weighted regression.

PubMed

Choi, Hyungyun; Kim, Ho

2017-01-01

Achieving national health equity is currently a pressing issue. Large regional variations in the health determinants are observed. Depression, one of the most common mental disorders, has large variations in incidence among different populations, and thus must be regionally analyzed. The present study aimed at analyzing regional disparities in depressive symptoms and identifying the health determinants that require regional interventions. Using health indicators of depression in the Korea Community Health Survey 2011 and 2013, the Moran's I was calculated for each variable to assess spatial autocorrelation, and a validated geographically weighted regression analysis using ArcGIS version 10.1 of different domains: health behavior, morbidity, and the social and physical environments were created, and the final model included a combination of significant variables in these models. In the health behavior domain, the weekly breakfast intake frequency of 1-2 times was the most significantly correlated with depression in all regions, followed by exposure to secondhand smoke and the level of perceived stress in some regions. In the morbidity domain, the rate of lifetime diagnosis of myocardial infarction was the most significantly correlated with depression. In the social and physical environment domain, the trust environment within the local community was highly correlated with depression, showing that lower the level of trust, higher was the level of depression. A final model was constructed and analyzed using highly influential variables from each domain. The models were divided into two groups according to the significance of correlation of each variable with the experience of depression symptoms. The indicators of the regional health status are significantly associated with the incidence of depressive symptoms within a region. The significance of this correlation varied across regions.

Genetic influences on heart rate variability

PubMed Central

Golosheykin, Simon; Grant, Julia D.; Novak, Olga V.; Heath, Andrew C.; Anokhin, Andrey P.

2016-01-01

Heart rate variability (HRV) is the variation of cardiac inter-beat intervals over time resulting largely from the interplay between the sympathetic and parasympathetic branches of the autonomic nervous system. Individual differences in HRV are associated with emotion regulation, personality, psychopathology, cardiovascular health, and mortality. Previous studies have shown significant heritability of HRV measures. Here we extend genetic research on HRV by investigating sex differences in genetic underpinnings of HRV, the degree of genetic overlap among different measurement domains of HRV, and phenotypic and genetic relationships between HRV and the resting heart rate (HR). We performed electrocardiogram (ECG) recordings in a large population-representative sample of young adult twins (n = 1060 individuals) and computed HRV measures from three domains: time, frequency, and nonlinear dynamics. Genetic and environmental influences on HRV measures were estimated using linear structural equation modeling of twin data. The results showed that variability of HRV and HR measures can be accounted for by additive genetic and non-shared environmental influences (AE model), with no evidence for significant shared environmental effects. Heritability estimates ranged from 47 to 64%, with little difference across HRV measurement domains. Genetic influences did not differ between genders for most variables except the square root of the mean squared differences between successive R-R intervals (RMSSD, higher heritability in males) and the ratio of low to high frequency power (LF/HF, distinct genetic factors operating in males and females). The results indicate high phenotypic and especially genetic correlations between HRV measures from different domains, suggesting that >90% of genetic influences are shared across measures. Finally, about 40% of genetic variance in HRV was shared with HR. In conclusion, both HR and HRV measures are highly heritable traits in the general population of young adults, with high degree of genetic overlap across different measurement domains. PMID:27114045

Unfolding of titin immunoglobulin domains by steered molecular dynamics simulation.

PubMed

Lu, H; Isralewitz, B; Krammer, A; Vogel, V; Schulten, K

1998-08-01

Titin, a 1-microm-long protein found in striated muscle myofibrils, possesses unique elastic and extensibility properties in its I-band region, which is largely composed of a PEVK region (70% proline, glutamic acid, valine, and lysine residue) and seven-strand beta-sandwich immunoglobulin-like (Ig) domains. The behavior of titin as a multistage entropic spring has been shown in atomic force microscope and optical tweezer experiments to partially depend on the reversible unfolding of individual Ig domains. We performed steered molecular dynamics simulations to stretch single titin Ig domains in solution with pulling speeds of 0.5 and 1.0 A/ps. Resulting force-extension profiles exhibit a single dominant peak for each Ig domain unfolding, consistent with the experimentally observed sequential, as opposed to concerted, unfolding of Ig domains under external stretching forces. This force peak can be attributed to an initial burst of backbone hydrogen bonds, which takes place between antiparallel beta-strands A and B and between parallel beta-strands A' and G. Additional features of the simulations, including the position of the force peak and relative unfolding resistance of different Ig domains, can be related to experimental observations.

Two zinc-binding domains in the transporter AdcA from Streptococcus pyogenes facilitate high-affinity binding and fast transport of zinc.

PubMed

Cao, Kun; Li, Nan; Wang, Hongcui; Cao, Xin; He, Jiaojiao; Zhang, Bing; He, Qing-Yu; Zhang, Gong; Sun, Xuesong

2018-04-20

Zinc is an essential metal in bacteria. One important bacterial zinc transporter is AdcA, and most bacteria possess AdcA homologs that are single-domain small proteins due to better efficiency of protein biogenesis. However, a double-domain AdcA with two zinc-binding sites is significantly overrepresented in Streptococcus species, many of which are major human pathogens. Using molecular simulation and experimental validations of AdcA from Streptococcus pyogenes , we found here that the two AdcA domains sequentially stabilize the structure upon zinc binding, indicating an organization required for both increased zinc affinity and transfer speed. This structural organization appears to endow Streptococcus species with distinct advantages in zinc-depleted environments, which would not be achieved by each single AdcA domain alone. This enhanced zinc transport mechanism sheds light on the significance of the evolution of the AdcA domain fusion, provides new insights into double-domain transporter proteins with two binding sites for the same ion, and indicates a potential target of antimicrobial drugs against pathogenic Streptococcus species. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Single-molecule FRET-Rosetta reveals RNA structural rearrangements during human telomerase catalysis

PubMed Central

Parks, Joseph W.; Kappel, Kalli; Das, Rhiju; Stone, Michael D.

2017-01-01

Maintenance of telomeres by telomerase permits continuous proliferation of rapidly dividing cells, including the majority of human cancers. Despite its direct biomedical significance, the architecture of the human telomerase complex remains unknown. Generating homogeneous telomerase samples has presented a significant barrier to developing improved structural models. Here we pair single-molecule Förster resonance energy transfer (smFRET) measurements with Rosetta modeling to map the conformations of the essential telomerase RNA core domain within the active ribonucleoprotein. FRET-guided modeling places the essential pseudoknot fold distal to the active site on a protein surface comprising the C-terminal element, a domain that shares structural homology with canonical polymerase thumb domains. An independently solved medium-resolution structure of Tetrahymena telomerase provides a blind test of our modeling methodology and sheds light on the structural homology of this domain across diverse organisms. Our smFRET-Rosetta models reveal nanometer-scale rearrangements within the RNA core domain during catalysis. Taken together, our FRET data and pseudoatomic molecular models permit us to propose a possible mechanism for how RNA core domain rearrangement is coupled to template hybrid elongation. PMID:28096444

Compact high-power red-green-blue laser light source generation from a single lithium tantalate with cascaded domain modulation.

PubMed

Xu, P; Zhao, L N; Lv, X J; Lu, J; Yuan, Y; Zhao, G; Zhu, S N

2009-06-08

1W quasi-white-light source has been generated from a single lithium tantalate with cascaded domain modulation. The quasi-white-light is combined by proper proportion of the red, green and blue laser light. The red and the blue result from a compact self-sum frequency optical parametric oscillation when pumped by a single green laser. The efficiency of quasi-white-light from the green pump reaches 27%. This compact design can be employed not only as a stable and powerful RGB light source but also an effective blue laser generator.

Notes on the boundaries of quadrature domains

NASA Astrophysics Data System (ADS)

Verma, Kaushal

2018-03-01

We highlight an intrinsic connection between classical quadrature domains and the well-studied theme of removable singularities of analytic sets in several complex variables. Exploiting this connection provides a new framework to recover several basic properties of such domains, namely the algebraicity of their boundary, a better understanding of the associated defining polynomial and the possible boundary singularities that can occur.

Interannual rainfall variability and SOM-based circulation classification

NASA Astrophysics Data System (ADS)

Wolski, Piotr; Jack, Christopher; Tadross, Mark; van Aardenne, Lisa; Lennard, Christopher

2018-01-01

Self-Organizing Maps (SOM) based classifications of synoptic circulation patterns are increasingly being used to interpret large-scale drivers of local climate variability, and as part of statistical downscaling methodologies. These applications rely on a basic premise of synoptic climatology, i.e. that local weather is conditioned by the large-scale circulation. While it is clear that this relationship holds in principle, the implications of its implementation through SOM-based classification, particularly at interannual and longer time scales, are not well recognized. Here we use a SOM to understand the interannual synoptic drivers of climate variability at two locations in the winter and summer rainfall regimes of South Africa. We quantify the portion of variance in seasonal rainfall totals that is explained by year to year differences in the synoptic circulation, as schematized by a SOM. We furthermore test how different spatial domain sizes and synoptic variables affect the ability of the SOM to capture the dominant synoptic drivers of interannual rainfall variability. Additionally, we identify systematic synoptic forcing that is not captured by the SOM classification. The results indicate that the frequency of synoptic states, as schematized by a relatively disaggregated SOM (7 × 9) of prognostic atmospheric variables, including specific humidity, air temperature and geostrophic winds, captures only 20-45% of interannual local rainfall variability, and that the residual variance contains a strong systematic component. Utilising a multivariate linear regression framework demonstrates that this residual variance can largely be explained using synoptic variables over a particular location; even though they are used in the development of the SOM their influence, however, diminishes with the size of the SOM spatial domain. The influence of the SOM domain size, the choice of SOM atmospheric variables and grid-point explanatory variables on the levels of explained variance, is consistent with the general understanding of the dominant processes and atmospheric variables that affect rainfall variability at a particular location.

American parent perspectives on quality of life in pediatric cochlear implant recipients.

PubMed

Kumar, Roshini; Warner-Czyz, Andrea; Silver, Cheryl H; Loy, Betty; Tobey, Emily

2015-01-01

Cochlear implantation influences not only communication but also psychosocial outcomes in children with severe to profound hearing loss. Focusing on issues specific to cochlear implantation (e.g., self-reliance, social relations, education, effects of implantation, and supporting the child) may provide a more accurate and relative view of functional status of pediatric cochlear implant (CI) recipients. The present study analyzes parental perspectives of CI-specific health-related quality of life (HRQoL) in children with CIs to determine (a) if parents differentially rate their child's quality of life according to psychosocial domain (e.g., communication, self-reliance, education); (b) if associations exist between quality of life domains specific to cochlear implantation in pediatric implant recipients; and (c) if demographic variables (i.e., chronologic age, age at cochlear implantation, duration of device experience) mediate parent ratings of quality of life in pediatric CI recipients. Parents of 33 children with CIs (mean age, 9.85 years; mean age of CI activation, 2.47 years; mean device experience, 7.47 years) completed a validated condition-specific questionnaire, Children With Cochlear Implants: Parental Perspectives. Parents positively rated most HRQoL domains, although education and effects of implantation received significantly less positive ratings (p < 0.01). Three domains (communication, self-reliance, and well-being) significantly correlated with at least 5 other domains, suggesting that positivity in one domain co-occurs with positivity in other domains. Demographic variables (chronologic age, CI activation age, and duration of CI use) did not correlate significantly with psychosocial outcomes; rather, parents reported positive HRQoL and successful functional use of CI across demographic variables. Parents of children and adolescents with CIs rate overall HRQoL positively across psychosocial domains. Significantly less positive ratings of education and effects of implantation may result from limited access to CI-related accommodations and varying parent expectations, warranting further exploration to maximize psychosocial and performance outcomes in pediatric CI users.

Bacterial natural product biosynthetic domain composition in soil correlates with changes in latitude on a continent-wide scale.

PubMed

Lemetre, Christophe; Maniko, Jeffrey; Charlop-Powers, Zachary; Sparrow, Ben; Lowe, Andrew J; Brady, Sean F

2017-10-31

Although bacterial bioactive metabolites have been one of the most prolific sources of lead structures for the development of small-molecule therapeutics, very little is known about the environmental factors associated with changes in secondary metabolism across natural environments. Large-scale sequencing of environmental microbiomes has the potential to shed light on the richness of bacterial biosynthetic diversity hidden in the environment, how it varies from one environment to the next, and what environmental factors correlate with changes in biosynthetic diversity. In this study, the sequencing of PCR amplicons generated using primers targeting either ketosynthase domains from polyketide biosynthesis or adenylation domains from nonribosomal peptide biosynthesis was used to assess biosynthetic domain composition and richness in soils collected across the Australian continent. Using environmental variables collected at each soil site, we looked for environmental factors that correlated with either high overall domain richness or changes in the domain composition. Among the environmental variables we measured, changes in biosynthetic domain composition correlate most closely with changes in latitude and to a lesser extent changes in pH. Although it is unclear at this time the exact mix of factors that may drive the relationship between biosynthetic domain composition and latitude, from a practical perspective the identification of a latitudinal basis for differences in soil metagenome biosynthetic domain compositions should help guide future natural product discovery efforts. Published under the PNAS license.

Shared and Unique Genetic and Environmental Influences on Aging-Related Changes in Multiple Cognitive Abilities

PubMed Central

Tucker-Drob, Elliot M.; Reynolds, Chandra A.; Finkel, Deborah; Pedersen, Nancy L.

2013-01-01

Aging-related declines occur in many different domains of cognitive function during later adulthood. However, whether a global dimension underlies individual differences in changes in different domains of cognition, and whether global genetic influences on cognitive changes exist, is less clear. We addressed these issues by applying multivariate growth curve models to longitudinal data from 857 individuals from the Swedish Adoption/Twin Study of Aging, who had been measured on 11 cognitive variables representative of verbal, spatial, memory, and processing speed abilities up to 5 times over up to 16 years between ages 50 and 96 years. Between ages 50 and 65 years scores on different tests changed relatively independently of one another, and there was little evidence for strong underlying dimensions of change. In contrast, over the period between 65 and 96 years of age, there were strong interrelations among rates of change both within and across domains. During this age period, variability in rates of change were, on average, 52% domain-general, 8% domain-specific, and 39% test specific. Quantitative genetic decomposition indicated that 29% of individual differences in a global domain-general dimension of cognitive changes from 65 to 96 years were attributable to genetic influences, but some domain-specific genetic influences were also evident, even after accounting for domain-general contributions. These findings are consistent with a balanced global and domain-specific account of the genetics of cognitive aging. PMID:23586942

Shared and unique genetic and environmental influences on aging-related changes in multiple cognitive abilities.

PubMed

Tucker-Drob, Elliot M; Reynolds, Chandra A; Finkel, Deborah; Pedersen, Nancy L

2014-01-01

Aging-related declines occur in many different domains of cognitive function during middle and late adulthood. However, whether a global dimension underlies individual differences in changes in different domains of cognition and whether global genetic influences on cognitive changes exist is less clear. We addressed these issues by applying multivariate growth curve models to longitudinal data from 857 individuals from the Swedish Adoption/Twin Study of Aging, who had been measured on 11 cognitive variables representative of verbal, spatial, memory, and processing speed abilities up to 5 times over up to 16 years between ages 50 and 96 years. Between ages 50 and 65 years scores on different tests changed relatively independently of one another, and there was little evidence for strong underlying dimensions of change. In contrast, over the period between 65 and 96 years of age, there were strong interrelations among rates of change both within and across domains. During this age period, variability in rates of change were, on average, 52% domain-general, 8% domain-specific, and 39% test-specific. Quantitative genetic decomposition indicated that 29% of individual differences in a global domain-general dimension of cognitive changes during this age period were attributable to genetic influences, but some domain-specific genetic influences were also evident, even after accounting for domain-general contributions. These findings are consistent with a balanced global and domain-specific account of the genetics of cognitive aging. PsycINFO Database Record (c) 2014 APA, all rights reserved.

Centromeres Off the Hook: Massive Changes in Centromere Size and Structure Following Duplication of CenH3 Gene in Fabeae Species.

PubMed

Neumann, Pavel; Pavlíková, Zuzana; Koblížková, Andrea; Fuková, Iva; Jedličková, Veronika; Novák, Petr; Macas, Jiří

2015-07-01

In most eukaryotes, centromere is determined by the presence of the centromere-specific histone variant CenH3. Two types of chromosome morphology are generally recognized with respect to centromere organization. Monocentric chromosomes possess a single CenH3-containing domain in primary constriction, whereas holocentric chromosomes lack the primary constriction and display dispersed distribution of CenH3. Recently, metapolycentric chromosomes have been reported in Pisum sativum, representing an intermediate type of centromere organization characterized by multiple CenH3-containing domains distributed across large parts of chromosomes that still form a single constriction. In this work, we show that this type of centromere is also found in other Pisum and closely related Lathyrus species, whereas Vicia and Lens genera, which belong to the same legume tribe Fabeae, possess only monocentric chromosomes. We observed extensive variability in the size of primary constriction and the arrangement of CenH3 domains both between and within individual Pisum and Lathyrus species, with no obvious correlation to genome or chromosome size. Search for CenH3 gene sequences revealed two paralogous variants, CenH3-1 and CenH3-2, which originated from a duplication event in the common ancestor of Fabeae species. The CenH3-1 gene was subsequently lost or silenced in the lineage leading to Vicia and Lens, whereas both genes are retained in Pisum and Lathyrus. Both of these genes appear to have evolved under purifying selection and produce functional CenH3 proteins which are fully colocalized. The findings described here provide the first evidence for a highly dynamic centromere structure within a group of closely related species, challenging previous concepts of centromere evolution. © The Author 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Is patient-reported outcome improved by nalfurafine hydrochloride in patients with primary biliary cholangitis and refractory pruritus? A post-marketing, single-arm, prospective study.

PubMed

Yagi, Minami; Tanaka, Atsushi; Namisaki, Tadashi; Takahashi, Atsushi; Abe, Masanori; Honda, Akira; Matsuzaki, Yasushi; Ohira, Hiromasa; Yoshiji, Hitoshi; Takikawa, Hajime

2018-04-16

Patients with primary biliary cholangitis (PBC) frequently suffer from pruritus, which can severely impair their health-related quality of life (HRQOL). Nalfurafine hydrochloride, a selective κ-opioid receptor agonist, was recently approved in Japan for refractory pruritus in patients with chronic liver diseases, but it still remains unclear whether this treatment improves the patient-reported outcome (PRO) in PBC patients with refractory pruritus. Herein, we conducted a multicenter, post-marketing, single-arm prospective study to investigate the efficacy of nalfurafine in terms of PRO, and the associations of the efficacy with any clinical characteristics. After screening for pruritus in 496 patients with PBC using PBC-40 and the visual analog scale (VAS), we identified 141 patients with moderate to severe pruritus; these were invited to participate in the study. The participants received 2.5 μg nalfurafine once daily for 12 weeks, and pruritus and HRQOL were assessed in week 12 of this treatment. Generic HRQOL, short form 36, blood chemistries, and serum autotaxin levels were also measured at baseline and at week 12. Forty-four patients participated in this study. The mean PBC-40 itch domain scores and VAS declined during the study period, from 8.56 to 7.63 (P = 0.041) and from 42.9 to 29.3 (P = 0.001) at baseline and at week 12, respectively, indicating a significant effect of nalfurafine. The other domains of PBC-40 and all domains of SF-36 were not significantly altered by this treatment. We failed to find any association between the change in VAS and PBC-40 itch scores and any clinical variable. Serum autotaxin levels were significantly increased during the study period. This study demonstrated that nalfurafine improved pruritus in patients with PBC, independent of their clinical characteristics, but had a limited effect on the PRO.

Coupled Data Assimilation for Integrated Earth System Analysis and Prediction: Goals, Challenges, and Recommendations

NASA Technical Reports Server (NTRS)

Penny, Stephen G.; Akella, Santha; Buehner, Mark; Chevallier, Matthieu; Counillon, Francois; Draper, Clara; Frolov, Sergey; Fujii, Yosuke; Karspeck, Alicia; Kumar, Arun

2017-01-01

The purpose of this report is to identify fundamental issues for coupled data assimilation (CDA), such as gaps in science and limitations in forecasting systems, in order to provide guidance to the World Meteorological Organization (WMO) on how to facilitate more rapid progress internationally. Coupled Earth system modeling provides the opportunity to extend skillful atmospheric forecasts beyond the traditional two-week barrier by extracting skill from low-frequency state components such as the land, ocean, and sea ice. More generally, coupled models are needed to support seamless prediction systems that span timescales from weather, subseasonal to seasonal (S2S), multiyear, and decadal. Therefore, initialization methods are needed for coupled Earth system models, either applied to each individual component (called Weakly Coupled Data Assimilation - WCDA) or applied the coupled Earth system model as a whole (called Strongly Coupled Data Assimilation - SCDA). Using CDA, in which model forecasts and potentially the state estimation are performed jointly, each model domain benefits from observations in other domains either directly using error covariance information known at the time of the analysis (SCDA), or indirectly through flux interactions at the model boundaries (WCDA). Because the non-atmospheric domains are generally under-observed compared to the atmosphere, CDA provides a significant advantage over single-domain analyses. Next, we provide a synopsis of goals, challenges, and recommendations to advance CDA: Goals: (a) Extend predictive skill beyond the current capability of NWP (e.g. as demonstrated by improving forecast skill scores), (b) produce physically consistent initial conditions for coupled numerical prediction systems and reanalyses (including consistent fluxes at the domain interfaces), (c) make best use of existing observations by allowing observations from each domain to influence and improve the full earth system analysis, (d) develop a robust observation-based identification and understanding of mechanisms that determine the variability of weather and climate, (e) identify critical weaknesses in coupled models and the earth observing system, (f) generate full-field estimates of unobserved or sparsely observed variables, (g) improve the estimation of the external forcings causing changes to climate, (h) transition successes from idealized CDA experiments to real-world applications. Challenges: (a) Modeling at the interfaces between interacting components of coupled Earth system models may be inadequate for estimating uncertainty or error covariances between domains, (b) current data assimilation methods may be insufficient to simultaneously analyze domains containing multiple spatiotemporal scales of interest, (c) there is no standardization of observation data or their delivery systems across domains, (d) the size and complexity of many large-scale coupled Earth system models makes it is difficult to accurately represent uncertainty due to model parameters and coupling parameters, (e) model errors lead to local biases that can transfer between the different Earth system components and lead to coupled model biases and long-term model drift, (e) information propagation across model components with different spatiotemporal scales is extremely complicated, and must be improved in current coupled modeling frameworks, (h) there is insufficient knowledge on how to represent evolving errors in non-atmospheric model components (e.g. as sea ice, land and ocean) on the timescales of NWP.

Surface properties of atomically flat poly-crystalline SrTiO3

PubMed Central

Woo, Sungmin; Jeong, Hoidong; Lee, Sang A.; Seo, Hosung; Lacotte, Morgane; David, Adrian; Kim, Hyun You; Prellier, Wilfrid; Kim, Yunseok; Choi, Woo Seok

2015-01-01

Comparison between single- and the poly-crystalline structures provides essential information on the role of long-range translational symmetry and grain boundaries. In particular, by comparing single- and poly-crystalline transition metal oxides (TMOs), one can study intriguing physical phenomena such as electronic and ionic conduction at the grain boundaries, phonon propagation, and various domain properties. In order to make an accurate comparison, however, both single- and poly-crystalline samples should have the same quality, e.g., stoichiometry, crystallinity, thickness, etc. Here, by studying the surface properties of atomically flat poly-crystalline SrTiO3 (STO), we propose an approach to simultaneously fabricate both single- and poly-crystalline epitaxial TMO thin films on STO substrates. In order to grow TMOs epitaxially with atomic precision, an atomically flat, single-terminated surface of the substrate is a prerequisite. We first examined (100), (110), and (111) oriented single-crystalline STO surfaces, which required different annealing conditions to achieve atomically flat surfaces, depending on the surface energy. A poly-crystalline STO surface was then prepared at the optimum condition for which all the domains with different crystallographic orientations could be successfully flattened. Based on our atomically flat poly-crystalline STO substrates, we envision expansion of the studies regarding the TMO domains and grain boundaries. PMID:25744275

Functional diversity of Csk, Chk, and Src SH2 domains due to a single residue variation.

PubMed

Ayrapetov, Marina K; Nam, Nguyen Hai; Ye, Guofeng; Kumar, Anil; Parang, Keykavous; Sun, Gongqin

2005-07-08

The C-terminal Src kinase (Csk) family of protein tyrosine kinases contains two members: Csk and Csk homologous kinase (Chk). Both phosphorylate and inactivate Src family kinases. Recent reports suggest that the Src homology (SH) 2 domains of Csk and Chk may bind to different phosphoproteins, which provides a basis for different cellular functions for Csk and Chk. To verify and characterize such a functional divergence, we compared the binding properties of the Csk, Chk, and Src SH2 domains and investigated the structural basis for the functional divergence. First, the study demonstrated striking functional differences between the Csk and Chk SH2 domains and revealed functional similarities between the Chk and Src SH2 domains. Second, structural analysis and mutagenic studies revealed that the functional differences among the three SH2 domains were largely controlled by one residue, Glu127 in Csk, Ile167 in Chk, and Lys200 in Src. Mutating these residues in the Csk or Chk SH2 domain to the Src counterpart resulted in dramatic gain of function similar to Src SH2 domain, whereas mutating Lys200 in Src SH2 domain to Glu (the Csk counterpart) resulted in loss of Src SH2 function. Third, a single point mutation of E127K rendered Csk responsive to activation by a Src SH2 domain ligand. Finally, the optimal phosphopeptide sequence for the Chk SH2 domain was determined. These results provide a compelling explanation for the functional differences between two homologous protein tyrosine kinases and reveal a new structure-function relationship for the SH2 domains.

Stability of topological defects in chiral superconductors: London theory.

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

Vakaryuk, V.

2011-12-22

This paper examines the thermodynamic stability of chiral domain walls and vortices-topological defects which can exist in chiral superconductors. Using London theory it is demonstrated that at sufficiently small applied and chiral fields the existence of domain walls and vortices in the sample is not favored and the sample's configuration is a single domain. The particular chirality of the single-domain configuration is neither favored nor disfavored by the applied field. Increasing the field leads to an entry of a domain-wall loop or a vortex into the sample. The formation of a straight domain wall is never preferred in equilibrium. Valuesmore » of the entry (critical) fields for both types of defects, as well as the equilibrium size of the domain-wall loop, are calculated. We also consider a mesoscopic chiral sample and calculate its zero-field magnetization, susceptibility, and a change in the magnetic moment due to a vortex or a domain-wall entry. We show that in the case of a soft domain wall whose energetics is dominated by the chiral current (and not by the surface tension) its behavior in mesoscopic samples is substantially different from that in the bulk case and can be used for a controllable transfer of edge excitations. The applicability of these results to Sr{sub 2}RuO{sub 4} - a tentative chiral superconductor - is discussed.« less

Stability of topological defects in chiral superconductors: London theory

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

Vakaryuk, Victor

2011-12-01

This paper examines the thermodynamic stability of chiral domain walls and vortices—topological defects which can exist in chiral superconductors. Using London theory it is demonstrated that at sufficiently small applied and chiral fields the existence of domain walls and vortices in the sample is not favored and the sample's configuration is a single domain. The particular chirality of the single-domain configuration is neither favored nor disfavored by the applied field. Increasing the field leads to an entry of a domain-wall loop or a vortex into the sample. The formation of a straight domain wall is never preferred in equilibrium. Valuesmore » of the entry (critical) fields for both types of defects, as well as the equilibrium size of the domain-wall loop, are calculated. We also consider a mesoscopic chiral sample and calculate its zero-field magnetization, susceptibility, and a change in the magnetic moment due to a vortex or a domain-wall entry. We show that in the case of a soft domain wall whose energetics is dominated by the chiral current (and not by the surface tension) its behavior in mesoscopic samples is substantially different from that in the bulk case and can be used for a controllable transfer of edge excitations. The applicability of these results to Sr 2 RuO 4 —a tentative chiral superconductor—is discussed.« less

Irreversible transformation of ferromagnetic ordered stripe domains in single-shot infrared-pump/resonant-x-ray-scattering-probe experiments

NASA Astrophysics Data System (ADS)

Bergeard, Nicolas; Schaffert, Stefan; López-Flores, Víctor; Jaouen, Nicolas; Geilhufe, Jan; Günther, Christian M.; Schneider, Michael; Graves, Catherine; Wang, Tianhan; Wu, Benny; Scherz, Andreas; Baumier, Cédric; Delaunay, Renaud; Fortuna, Franck; Tortarolo, Marina; Tudu, Bharati; Krupin, Oleg; Minitti, Michael P.; Robinson, Joe; Schlotter, William F.; Turner, Joshua J.; Lüning, Jan; Eisebitt, Stefan; Boeglin, Christine

2015-02-01

The evolution of a magnetic domain structure upon excitation by an intense, femtosecond infrared (IR) laser pulse has been investigated using single-shot based time-resolved resonant x-ray scattering at the x-ray free electron laser LCLS. A well-ordered stripe domain pattern as present in a thin CoPd alloy film has been used as a prototype magnetic domain structure for this study. The fluence of the IR laser pump pulse was sufficient to lead to an almost complete quenching of the magnetization within the ultrafast demagnetization process taking place within the first few hundreds of femtoseconds following the IR laser pump pulse excitation. On longer time scales this excitation gave rise to subsequent irreversible transformations of the magnetic domain structure. Under our specific experimental conditions, it took about 2 ns before the magnetization started to recover. After about 5 ns the previously ordered stripe domain structure had evolved into a disordered labyrinth domain structure. Surprisingly, we observe after about 7 ns the occurrence of a partially ordered stripe domain structure reoriented into a novel direction. It is this domain structure in which the sample's magnetization stabilizes as revealed by scattering patterns recorded long after the initial pump-probe cycle. Using micromagnetic simulations we can explain this observation based on changes of the magnetic anisotropy going along with heat dissipation in the film.

Using existing questionnaires in latent class analysis: should we use summary scores or single items as input? A methodological study using a cohort of patients with low back pain.

PubMed

Nielsen, Anne Molgaard; Vach, Werner; Kent, Peter; Hestbaek, Lise; Kongsted, Alice

2016-01-01

Latent class analysis (LCA) is increasingly being used in health research, but optimal approaches to handling complex clinical data are unclear. One issue is that commonly used questionnaires are multidimensional, but expressed as summary scores. Using the example of low back pain (LBP), the aim of this study was to explore and descriptively compare the application of LCA when using questionnaire summary scores and when using single items to subgrouping of patients based on multidimensional data. Baseline data from 928 LBP patients in an observational study were classified into four health domains (psychology, pain, activity, and participation) using the World Health Organization's International Classification of Functioning, Disability, and Health framework. LCA was performed within each health domain using the strategies of summary-score and single-item analyses. The resulting subgroups were descriptively compared using statistical measures and clinical interpretability. For each health domain, the preferred model solution ranged from five to seven subgroups for the summary-score strategy and seven to eight subgroups for the single-item strategy. There was considerable overlap between the results of the two strategies, indicating that they were reflecting the same underlying data structure. However, in three of the four health domains, the single-item strategy resulted in a more nuanced description, in terms of more subgroups and more distinct clinical characteristics. In these data, application of both the summary-score strategy and the single-item strategy in the LCA subgrouping resulted in clinically interpretable subgroups, but the single-item strategy generally revealed more distinguishing characteristics. These results 1) warrant further analyses in other data sets to determine the consistency of this finding, and 2) warrant investigation in longitudinal data to test whether the finer detail provided by the single-item strategy results in improved prediction of outcomes and treatment response.

Sequence Tolerance of a Highly Stable Single Domain Antibody: Comparison of Computational and Experimental Profiles

DTIC Science & Technology

2016-09-09

evaluating 18 mutants using either the A or B conformer is only r = ~ 0.2. Given the poor performance of approximating the observed experimental ...1    Sequence Tolerance of a Highly Stable Single Domain Antibody: Comparison of Computational and Experimental Profiles Mark A. Olson,1 Patricia...unusually high thermal stability is explored by a combined computational and experimental study. Starting with the crystallographic structure

Synthetic single domain antibodies for the conformational trapping of membrane proteins

PubMed Central

Arnold, Fabian M; Stohler, Peter; Bocquet, Nicolas; Hug, Melanie N; Huber, Sylwia; Siegrist, Martin; Hetemann, Lisa; Gera, Jennifer; Gmür, Samira; Spies, Peter; Gygax, Daniel

2018-01-01

Mechanistic and structural studies of membrane proteins require their stabilization in specific conformations. Single domain antibodies are potent reagents for this purpose, but their generation relies on immunizations, which impedes selections in the presence of ligands typically needed to populate defined conformational states. To overcome this key limitation, we developed an in vitro selection platform based on synthetic single domain antibodies named sybodies. To target the limited hydrophilic surfaces of membrane proteins, we designed three sybody libraries that exhibit different shapes and moderate hydrophobicity of the randomized surface. A robust binder selection cascade combining ribosome and phage display enabled the generation of conformation-selective, high affinity sybodies against an ABC transporter and two previously intractable human SLC transporters, GlyT1 and ENT1. The platform does not require access to animal facilities and builds exclusively on commercially available reagents, thus enabling every lab to rapidly generate binders against challenging membrane proteins. PMID:29792401

Molecular dynamics simulations and docking enable to explore the biophysical factors controlling the yields of engineered nanobodies.

PubMed

Soler, Miguel A; de Marco, Ario; Fortuna, Sara

2016-10-10

Nanobodies (VHHs) have proved to be valuable substitutes of conventional antibodies for molecular recognition. Their small size represents a precious advantage for rational mutagenesis based on modelling. Here we address the problem of predicting how Camelidae nanobody sequences can tolerate mutations by developing a simulation protocol based on all-atom molecular dynamics and whole-molecule docking. The method was tested on two sets of nanobodies characterized experimentally for their biophysical features. One set contained point mutations introduced to humanize a wild type sequence, in the second the CDRs were swapped between single-domain frameworks with Camelidae and human hallmarks. The method resulted in accurate scoring approaches to predict experimental yields and enabled to identify the structural modifications induced by mutations. This work is a promising tool for the in silico development of single-domain antibodies and opens the opportunity to customize single functional domains of larger macromolecules.

Molecular dynamics simulations and docking enable to explore the biophysical factors controlling the yields of engineered nanobodies

NASA Astrophysics Data System (ADS)

Soler, Miguel A.; De Marco, Ario; Fortuna, Sara

2016-10-01

Nanobodies (VHHs) have proved to be valuable substitutes of conventional antibodies for molecular recognition. Their small size represents a precious advantage for rational mutagenesis based on modelling. Here we address the problem of predicting how Camelidae nanobody sequences can tolerate mutations by developing a simulation protocol based on all-atom molecular dynamics and whole-molecule docking. The method was tested on two sets of nanobodies characterized experimentally for their biophysical features. One set contained point mutations introduced to humanize a wild type sequence, in the second the CDRs were swapped between single-domain frameworks with Camelidae and human hallmarks. The method resulted in accurate scoring approaches to predict experimental yields and enabled to identify the structural modifications induced by mutations. This work is a promising tool for the in silico development of single-domain antibodies and opens the opportunity to customize single functional domains of larger macromolecules.

Defect-phase-dynamics approach to statistical domain-growth problem of clock models

NASA Technical Reports Server (NTRS)

Kawasaki, K.

1985-01-01

The growth of statistical domains in quenched Ising-like p-state clock models with p = 3 or more is investigated theoretically, reformulating the analysis of Ohta et al. (1982) in terms of a phase variable and studying the dynamics of defects introduced into the phase field when the phase variable becomes multivalued. The resulting defect/phase domain-growth equation is applied to the interpretation of Monte Carlo simulations in two dimensions (Kaski and Gunton, 1983; Grest and Srolovitz, 1984), and problems encountered in the analysis of related Potts models are discussed. In the two-dimensional case, the problem is essentially that of a purely dissipative Coulomb gas, with a sq rt t growth law complicated by vertex-pinning effects at small t.

¹⁵N, ¹³C and ¹H resonance assignments and secondary structure determination of a variable heavy domain of a heavy chain antibody.

PubMed

Prosser, Christine E; Waters, Lorna C; Muskett, Frederick W; Veverka, Vaclav; Addis, Philip W; Griffin, Laura M; Baker, Terry S; Lawson, Alastair D G; Wernery, Ulrich; Kinne, Jorg; Henry, Alistair J; Taylor, Richard J; Carr, Mark D

2014-04-01

Heavy chain antibodies differ in structure to conventional antibodies lacking both the light chain and the first heavy chain constant domain (CH1). Characteristics of the antigen-binding variable heavy domain of the heavy chain antibody (VHH) including the smaller size, high solubility and stability make them an attractive alternative to more traditional antibody fragments for detailed NMR-based structural analysis. Here we report essentially complete backbone and side chain (15)N, (13)C and (1)H assignments for a free VHH. Analysis of the backbone chemical shift data obtained indicates that the VHH is comprised predominantly of β-sheets corresponding to nearly 60% of the protein backbone.

A single circularly permuted GFP sensor for inositol-1,3,4,5-tetrakisphosphate based on a split PH domain.

PubMed

Sakaguchi, Reiko; Endoh, Takashi; Yamamoto, Seigo; Tainaka, Kazuki; Sugimoto, Kenji; Fujieda, Nobutaka; Kiyonaka, Shigeki; Mori, Yasuo; Morii, Takashi

2009-10-15

A fluorescent sensor for the detection of inositol-1,3,4,5-tetrakisphosphate, Ins(1,3,4,5)P(4), was constructed from a split PH domain and a single circularly permuted GFP. A structure-based design was conducted to transduce a ligand-induced subtle structural perturbation of the split PH domain to an alteration in the population of the protonated and the deprotonated states of the GFP chromophore. Excitation of each distinct absorption band corresponding to the protonated or the deprotonated state of GFP resulted an increase and a decrease, respectively, in the intensity of emission spectra upon addition of Ins(1,3,4,5)P(4) to the split PH domain-based sensor. The Ins(1,3,4,5)P(4) sensor retained the ligand affinity and the selectivity of the parent PH domain, and realized the ratiometric fluorescence detection of Ins(1,3,4,5)P(4).

Hierarchical domain structure of lead-free piezoelectric (Na{sub 1/2} Bi{sub 1/2})TiO{sub 3}-(K{sub 1/2} Bi{sub 1/2})TiO{sub 3} single crystals

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

Luo, Chengtao, E-mail: lchentao@vt.edu; Wang, Yaojin; Ge, Wenwei

2016-05-07

We report a unique hierarchical domain structure in single crystals of (Na{sub 1/2}Bi{sub 1/2})TiO{sub 3}-xat. %(K{sub 1/2}Bi{sub 1/2})TiO{sub 3} for x = 5 and 8 by transmission electron microscopy (TEM). A high density of polar nano-domains with a lamellar morphology was found, which were self-assembled into a quadrant-like configuration, which then assembled into conventional ferroelectric macro-domains. Studies by high resolution TEM revealed that the polar lamellar regions contained a coexistence of in-phase and anti-phase oxygen octahedral tilt regions of a few nanometers in size. Domain frustration over multiple length scales may play an important role in the stabilization of the hierarchy, andmore » in reducing the piezoelectric response of this Pb-free piezoelectric solid solution.« less

Domain walls in single-chain magnets

NASA Astrophysics Data System (ADS)

Pianet, Vivien; Urdampilleta, Matias; Colin, Thierry; Clérac, Rodolphe; Coulon, Claude

2017-12-01

The topology and creation energy of domain walls in different magnetic chains (called Single-Chain Magnets or SCMs) are discussed. As these domain walls, that can be seen as "defects", are known to control both static and dynamic properties of these one-dimensional systems, their study and understanding are necessary first steps before a deeper discussion of the SCM properties at finite temperature. The starting point of the paper is the simple regular ferromagnetic chain for which the characteristics of the domain walls are well known. Then two cases will be discussed (i) the "mixed chains" in which isotropic and anisotropic classical spins alternate, and (ii) the so-called "canted chains" where two different easy axis directions are present. In particular, we show that "strictly narrow" domain walls no longer exist in these more complex cases, while a cascade of phase transitions is found for canted chains as the canting angle approaches 45∘. The consequence for thermodynamic properties is briefly discussed in the last part of the paper.

Nanoscale current imaging of the conducting channels in proton exchange membrane fuel cells.

PubMed

Bussian, David A; O'Dea, James R; Metiu, Horia; Buratto, Steven K

2007-02-01

The electrochemically active area of a proton exchange membrane fuel cell (PEMFC) is investigated using conductive probe atomic force microscopy (CP-AFM). A platinum-coated AFM tip is used as a nanoscale cathode in an operating PEMFC. We present results that show highly inhomogeneous distributions of conductive surface domains at several length scales. At length scales on the order of the aqueous domains of the membrane, approximately 50 nm, we observe single channel electrochemistry. I-V curves for single conducting channels are obtained, which yield insight into the nature of conductive regions across the PEM. In addition, we demonstrate a new characterization technique, phase current correlation microscopy, which gives a direct measure of the electrochemical activity for each aqueous domain. This shows that a large number ( approximately 60%) of the aqueous domains present at the surface of an operating Nafion membrane are inactive. We attribute this to a combination of limited aqueous domain connectivity and catalyst accessibility.

DEPDC5 takes a second hit in familial focal epilepsy.

PubMed

Anderson, Matthew P

2018-04-30

Loss-of-function mutations in a single allele of the gene encoding DEP domain-containing 5 protein (DEPDC5) are commonly linked to familial focal epilepsy with variable foci; however, a subset of patients presents with focal cortical dysplasia that is proposed to result from a second-hit somatic mutation. In this issue of the JCI, Ribierre and colleagues provide several lines of evidence to support second-hit DEPDC5 mutations in this disorder. Moreover, the authors use in vivo, in utero electroporation combined with CRISPR-Cas9 technology to generate a murine model of the disease that recapitulates human manifestations, including cortical dysplasia-like changes, focal seizures, and sudden unexpected death. This study provides important insights into familial focal epilepsy and provides a preclinical model for evaluating potential therapies.

Personality in 100,000 Words: A large-scale analysis of personality and word use among bloggers

PubMed Central

Yarkoni, Tal

2010-01-01

Previous studies have found systematic associations between personality and individual differences in word use. Such studies have typically focused on broad associations between major personality domains and aggregate word categories, potentially masking more specific associations. Here I report the results of a large-scale analysis of personality and word use in a large sample of blogs (N=694). The size of the dataset enabled pervasive correlations with personality to be identified for a broad range of lexical variables, including both aggregate word categories and individual English words. The results replicated category-level findings from previous offline studies, identified numerous novel associations at both a categorical and single-word level, and underscored the value of complementary approaches to the study of personality and word use. PMID:20563301

The Myth of Optimality in Clinical Neuroscience.

PubMed

Holmes, Avram J; Patrick, Lauren M

2018-03-01

Clear evidence supports a dimensional view of psychiatric illness. Within this framework the expression of disorder-relevant phenotypes is often interpreted as a breakdown or departure from normal brain function. Conversely, health is reified, conceptualized as possessing a single ideal state. We challenge this concept here, arguing that there is no universally optimal profile of brain functioning. The evolutionary forces that shape our species select for a staggering diversity of human behaviors. To support our position we highlight pervasive population-level variability within large-scale functional networks and discrete circuits. We propose that, instead of examining behaviors in isolation, psychiatric illnesses can be best understood through the study of domains of functioning and associated multivariate patterns of variation across distributed brain systems. Copyright © 2018 Elsevier Ltd. All rights reserved.

Time-resolved single-shot terahertz time-domain spectroscopy for ultrafast irreversible processes

NASA Astrophysics Data System (ADS)

Zhai, Zhao-Hui; Zhong, Sen-Cheng; Li, Jun; Zhu, Li-Guo; Meng, Kun; Li, Jiang; Liu, Qiao; Peng, Qi-Xian; Li, Ze-Ren; Zhao, Jian-Heng

2016-09-01

Pulsed terahertz spectroscopy is suitable for spectroscopic diagnostics of ultrafast events. However, the study of irreversible or single shot ultrafast events requires ability to record transient properties at multiple time delays, i.e., time resolved at single shot level, which is not available currently. Here by angular multiplexing use of femtosecond laser pulses, we developed and demonstrated a time resolved, transient terahertz time domain spectroscopy technique, where burst mode THz pulses were generated and then detected in a single shot measurement manner. The burst mode THz pulses contain 2 sub-THz pulses, and the time gap between them is adjustable up to 1 ns with picosecond accuracy, thus it can be used to probe the single shot event at two different time delays. The system can detect the sub-THz pulses at 0.1 THz-2.5 THz range with signal to noise ratio (SNR) of ˜400 and spectrum resolution of 0.05 THz. System design was described here, and optimizations of single shot measurement of THz pulses were discussed in detail. Methods to improve SNR were also discussed in detail. A system application was demonstrated where pulsed THz signals at different time delays of the ultrafast process were successfully acquired within single shot measurement. This time resolved transient terahertz time domain spectroscopy technique provides a new diagnostic tool for irreversible or single shot ultrafast events where dynamic information can be extracted at terahertz range within one-shot experiment.

Time-resolved single-shot terahertz time-domain spectroscopy for ultrafast irreversible processes.

PubMed

Zhai, Zhao-Hui; Zhong, Sen-Cheng; Li, Jun; Zhu, Li-Guo; Meng, Kun; Li, Jiang; Liu, Qiao; Peng, Qi-Xian; Li, Ze-Ren; Zhao, Jian-Heng

2016-09-01

Pulsed terahertz spectroscopy is suitable for spectroscopic diagnostics of ultrafast events. However, the study of irreversible or single shot ultrafast events requires ability to record transient properties at multiple time delays, i.e., time resolved at single shot level, which is not available currently. Here by angular multiplexing use of femtosecond laser pulses, we developed and demonstrated a time resolved, transient terahertz time domain spectroscopy technique, where burst mode THz pulses were generated and then detected in a single shot measurement manner. The burst mode THz pulses contain 2 sub-THz pulses, and the time gap between them is adjustable up to 1 ns with picosecond accuracy, thus it can be used to probe the single shot event at two different time delays. The system can detect the sub-THz pulses at 0.1 THz-2.5 THz range with signal to noise ratio (SNR) of ∼400 and spectrum resolution of 0.05 THz. System design was described here, and optimizations of single shot measurement of THz pulses were discussed in detail. Methods to improve SNR were also discussed in detail. A system application was demonstrated where pulsed THz signals at different time delays of the ultrafast process were successfully acquired within single shot measurement. This time resolved transient terahertz time domain spectroscopy technique provides a new diagnostic tool for irreversible or single shot ultrafast events where dynamic information can be extracted at terahertz range within one-shot experiment.

Over expression of anti-MUC1 single-domain antibody fragments in the yeast Pichia pastoris.

PubMed

Rahbarizadeh, Fatemeh; Rasaee, Mohammad J; Forouzandeh, Mehdi; Allameh, Abdol-Amir

2006-02-01

The methylotrophic yeast Pichia pastoris has become a highly popular expression host system for the recombinant production of a wide variety of proteins, such as antibody fragments. Camelids produce functional antibodies devoid of light chains and constant heavy-chain domain (CH1). The antigen binding fragments of such heavy chain antibodies are therefore comprised in one single domain, the so-called VH of the camelid heavy chain antibody (VHH). To test the feasibility of expressing VHHs in the yeast, which on account of their small size and antigen recognition properties would have a major impact on antibody engineering strategies, we constructed two VHH genes encoding the single-domain antibody fragments with specificity for a cancer associated mucin, MUC1. The recombinant strains of the yeast P. pastoris were developed which secrete single-domain antibody fragment to the culture supernatant as a biologically active protein. Supplementation of medium with sorbitol (in pre-induction phase) and casamino acid or EDTA (in induction phase) provided ideal condition of increasing the yield of VHH production compared to culture condition devoid of above recipe. The secreted protein was purified following a 80% ammonium sulfate precipitation step, followed by a affinity chromatography column. The specific activity in enzyme-linked immunosorbant assay (ELISA) of the purified yeast VHH was higher than that of a bacterial periplasmic counterpart. These results reaffirm that the yeast P. pastoris is a suitable host for high level and correctly folded production of VHH antibody fragments with potential in vivo diagnostic and therapeutic applications. This is the first report of expression of VHH in P. pastoris.

Domain wall conductivity in KTiOPO4 crystals

NASA Astrophysics Data System (ADS)

Lindgren, G.; Canalias, C.

2017-07-01

We study the local ionic conductivity of ferroelectric domain walls and domains in KTiOPO4 single-crystals. We show a fourfold increase in conductivity at the domain walls, compared to that of the domains, attributed to an increased concentration of defects. Our current-voltage measurements reveal memristive-like behavior associated with topographic changes and permanent charge displacement. This behavior is observed for all the voltage sweep-rates at the domain walls, while it only occurs for low frequencies at the domains. We attribute these findings to the redistribution of ions due to the applied bias and their effect on the tip-sample barrier.

Zipf’s Law Arises Naturally When There Are Underlying, Unobserved Variables

PubMed Central

Corradi, Nicola

2016-01-01

Zipf’s law, which states that the probability of an observation is inversely proportional to its rank, has been observed in many domains. While there are models that explain Zipf’s law in each of them, those explanations are typically domain specific. Recently, methods from statistical physics were used to show that a fairly broad class of models does provide a general explanation of Zipf’s law. This explanation rests on the observation that real world data is often generated from underlying causes, known as latent variables. Those latent variables mix together multiple models that do not obey Zipf’s law, giving a model that does. Here we extend that work both theoretically and empirically. Theoretically, we provide a far simpler and more intuitive explanation of Zipf’s law, which at the same time considerably extends the class of models to which this explanation can apply. Furthermore, we also give methods for verifying whether this explanation applies to a particular dataset. Empirically, these advances allowed us extend this explanation to important classes of data, including word frequencies (the first domain in which Zipf’s law was discovered), data with variable sequence length, and multi-neuron spiking activity. PMID:27997544

Between Domain Cognitive Dispersion and Functional Abilities in Older Adults

PubMed Central

Fellows, Robert P.; Schmitter-Edgecombe, Maureen

2016-01-01

Objective Within-person variability in cognitive performance is related to neurological integrity, but the association with functional abilities is less clear. The primary aim of this study was to examine the association between cognitive dispersion, or within-person variability, and everyday multitasking and the way in which these variables may influence performance on a naturalistic assessment of functional abilities. Method Participants were 156 community-dwelling adults, age 50 or older. Cognitive dispersion was calculated by measuring within-person variability in cognitive domains, established through principal components analysis. Path analysis was used to determine the independent contribution of cognitive dispersion to functional ability, mediated by multitasking. Results Results of the path analysis revealed that the number of subtasks interweaved (i.e., multitasked) mediated the association between cognitive dispersion and task sequencing and accuracy. Although increased multitasking was associated with worse task performance in the path model, secondary analyses revealed that for individuals with low cognitive dispersion, increased multitasking was associated with better task performance, whereas for those with higher levels of dispersion multitasking was negatively correlated with task performance. Conclusion These results suggest that cognitive dispersion between domains may be a useful indicator of multitasking and daily living skills among older adults. PMID:26300441

Phylogenetic and specificity studies of two-domain GNA-related lectins: generation of multispecificity through domain duplication and divergent evolution

PubMed Central

Van Damme, Els J. M.; Nakamura-Tsuruta, Sachiko; Smith, David F.; Ongenaert, Maté; Winter, Harry C.; Rougé, Pierre; Goldstein, Irwin J.; Mo, Hanqing; Kominami, Junko; Culerrier, Raphaël; Barre, Annick; Hirabayashi, Jun; Peumans, Willy J.

2007-01-01

A re-investigation of the occurrence and taxonomic distribution of proteins built up of protomers consisting of two tandem arrayed domains equivalent to the GNA [Galanthus nivalis (snowdrop) agglutinin] revealed that these are widespread among monotyledonous plants. Phylogenetic analysis of the available sequences indicated that these proteins do not represent a monophylogenetic group but most probably result from multiple independent domain duplication/in tandem insertion events. To corroborate the relationship between inter-domain sequence divergence and the widening of specificity range, a detailed comparative analysis was made of the sequences and specificity of a set of two-domain GNA-related lectins. Glycan microarray analyses, frontal affinity chromatography and surface plasmon resonance measurements demonstrated that the two-domain GNA-related lectins acquired a marked diversity in carbohydrate-binding specificity that strikingly contrasts the canonical exclusive specificity of their single domain counterparts towards mannose. Moreover, it appears that most two-domain GNA-related lectins interact with both high mannose and complex N-glycans and that this dual specificity relies on the simultaneous presence of at least two different independently acting binding sites. The combined phylogenetic, specificity and structural data strongly suggest that plants used domain duplication followed by divergent evolution as a mechanism to generate multispecific lectins from a single mannose-binding domain. Taking into account that the shift in specificity of some binding sites from high mannose to complex type N-glycans implies that the two-domain GNA-related lectins are primarily directed against typical animal glycans, it is tempting to speculate that plants developed two-domain GNA-related lectins for defence purposes. PMID:17288538

A micromechanical constitutive model for anisotropic cyclic deformation of super-elastic NiTi shape memory alloy single crystals

NASA Astrophysics Data System (ADS)

Yu, Chao; Kang, Guozheng; Kan, Qianhua

2015-09-01

Based on the experimental observations on the anisotropic cyclic deformation of super-elastic NiTi shape memory alloy single crystals done by Gall and Maier (2002), a crystal plasticity based micromechanical constitutive model is constructed to describe such anisotropic cyclic deformation. To model the internal stress caused by the unmatched inelastic deformation between the austenite and martensite phases on the plastic deformation of austenite phase, 24 induced martensite variants are assumed to be ellipsoidal inclusions with anisotropic elasticity and embedded in the austenite matrix. The homogeneous stress fields in the austenite matrix and each induced martensite variant are obtained by using the Mori-Tanaka homogenization method. Two different inelastic mechanisms, i.e., martensite transformation and transformation-induced plasticity, and their interactions are considered in the proposed model. Following the assumption of instantaneous domain growth (Cherkaoui et al., 1998), the Helmholtz free energy of a representative volume element of a NiTi shape memory single crystal is established and the thermodynamic driving forces of the internal variables are obtained from the dissipative inequalities. The capability of the proposed model to describe the anisotropic cyclic deformation of super-elastic NiTi single crystals is first verified by comparing the predicted results with the experimental ones. It is concluded that the proposed model can capture the main quantitative features observed in the experiments. And then, the proposed model is further used to predict the uniaxial and multiaxial transformation ratchetting of a NiTi single crystal.

On Latent Growth Models for Composites and Their Constituents.

PubMed

Hancock, Gregory R; Mao, Xiulin; Kher, Hemant

2013-09-01

Over the last decade and a half, latent growth modeling has become an extremely popular and versatile technique for evaluating longitudinal change and its determinants. Most common among the models applied are those for a single measured variable over time. This model has been extended in a variety of ways, most relevant for the current work being the multidomain and the second-order latent growth models. Whereas the former allows for growth function characteristics to be modeled for multiple outcomes simultaneously, with the degree of growth characteristics' relations assessed within the model (e.g., cross-domain slope factor correlations), the latter models growth in latent outcomes, each of which has effect indicators repeated over time. But what if one has an outcome that is believed to be formative relative to its indicator variables rather than latent? In this case, where the outcome is a composite of multiple constituents, modeling change over time is less straightforward. This article provides analytical and applied details for simultaneously modeling growth in composites and their constituent elements, including a real data example using a general computer self-efficacy questionnaire.

Variability of mass-wasting processes in the tectonically-controlled Calabro Tyrrhenian continental margin (Southern Italy)

NASA Astrophysics Data System (ADS)

Casalbore, D.; Bosman, A.; Casas, D.; Chiocci, F. L.; Martorelli, E.; Ridente, D.

2017-12-01

The recent collection of multibeam bathymetry and single-channel seismic profiles on the Calabro-Tyrrhenian continental margin in Southern Italy allowed us to depict a large suite of mass-wasting processes, ranging from gullies up to shelf-indenting canyon system along with over 400 landslide scars, affecting the 52% of the entire area. In detail, slide scars occur from the coast down to -1700 m, with mobilized volumes ranging from some hundreds of m3 up to tens of millions of m3. On the whole, they affect an area of >85 km2, being able to mobilize approximately 1.4 km3. These slides also show a large variability of features both in the headwall, translational and toe domain, thus providing useful insights for a better understanding of their failure and post-failure behavior. The aim of this study is to show the magnitude-frequency relationship of this large amount of slides in order to quantify a range of probabilities for the occurrence of new landslide events as well as to illustrate the main mechanisms that control their development and emplacement.

Naturally Occurring Structural Isomers in Serum IgA1 O-Glycosylation

PubMed Central

Takahashi, Kazuo; Smith, Archer D.; Poulsen, Knud; Kilian, Mogens; Julian, Bruce A.; Mestecky, Jiri; Novak, Jan; Renfrow, Matthew B.

2013-01-01

IgA is the most abundantly produced antibody and plays an important role in the mucosal immune system. Human IgA is represented by two isotypes, IgA1 and IgA2. The major structural difference between these two subclasses is the presence of nine potential sites of O-glycosylation in the hinge region between the first and second constant region domains of the heavy chain. Thr225, Thr228, Ser230, Ser232 and Thr236 have been identified as the predominant sites of O-glycan attachment. The range and distribution of O-glycan chains at each site within the context of adjacent sites in this clustered region create a complex heterogeneity of surface epitopes that is incompletely defined. We previously described the analysis of IgA1 O-glycan heterogeneity by use of high resolution LC/MS and electron capture dissociation tandem MS to unambiguously localize all amino acid attachment sites in IgA1 (Ale) myeloma protein. Here, we report the identification and elucidation of IgA1 O-glycopeptide structural isomers that occur based on amino acid position of the attached glycans (positional isomers) and the structure of the O-glycan chains at individual sites (glycan isomers). These isomers are present in a model IgA1 (Mce1) myeloma protein and occur naturally in normal human serum IgA1. Variable O-glycan chains attached to Ser230, Thr233 or Thr236 produce the predominant positional isomers, including O-glycans composed of a single GalNAc residue. These findings represent the first definitive identification of structural isomeric IgA1 O-glycoforms, define the single-site heterogeneity for all O-glycan sites in a single sample, and have implications for defining epitopes based on clustered O-glycan variability. PMID:22067045

eClims: An Extensible and Dynamic Integration Framework for Biomedical Information Systems.

PubMed

Savonnet, Marinette; Leclercq, Eric; Naubourg, Pierre

2016-11-01

Biomedical information systems (BIS) require consideration of three types of variability: data variability induced by new high throughput technologies, schema or model variability induced by large scale studies or new fields of research, and knowledge variability resulting from new discoveries. Beyond data heterogeneity, managing variabilities in the context of BIS requires extensible and dynamic integration process. In this paper, we focus on data and schema variabilities and we propose an integration framework based on ontologies, master data, and semantic annotations. The framework addresses issues related to: 1) collaborative work through a dynamic integration process; 2) variability among studies using an annotation mechanism; and 3) quality control over data and semantic annotations. Our approach relies on two levels of knowledge: BIS-related knowledge is modeled using an application ontology coupled with UML models that allow controlling data completeness and consistency, and domain knowledge is described by a domain ontology, which ensures data coherence. A system build with the eClims framework has been implemented and evaluated in the context of a proteomic platform.

An anti-hapten camelid antibody reveals a cryptic binding site with significant energetic contributions from a nonhypervariable loop

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

Fanning, Sean W.; Horn, James R.

2014-03-05

Conventional anti-hapten antibodies typically bind low-molecular weight compounds (haptens) in the crevice between the variable heavy and light chains. Conversely, heavy chain-only camelid antibodies, which lack a light chain, must rely entirely on a single variable domain to recognize haptens. While several anti-hapten VHHs have been generated, little is known regarding the underlying structural and thermodynamic basis for hapten recognition. Here, an anti-methotrexate VHH (anti-MTX VHH) was generated using grafting methods whereby the three complementarity determining regions (CDRs) were inserted onto an existing VHH framework. Thermodynamic analysis of the anti-MTX VHH CDR1-3 Graft revealed a micromolar binding affinity, while themore » crystal structure of the complex revealed a somewhat surprising noncanonical binding site which involved MTX tunneling under the CDR1 loop. Due to the close proximity of MTX to CDR4, a nonhypervariable loop, the CDR4 loop sequence was subsequently introduced into the CDR1-3 graft, which resulted in a dramatic 1000-fold increase in the binding affinity. Crystal structure analysis of both the free and complex anti-MTX CDR1-4 graft revealed CDR4 plays a significant role in both intermolecular contacts and binding site conformation that appear to contribute toward high affinity binding. Additionally, the anti-MTX VHH possessed relatively high specificity for MTX over closely related compounds aminopterin and folate, demonstrating that VHH domains are capable of binding low-molecular weight ligands with high affinity and specificity, despite their reduced interface.« less

Dynamic DNA-controlled "stop-and-go" assembly of well-defined protein domains on RNA-scaffolded TMV-like nanotubes.

PubMed

Schneider, Angela; Eber, Fabian J; Wenz, Nana L; Altintoprak, Klara; Jeske, Holger; Eiben, Sabine; Wege, Christina

2016-12-01

A DNA-based approach allows external control over the self-assembly process of tobacco mosaic virus (TMV)-like ribonucleoprotein nanotubes: their growth from viral coat protein (CP) subunits on five distinct RNA scaffolds containing the TMV origin of assembly (OAs) could be temporarily blocked by a stopper DNA oligomer hybridized downstream (3') of the OAs. At two upstream (5') sites tested, simple hybridization was not sufficient for stable stalling, which correlates with previous findings on a non-symmetric assembly of TMV. The growth of DNA-arrested particles could be restarted efficiently by displacement of the stopper via its toehold by using a release DNA oligomer, even after storage for twelve days. This novel strategy for growing proteinaceous tubes under tight kinetic and spatial control combines RNA guidance and its site-specific but reversible interruption by DNA blocking elements. As three of the RNA scaffolds contained long heterologous non-TMV sequence portions that included the stopping sites, this method is applicable to all RNAs amenable to TMV CP encapsidation, albeit with variable efficiency most likely depending on the scaffolds' secondary structures. The use of two distinct, selectively addressable CP variants during the serial assembly stages finally enabled an externally configured fabrication of nanotubes with highly defined subdomains. The "stop-and-go" strategy thus might pave the way towards production routines of TMV-like particles with variable aspect ratios from a single RNA scaffold, and of nanotubes with two or even more adjacent protein domains of tightly pre-defined lengths.

Combining phage display with de novo protein sequencing for reverse engineering of monoclonal antibodies.

PubMed

Rickert, Keith W; Grinberg, Luba; Woods, Robert M; Wilson, Susan; Bowen, Michael A; Baca, Manuel

2016-01-01

The enormous diversity created by gene recombination and somatic hypermutation makes de novo protein sequencing of monoclonal antibodies a uniquely challenging problem. Modern mass spectrometry-based sequencing will rarely, if ever, provide a single unambiguous sequence for the variable domains. A more likely outcome is computation of an ensemble of highly similar sequences that can satisfy the experimental data. This outcome can result in the need for empirical testing of many candidate sequences, sometimes iteratively, to identity one which can replicate the activity of the parental antibody. Here we describe an improved approach to antibody protein sequencing by using phage display technology to generate a combinatorial library of sequences that satisfy the mass spectrometry data, and selecting for functional candidates that bind antigen. This approach was used to reverse engineer 2 commercially-obtained monoclonal antibodies against murine CD137. Proteomic data enabled us to assign the majority of the variable domain sequences, with the exception of 3-5% of the sequence located within or adjacent to complementarity-determining regions. To efficiently resolve the sequence in these regions, small phage-displayed libraries were generated and subjected to antigen binding selection. Following enrichment of antigen-binding clones, 2 clones were selected for each antibody and recombinantly expressed as antigen-binding fragments (Fabs). In both cases, the reverse-engineered Fabs exhibited identical antigen binding affinity, within error, as Fabs produced from the commercial IgGs. This combination of proteomic and protein engineering techniques provides a useful approach to simplifying the technically challenging process of reverse engineering monoclonal antibodies from protein material.

Combining phage display with de novo protein sequencing for reverse engineering of monoclonal antibodies

PubMed Central

Rickert, Keith W.; Grinberg, Luba; Woods, Robert M.; Wilson, Susan; Bowen, Michael A.; Baca, Manuel

2016-01-01

ABSTRACT The enormous diversity created by gene recombination and somatic hypermutation makes de novo protein sequencing of monoclonal antibodies a uniquely challenging problem. Modern mass spectrometry-based sequencing will rarely, if ever, provide a single unambiguous sequence for the variable domains. A more likely outcome is computation of an ensemble of highly similar sequences that can satisfy the experimental data. This outcome can result in the need for empirical testing of many candidate sequences, sometimes iteratively, to identity one which can replicate the activity of the parental antibody. Here we describe an improved approach to antibody protein sequencing by using phage display technology to generate a combinatorial library of sequences that satisfy the mass spectrometry data, and selecting for functional candidates that bind antigen. This approach was used to reverse engineer 2 commercially-obtained monoclonal antibodies against murine CD137. Proteomic data enabled us to assign the majority of the variable domain sequences, with the exception of 3–5% of the sequence located within or adjacent to complementarity-determining regions. To efficiently resolve the sequence in these regions, small phage-displayed libraries were generated and subjected to antigen binding selection. Following enrichment of antigen-binding clones, 2 clones were selected for each antibody and recombinantly expressed as antigen-binding fragments (Fabs). In both cases, the reverse-engineered Fabs exhibited identical antigen binding affinity, within error, as Fabs produced from the commercial IgGs. This combination of proteomic and protein engineering techniques provides a useful approach to simplifying the technically challenging process of reverse engineering monoclonal antibodies from protein material. PMID:26852694

GRID2D/3D: A computer program for generating grid systems in complex-shaped two- and three-dimensional spatial domains. Part 2: User's manual and program listing

NASA Technical Reports Server (NTRS)

Bailey, R. T.; Shih, T. I.-P.; Nguyen, H. L.; Roelke, R. J.

1990-01-01

An efficient computer program, called GRID2D/3D, was developed to generate single and composite grid systems within geometrically complex two- and three-dimensional (2- and 3-D) spatial domains that can deform with time. GRID2D/3D generates single grid systems by using algebraic grid generation methods based on transfinite interpolation in which the distribution of grid points within the spatial domain is controlled by stretching functions. All single grid systems generated by GRID2D/3D can have grid lines that are continuous and differentiable everywhere up to the second-order. Also, grid lines can intersect boundaries of the spatial domain orthogonally. GRID2D/3D generates composite grid systems by patching together two or more single grid systems. The patching can be discontinuous or continuous. For continuous composite grid systems, the grid lines are continuous and differentiable everywhere up to the second-order except at interfaces where different single grid systems meet. At interfaces where different single grid systems meet, the grid lines are only differentiable up to the first-order. For 2-D spatial domains, the boundary curves are described by using either cubic or tension spline interpolation. For 3-D spatial domains, the boundary surfaces are described by using either linear Coon's interpolation, bi-hyperbolic spline interpolation, or a new technique referred to as 3-D bi-directional Hermite interpolation. Since grid systems generated by algebraic methods can have grid lines that overlap one another, GRID2D/3D contains a graphics package for evaluating the grid systems generated. With the graphics package, the user can generate grid systems in an interactive manner with the grid generation part of GRID2D/3D. GRID2D/3D is written in FORTRAN 77 and can be run on any IBM PC, XT, or AT compatible computer. In order to use GRID2D/3D on workstations or mainframe computers, some minor modifications must be made in the graphics part of the program; no modifications are needed in the grid generation part of the program. The theory and method used in GRID2D/3D is described.

GRID2D/3D: A computer program for generating grid systems in complex-shaped two- and three-dimensional spatial domains. Part 1: Theory and method

NASA Technical Reports Server (NTRS)

Shih, T. I.-P.; Bailey, R. T.; Nguyen, H. L.; Roelke, R. J.

1990-01-01

An efficient computer program, called GRID2D/3D was developed to generate single and composite grid systems within geometrically complex two- and three-dimensional (2- and 3-D) spatial domains that can deform with time. GRID2D/3D generates single grid systems by using algebraic grid generation methods based on transfinite interpolation in which the distribution of grid points within the spatial domain is controlled by stretching functions. All single grid systems generated by GRID2D/3D can have grid lines that are continuous and differentiable everywhere up to the second-order. Also, grid lines can intersect boundaries of the spatial domain orthogonally. GRID2D/3D generates composite grid systems by patching together two or more single grid systems. The patching can be discontinuous or continuous. For continuous composite grid systems, the grid lines are continuous and differentiable everywhere up to the second-order except at interfaces where different single grid systems meet. At interfaces where different single grid systems meet, the grid lines are only differentiable up to the first-order. For 2-D spatial domains, the boundary curves are described by using either cubic or tension spline interpolation. For 3-D spatial domains, the boundary surfaces are described by using either linear Coon's interpolation, bi-hyperbolic spline interpolation, or a new technique referred to as 3-D bi-directional Hermite interpolation. Since grid systems generated by algebraic methods can have grid lines that overlap one another, GRID2D/3D contains a graphics package for evaluating the grid systems generated. With the graphics package, the user can generate grid systems in an interactive manner with the grid generation part of GRID2D/3D. GRID2D/3D is written in FORTRAN 77 and can be run on any IBM PC, XT, or AT compatible computer. In order to use GRID2D/3D on workstations or mainframe computers, some minor modifications must be made in the graphics part of the program; no modifications are needed in the grid generation part of the program. This technical memorandum describes the theory and method used in GRID2D/3D.

The Power of Theory, Research Design, and Transdisciplinary Integration in Moving Psychopathology Forward.

PubMed

Vaidyanathan, Uma; Vrieze, Scott I; Iacono, William G

While the past few decades have seen much work in psychopathology research that has yielded provocative insights, relatively little progress has been made in understanding the etiology of mental disorders. We contend that this is due to an overreliance on statistics and technology with insufficient attention to adequacy of experimental design, a lack of integration of data across various domains of research, and testing of theoretical models using relatively weak study designs. We provide a conceptual discussion of these issues and follow with a concrete demonstration of our proposed solution. Using two different disorders - depression and substance use - as examples, we illustrate how we can evaluate competing theories regarding their etiology by integrating information from various domains including latent variable models, neurobiology, and quasi-experimental data such as twin and adoption studies, rather than relying on any single methodology alone. More broadly, we discuss the extent to which such integrative thinking allows for inferences about the etiology of mental disorders, rather than focusing on descriptive correlates alone. Greater scientific insight will require stringent tests of competing theories and a deeper conceptual understanding of the advantages and pitfalls of methodologies and criteria we use in our studies.

Characterisation of single domain ATP-binding cassette protien homologues of Theileria parva.

PubMed

Kibe, M K; Macklin, M; Gobright, E; Bishop, R; Urakawa, T; ole-MoiYoi, O K

2001-09-01

Two distinct genes encoding single domain, ATP-binding cassette transport protein homologues of Theileria parva were cloned and sequenced. Neither of the genes is tandemly duplicated. One gene, TpABC1, encodes a predicted protein of 593 amino acids with an N-terminal hydrophobic domain containing six potential membrane-spanning segments. A single discontinuous ATP-binding element was located in the C-terminal region of TpABC1. The second gene, TpABC2, also contains a single C-terminal ATP-binding motif. Copies of TpABC2 were present at four loci in the T. parva genome on three different chromosomes. TpABC1 exhibited allelic polymorphism between stocks of the parasite. Comparison of cDNA and genomic sequences revealed that TpABC1 contained seven short introns, between 29 and 84 bp in length. The full-length TpABC1 protein was expressed in insect cells using the baculovirus system. Application of antibodies raised against the recombinant antigen to western blots of T. parva piroplasm lysates detected an 85 kDa protein in this life-cycle stage.

Preparation and characterization of SiO2-coated submicron-sized L10 Fe-Pt particles

NASA Astrophysics Data System (ADS)

Hayashi, Yoshiaki; Ogawa, Tomoyuki; Ishiyama, Kazushi

2018-05-01

The development of magnets with higher performance is attracting increasing interest. The optimization of their microstructure is essential to enhance their properties, and a microstructure comprising magnetically isolated hard magnetic grains of a single-domain size has been proposed as an ideal structure for enhancing the coercivity of magnets. To obtain magnets with an ideal structure, we consider the fabrication of magnets by an approach based on core/shell nanoparticles with a hard magnetic core and a non-magnetic shell. In this study, to obtain particles for our proposed approach, we attempted to fabricate L10 Fe-Pt/SiO2-core/shell particles with submicron-sized cores less than the critical single-domain size. The fabrication of such core/shell particles was confirmed from morphology observations and XRD analysis of the particles. Although the formation of more desirable core/shell particles with submicron-sized single-crystal cores in the single-domain size range was not achieved, the fabricated core/shell particles showed a high coercivity of 25 kOe.

Myosin conformational states determined by single fluorophore polarization

PubMed Central

Warshaw, David M.; Hayes, Eric; Gaffney, Donald; Lauzon, Anne-Marie; Wu, Junru; Kennedy, Guy; Trybus, Kathleen; Lowey, Susan; Berger, Christopher

1998-01-01

Muscle contraction is powered by the interaction of the molecular motor myosin with actin. With new techniques for single molecule manipulation and fluorescence detection, it is now possible to correlate, within the same molecule and in real time, conformational states and mechanical function of myosin. A spot-confocal microscope, capable of detecting single fluorophore polarization, was developed to measure orientational states in the smooth muscle myosin light chain domain during the process of motion generation. Fluorescently labeled turkey gizzard smooth muscle myosin was prepared by removal of endogenous regulatory light chain and re-addition of the light chain labeled at cysteine-108 with the 6-isomer of iodoacetamidotetramethylrhodamine (6-IATR). Single myosin molecule fluorescence polarization data, obtained in a motility assay, provide direct evidence that the myosin light chain domain adopts at least two orientational states during the cyclic interaction of myosin with actin, a randomly disordered state, most likely associated with myosin whereas weakly bound to actin, and an ordered state in which the light chain domain adopts a finite angular orientation whereas strongly bound after the powerstroke. PMID:9653135

HangOut: generating clean PSI-BLAST profiles for domains with long insertions.

PubMed

Kim, Bong-Hyun; Cong, Qian; Grishin, Nick V

2010-06-15

Profile-based similarity search is an essential step in structure-function studies of proteins. However, inclusion of non-homologous sequence segments into a profile causes its corruption and results in false positives. Profile corruption is common in multidomain proteins, and single domains with long insertions are a significant source of errors. We developed a procedure (HangOut) that, for a single domain with specified insertion position, cleans erroneously extended PSI-BLAST alignments to generate better profiles. HangOut is implemented in Python 2.3 and runs on all Unix-compatible platforms. The source code is available under the GNU GPL license at http://prodata.swmed.edu/HangOut/. Supplementary data are available at Bioinformatics online.

Investigating Simulated Driving Errors in Amnestic Single- and Multiple-Domain Mild Cognitive Impairment.

PubMed

Hird, Megan A; Vesely, Kristin A; Fischer, Corinne E; Graham, Simon J; Naglie, Gary; Schweizer, Tom A

2017-01-01

The areas of driving impairment characteristic of mild cognitive impairment (MCI) remain unclear. This study compared the simulated driving performance of 24 individuals with MCI, including amnestic single-domain (sd-MCI, n = 11) and amnestic multiple-domain MCI (md-MCI, n = 13), and 20 age-matched controls. Individuals with MCI committed over twice as many driving errors (20.0 versus 9.9), demonstrated difficulty with lane maintenance, and committed more errors during left turns with traffic compared to healthy controls. Specifically, individuals with md-MCI demonstrated greater driving difficulty compared to healthy controls, relative to those with sd-MCI. Differentiating between different subtypes of MCI may be important when evaluating driving safety.

Variability within a pea core collection of LEAM and HSP22, two mitochondrial seed proteins involved in stress tolerance.

PubMed

Avelange-Macherel, Marie-Hélène; Payet, Nicole; Lalanne, David; Neveu, Martine; Tolleter, Dimitri; Burstin, Judith; Macherel, David

2015-07-01

LEAM, a late embryogenesis abundant protein, and HSP22, a small heat shock protein, were shown to accumulate in the mitochondria during pea (Pisum sativum L.) seed development, where they are expected to contribute to desiccation tolerance. Here, their expression was examined in seeds of 89 pea genotypes by Western blot analysis. All genotypes expressed LEAM and HSP22 in similar amounts. In contrast with HSP22, LEAM displayed different isoforms according to apparent molecular mass. Each of the 89 genotypes harboured a single LEAM isoform. Genomic and RT-PCR analysis revealed four LEAM genes differing by a small variable indel in the coding region. These variations were consistent with the apparent molecular mass of each isoform. Indels, which occurred in repeated domains, did not alter the main properties of LEAM. Structural modelling indicated that the class A α-helix structure, which allows interactions with the mitochondrial inner membrane in the dry state, was preserved in all isoforms, suggesting functionality is maintained. The overall results point out the essential character of LEAM and HSP22 in pea seeds. LEAM variability is discussed in terms of pea breeding history as well as LEA gene evolution mechanisms. © 2014 John Wiley & Sons Ltd.

The partial volume effect in the quantification of 1H magnetic resonance spectroscopy in Alzheimer's disease and aging.

PubMed

Mato Abad, Virginia; Quirós, Alicia; García-Álvarez, Roberto; Loureiro, Javier Pereira; Alvarez-Linera, Juan; Frank, Ana; Hernández-Tamames, Juan Antonio

2014-01-01

1H-MRS variability increases due to normal aging and also as a result of atrophy in grey and white matter caused by neurodegeneration. In this work, an automatic process was developed to integrate data from spectra and high-resolution anatomical images to quantify metabolites, taking into account tissue partial volumes within the voxel of interest avoiding additional spectra acquisitions required for partial volume correction. To evaluate this method, we use a cohort of 135 subjects (47 male and 88 female, aged between 57 and 99 years) classified into 4 groups: 38 healthy participants, 20 amnesic mild cognitive impairment patients, 22 multi-domain mild cognitive impairment patients, and 55 Alzheimer's disease patients. Our findings suggest that knowing the voxel composition of white and grey matter and cerebrospinal fluid is necessary to avoid partial volume variations in a single-voxel study and to decrease part of the variability found in metabolites quantification, particularly in those studies involving elder patients and neurodegenerative diseases. The proposed method facilitates the use of 1H-MRS techniques in statistical studies in Alzheimer's disease, because it provides more accurate quantitative measurements, reduces the inter-subject variability, and improves statistical results when performing group comparisons.

Predicting ecological flow regime at ungaged sites: A comparison of methods

USGS Publications Warehouse

Murphy, Jennifer C.; Knight, Rodney R.; Wolfe, William J.; Gain, W. Scott

2012-01-01

Nineteen ecologically relevant streamflow characteristics were estimated using published rainfall–runoff and regional regression models for six sites with observed daily streamflow records in Kentucky. The regional regression model produced median estimates closer to the observed median for all but two characteristics. The variability of predictions from both models was generally less than the observed variability. The variability of the predictions from the rainfall–runoff model was greater than that from the regional regression model for all but three characteristics. Eight characteristics predicted by the rainfall–runoff model display positive or negative bias across all six sites; biases are not as pronounced for the regional regression model. Results suggest that a rainfall–runoff model calibrated on a single characteristic is less likely to perform well as a predictor of a range of other characteristics (flow regime) when compared with a regional regression model calibrated individually on multiple characteristics used to represent the flow regime. Poor model performance may misrepresent hydrologic conditions, potentially distorting the perceived risk of ecological degradation. Without prior selection of streamflow characteristics, targeted calibration, and error quantification, the widespread application of general hydrologic models to ecological flow studies is problematic. Published 2012. This article is a U.S. Government work and is in the public domain in the USA.

Statistical Frequency-Dependent Analysis of Trial-to-Trial Variability in Single Time Series by Recurrence Plots.

PubMed

Tošić, Tamara; Sellers, Kristin K; Fröhlich, Flavio; Fedotenkova, Mariia; Beim Graben, Peter; Hutt, Axel

2015-01-01

For decades, research in neuroscience has supported the hypothesis that brain dynamics exhibits recurrent metastable states connected by transients, which together encode fundamental neural information processing. To understand the system's dynamics it is important to detect such recurrence domains, but it is challenging to extract them from experimental neuroscience datasets due to the large trial-to-trial variability. The proposed methodology extracts recurrent metastable states in univariate time series by transforming datasets into their time-frequency representations and computing recurrence plots based on instantaneous spectral power values in various frequency bands. Additionally, a new statistical inference analysis compares different trial recurrence plots with corresponding surrogates to obtain statistically significant recurrent structures. This combination of methods is validated by applying it to two artificial datasets. In a final study of visually-evoked Local Field Potentials in partially anesthetized ferrets, the methodology is able to reveal recurrence structures of neural responses with trial-to-trial variability. Focusing on different frequency bands, the δ-band activity is much less recurrent than α-band activity. Moreover, α-activity is susceptible to pre-stimuli, while δ-activity is much less sensitive to pre-stimuli. This difference in recurrence structures in different frequency bands indicates diverse underlying information processing steps in the brain.

Statistical Frequency-Dependent Analysis of Trial-to-Trial Variability in Single Time Series by Recurrence Plots

PubMed Central

Tošić, Tamara; Sellers, Kristin K.; Fröhlich, Flavio; Fedotenkova, Mariia; beim Graben, Peter; Hutt, Axel

2016-01-01

For decades, research in neuroscience has supported the hypothesis that brain dynamics exhibits recurrent metastable states connected by transients, which together encode fundamental neural information processing. To understand the system's dynamics it is important to detect such recurrence domains, but it is challenging to extract them from experimental neuroscience datasets due to the large trial-to-trial variability. The proposed methodology extracts recurrent metastable states in univariate time series by transforming datasets into their time-frequency representations and computing recurrence plots based on instantaneous spectral power values in various frequency bands. Additionally, a new statistical inference analysis compares different trial recurrence plots with corresponding surrogates to obtain statistically significant recurrent structures. This combination of methods is validated by applying it to two artificial datasets. In a final study of visually-evoked Local Field Potentials in partially anesthetized ferrets, the methodology is able to reveal recurrence structures of neural responses with trial-to-trial variability. Focusing on different frequency bands, the δ-band activity is much less recurrent than α-band activity. Moreover, α-activity is susceptible to pre-stimuli, while δ-activity is much less sensitive to pre-stimuli. This difference in recurrence structures in different frequency bands indicates diverse underlying information processing steps in the brain. PMID:26834580

Latent Variable Modeling of Brain Gray Matter Volume and Psychopathy in Incarcerated Offenders

PubMed Central

Baskin-Sommers, Arielle R.; Neumann, Craig S.; Cope, Lora M.; Kiehl, Kent A.

2016-01-01

Advanced statistical modeling has become a prominent feature in psychological science and can be a useful approach for representing the neural architecture linked to psychopathology. Psychopathy, a disorder characterized by dysfunction in interpersonal-affective and impulsive-antisocial domains, is associated with widespread neural abnormalities. Several imaging studies suggest that underlying structural deficits in paralimbic regions are associated with psychopathy. While these studies are useful, they make assumptions about the organization of the brain and its relevance to individuals displaying psychopathic features. Capitalizing on statistical modeling, the present study (N=254) used latent variable methods to examine the structure of gray matter volume in male offenders, and assessed the latent relations between psychopathy and gray matter factors reflecting paralimbic and non-paralimbic regions. Results revealed good fit for a four-factor gray matter paralimbic model and these first-order factors were accounted for by a super-ordinate paralimbic ‘system’ factor. Moreover, a super-ordinate psychopathy factor significantly predicted the paralimbic, but not the non-paralimbic factor. The latent variable paralimbic model, specifically linked with psychopathy, goes beyond understanding of single brain regions within the system and provides evidence for psychopathy-related gray matter volume reductions in the paralimbic system as a whole. PMID:27269123