bluuebunny/crossref_metadata_2025 huggingface dataset:
Variance results for random walk models of choice reaction time
Authors: Schwarz W.
Published: August 2011

Approximate expressions for the conditional reaction time variances in general random walk models based on Wald's (1947) approximation are first derived, and then the corresponding exact results for a model assuming a Laplacean density of step sizes are derived. The results are applied to auditory choice reaction time data obtained by Green et al. (1983), and approximate and exact results are compared. The paper concludes with a discussion of whether the predictions, which are the first relevant results on conditional first passage time variances, increase the identifiability and the power of tests of the general random walk model.
Comparison of minimum logit chi‐square and Bayesian item parameter estimation
Authors: Baker Frank B.
Published: August 2011

Under the minimum logit chi‐square estimation procedures implemented in the MICRO‐IRT computer program, an ancillary outcome of the application of the 1/2n rule was that large‐valued estimates of discrimination can often be prevented. Since the use of prior distributions on the discrimination parameters in Bayesian estimation also prevents such values, a comparison of the two estimation procedures was conducted. The two estimation procedures were applied to 36 simulated data sets involving small numbers of items and groups of examinees to compare their parameter recovery characteristics. Overall, the item and ability parameter estimates yielded by the two estimation procedures were comparable to each other and to the results of previous parameter recovery studies. Both approaches seemed to prevent excessively large item discrimination estimates. However, the minimum logit chi‐square procedure yielded a higher proportion of deviant estimates of item difficulty than did the Bayesian procedures of the BILOG computer program. This appears to be due to the 1/2n rule yielding small‐valued item discrimination estimates. The results suggest that the Bayesian procedures of the BILOG computer program are to be preferred.
Investigating Mokken scalability of dichotomous items by means of ordinal latent class analysis
Authors: Croon M. A.
Published: August 2011

A method for investigating whether a set of items satisfies the conditions of a ‘latent scale’ is proposed. It is based on an adaptation of the latent class model in which the requirement of ‘double monotony’ is translated into systems of inequalities on the item response probabilities. The problem of obtaining the maximum likelihood estimates of the model parameters is discussed. Finally, this method is applied to real data from a large survey.
Mathematical models of cognitive development
Authors: Eckstein Shulamith G. , Shemesh Michal
Published: August 2011

Two mathematical models of cognitive development are investigated. One model assumes that cognitive growth proceeds by stages, and the other assumes that cognitive growth is continuous. Both models make predictions concerning the percentages of the population at different cognitive levels. In the stage model, the cognitive level is identified with the stage, and in the continuous learning model, the cognitive level is defined by attainment above a given threshold and below the next highest threshold. The models are applied to three large‐scale experimental studies which categorize adolescents according to their Piagetian stage, namely a study by Lawson & Renner (1974) in the USA, a study by Shayer & Wylam (1978) in England, and a study by Shemesh, Eckstein & Lazarowitz (1992) in Israel. In all cases, the fit of the stage model to the experimental data was better than the fit of the continuous learning model.
Robustness of some estimators for the analysis of covariance structures
Authors: Henly Susan J.
Published: August 2011

A sampling experiment was designed to evaluate the robustness of some estimators used in the analysis of covariance structures to misspecification of the discrepancy function in finite samples. The estimators were studied under four distribution (a multivariate normal, an elliptical, a non‐elliptically symmetric, and an asymmetric multivariate distribution, and eight sample size (75, 150, 300, 600, 1200, 2400, 4800, 9600) conditions. Parameters of the composite direct product model for a 6‐variable MTMM matrix were estimated using the Maximum Wishart Likelihood (MWL), generalized least squares (GLS), asymptotically distribution free (ADF), and approximate ADF (DADF) estimators. Browne's elliptical correction (CMWL) to the test statistic and standard errors for scale‐invariant models was also made for each sample. Each of the 32 distribution‐sample size conditions was replicated 300 times. The accuracy of the parameter estimates and estimated standard errors and the distribution of the test statistic were studied. The theoretically predicted importance of information contained i. higher‐order moments of arbitrary distributions was confirmed. Robustness of the MWL and normal theory GLS estimators cannot be taken for granted. Elliptical corrections may be a practical solution to some data analytic problems.
Statistical software for microcomputers: StatXact, and SPSS for Windows
Authors: MARSH NORMAN , LOVIE PAT
Published: August 2011

As there seems to be an epidemic of Windows versions of statistics packages at present, this section wouldn't be doing its job if it didn't put as many as possible under the microscope. So, we have lined up BMDP New System, Unistat for Windows and, all being well, MINITAB for Windows for May 1994, and for this issue SPSS for Windows. I haven't had the package long enough to report on much more than first impressions, so expect more in a future issue.
A reparameterization of the restricted factor analysis model for multitrait‐multimethod matrices
Authors: Dudgeon Paul
Published: August 2011

Some limitations in existing covariance structure models for multitrait multimethod (MTMM) data are discussed as an introduction to a re‐parameterization of the restricted factor analysis model. Unlike existing specifications of this model, the reparameterized model is consistent with Campbell & Fiske's underlying rationale for the MTMM design. It accommodates multiplicative as well as additive relationships in MTMM matrices and provides information concerning the extent to which any matrix conforms to Campbell & Fiske's (1959) four requirements for convergent and discriminant validity. It can also indicate the degree of trait variance in measures that is independent of method effects. Emphasis is placed on the specification of factor correlation matrices which accords with the hypothesized relationships among both traits and methods in an MTMM study. These suggestions are demonstrated by an application of the reparameterized model to an exemplar MTMM matrix which restricted factor analysis has previously found difficult in providing an interpretable solution.
Statistical methods for understanding cognitive growth: A review, a synthesis and an application
Authors: Plewis Ian
Published: August 2011

Methods for analysing data on cognitive growth are reviewed with emphasis given to the problems posed by scales which inevitably change over age. Multilevel growth curve and regression models are contrasted. A hybrid model is proposed which shares some of the advantages of these two approaches. The models are applied to a set of longitudinal data on mathematics growth from London primary school pupils. We find that conclusions about relative growth vary according to the scale adopted. Implications for the design and analysis of growth studies in psychology and education are discussed.
Interaction contrasts in repeated measures designs
Authors: Lix Lisa M. , Keselman H. J.
Published: August 2011

Specific information concerning the nature of interaction effects in factorial designs may be obtained through the use of tetrad contrasts. Empirical familywise Type I error rates and power rates associated with 10 procedures for conducting tetrad contrasts in groups‐by‐trials repeated measures designs were obtained when the assumptions of multisample sphericity and multivariate normality were not satisfied. Only three procedures provided acceptable control of familywise Type I error rates under the assumption violation conditions. These procedures relied on a test statistic formed using an estimate of the standard error of the contrast which was based on only that data used in defining the contrast, in combination with either a Studentized maximum modulus, Hochberg (1988) step‐up Bonferroni, or Shaffer (1986) modified sequentially rejective Bonferroni critical value. Minimal power differences between these three procedures were observed.
Confidence intervals for two robust regression lines with a heteroscedastic error term
Authors: Wilcox Rand R.
Published: August 2011

Recently, Wilcox (1994) suggested a method of computing a confidence interval for the slope of two robust regression methods. Results from Wu (1986) suggest that Wilcox's method will fail when the error term has non‐constant variance and simulations reported here confirm this. This paper describes a more satisfactory method for handling non‐constant variance when working with the biweight midregression line considered by Wilcox, with little or no loss in accuracy when the error term has constant variance. Moreover, this paper illustrates that the biweight midregression method, in its present form, can yield an unsatisfactory estimate of the slope when there is a heteroscedastic error term, even with a very large sample size. A simple method of correcting this problem is described which also eliminates the need for the bias correction term used by Wilcox. This paper also considers the problem of computing confidence intervals for the slope of the robust regression method derived by De Jongh, De Wet and Welsh (1988), and a fairly accurate method is found even when the error term has non‐constant variance.
The scaling of dispersion and correlation: A comparison of least‐squares and absolute‐deviation statistics
Authors: De Catanzaro Denys , Taylor James C.
Published: August 2011

In conventional measures of dispersion and correlation, the use of squared deviations from the mean causes a disproportionate influence of outliers. We have compared various conventional and unconventional measures of dispersion and correlation through repeated computer trials, taking large numbers of samples from populations of specified distributions. Under the normal distribution, the standard deviation and Pearson correlation provide the most stable estimates of dispersion and correlation. However, in other cases involving outliers within normal distributions, double exponential distributions, or skewed distributions, measures of dispersion and correlation involving absolute deviations from the mean are clearly more stable than arc conventional formulae.
The relationship of variance to interaction contrast in parallel systems factorial technology
Authors: Townsend James T. , Diederich Adele
Published: August 2011

Mean interaction contrast has been shown to be a beneficial statistic for testing between serial and parallel processes (e.g. Schweickert, 1978; Sternberg, 1969; Townscnd, 1984). The present theoretical note investigates a conjecture of Egeth & Dagenbach (1991) that the mean interaction contrast is largest when the parallel processes are each deterministic, that is possessing zero variance. We show that their conjecture is true in certain situations but not in others. We further demonstrate that the magnitude of mean interaction contrast may be a non‐monotonic function of processing time variance. Finally, implications for experimentation are pointed out.
An equivalence relation between correspondence analysis and classical metric multidimensional scaling for the recovery of Euclidean distances
Authors: Carroll J. Douglas , Kumbasar Ece , Romney A. Kimball
Published: August 2011

A theorem is proved showing that a special variant of correspondence analysis (CA), like classical two‐way metric multidimensional scaling (MMDS), recovers Euclidean distances (asymptotically, as a certain constant grows large) exactly, and in fact yields solutions equivalent up to a similarity transformation to MMDS, even in the case of ‘noisy’ data. Specifically, a slight modification of a use of CA for analysis of proximity data proposed independently by Gifi and by Weller & Romney, which depends on a certain additive constant, k, which should be ‘large’, is shown, as → ∞, to result in an R‐dimensional solution equivalent, up to a scale factor, to that obtained by a certain form of MMDS. It is conjectured that this asymptotic result may account for the apparent success of the closely related ‘Gifi/Weller/Romney’ CA procedure in recovering multidimensional structure underlying proximity data.
Can tests for treatment group equality be improved?: The bootstrap and trimmed means conjecture
Authors: Wilcox Rand R. , Keselman H. J. , Kowalchuk Rhonda K.
Published: August 2011

Westfall & Young's (1993) results suggest that by combining bootstrap methods with methods based on trimmed means researchers can obtain better Type I error control when testing for treatment group equality. Thus, the methods due to Alexander & Govern (1994), Box (1954), and Welch (1951) were compared under conditions of non‐normality and variance heterogeneity when group sizes were unequal, conditions known to produce liberal rates of error. We found that, typically, in one‐way designs better Type I error control can indeed be obtained when the bootstrap method is used in conjunction with test statistics based on trimmed means.
Conditional and unconditional tests of association in 2 × 2 tables
Authors: Macdonald Ranald R.
Published: August 2011

The long‐standing controversy concerning the use of conditional and unconditional tests of association in 2 × 2 tables is re‐examined from a signal detection perspective. Signal detection theory assumes that an observer's sensitivity can be estimated from the association present in a 2 × 2 table and that this sensitivity remains constant when extraneous factors change the probabilities of the 2 × 2 table's marginal totals. It is argued that the concepts of signal detection theory are quite general and that a signal detection type model can be said to apply to any population of 2 × 2 tables with different marginal totals where the degree of association present is measurable on an ordinal scale. It turns out that this measurability assumption is also central to the controversy concerning the testing of associations in 2 × 2 tables. It is noted that the extra power of unconditional tests arises because, unlike conditional tests, the unconditional tests confound whatever measure of association is under test with the table's marginal totals. Put in signal detection terms, this means that the unconditional tests are not pure tests of sensitivity. The argument is illustrated with reference to an example from Yates (1984) and an extension of it. However, it is suggested that there are cases where the associations in 2 × 2 tables cannot be measured on an ordinal scale, where the concordance of the row and column totals could be held to demonstrate the presence of an association and where no signal detection type model applies. In such cases the use of unconditional tests could be defended but, compared with conditional tests, they would require additional, possibly unrealistic, assumptions regarding the distributions of the marginal totals. It is concluded, therefore, that in most cases conditional tests should be preferred to unconditional ones. The paper ends by exhorting researchers to choose their chance distributions with care since objectively ‘correct’ chance distributions do not exist.
Thurstonian models for variants of the method of tetrads
Authors: Ennis John M. , Ennis Daniel M. , Yip Dorene , O'Mahony Michael
Published: August 2011

Variants of the method of tetrads are discussed and their psychometric functions are both derived and presented in table form. For the first variant, the Unspecified method, subject response is correct provided that the subject, when presented with two stimuli from one set and two stimuli from a second set, correctly segregates the four stimuli into their two appropriate groups. In the second variant, the Specified method, subject response is correct provided that the subject, when presented with two stimuli from one set and two stimuli from a second set, correctly discerns the two strongest stimuli. For the Unspecified method,

where Pc is the probability of correct response, and ø (x) and Φ (x) are the density and distribution functions respectively, for the standard normal distribution. The parameter δ is the perceptual difference between stimulus means and corresponds to the signal detection measure of sensitivity d. For the Specified method,

For each of the two variants, tables connect the probability of correct response to δ.
Glacial Cycles and Indian Monsoon—A Southern Push
Authors: Liu Zhengyu
Published: August 2011

An analysis of ancient lake bed sediments challenges traditional views of Indian monsoon dynamics.
Scourge of Snake Oil Salesmen Bids an Early Farewell
Authors: Kupferschmidt Kai
Published: August 2011

Edzard Ernst, professor of complementary and alternative medicine at the University of Exeter, has been forced to retire early in a deal to save the department he helped build.
Wayne Clough Wants Smithsonian Science to Escape Its Shadow
Authors: Mervis Jeffrey
Published: August 2011

Domestic politics compete with his billion-dollar plans for a global expansion of research to bolster the Smithsonian Institution's famed museums and collections.
Detection of Antibodies against Paracoccidioides brasiliensis Melanin inIn VitroandIn VivoStudies during Infection
Authors: Urán Martha E. , Nosanchuk Joshua D. , Restrepo Angela , Hamilton Andrew J. , Gómez Beatriz L. , Cano Luz E.
Published: August 2011

Several cell wall constituents, including melanins or melanin-like compounds, have been implicated in the pathogenesis of a wide variety of microbial diseases caused by diverse species of pathogenic bacteria, fungi, and helminthes. Among these microorganisms, the dimorphic fungal pathogenParacoccidioides brasiliensisproduces melanin in its conidial and yeast forms. In the present study, melanin particles fromP. brasiliensiswere injected into BALB/c mice in order to produce monoclonal antibodies (MAbs). We identified five immunoglobulin G1 (IgG1) κ-chain and four IgM melanin-binding MAbs. The five IgG1 κ-chain isotypes are the first melanin-binding IgG MAbs ever reported. The nine MAbs labeledP. brasiliensisconidia and yeast cells bothin vitroand in pulmonary tissues. The MAbs cross-reacted with melanin-like purified particles from other fungi and also with commercial melanins, such as synthetic andSepia officinalismelanin. Melanization during paracoccidioidomycosis (PCM) was also further supported by the detection of IgG antibodies reactive to melanin fromP. brasiliensisconidia and yeast in sera and bronchoalveolar lavage fluids fromP. brasiliensis-infected mice, as well as in sera from human patients with PCM. Serum specimens from patients with other mycoses were also tested for melanin-binding antibodies by enzyme-linked immunosorbent assay, and cross-reactivities were detected for melanin particles from different fungal sources. These results suggest that melanin fromP. brasiliensisis an immunologically active fungal structure that activates a strong IgG humoral response in humans and mice.
A Tripartite Fusion, FaeG-FedF-LT192A2:B, of Enterotoxigenic Escherichia coli (ETEC) Elicits Antibodies That Neutralize Cholera Toxin, Inhibit Adherence of K88 (F4) and F18 Fimbriae, and Protect Pigs against K88ac/Heat-Labile Toxin Infection
Authors: Ruan Xiaosai , Liu Mei , Casey Thomas A. , Zhang Weiping
Published: August 2011

EnterotoxigenicEscherichia coli(ETEC) strains expressing K88 (F4) or F18 fimbriae and heat-labile (LT) and/or heat-stable (ST) toxins are the major cause of diarrhea in young pigs. Effective vaccines inducing antiadhesin (anti-K88 and anti-F18) and antitoxin (anti-LT and anti-ST) immunity would provide broad protection to young pigs against ETEC. In this study, we genetically fused nucleotides coding for peptides from K88ac major subunit FaeG, F18 minor subunit FedF, and LT toxoid (LT192) A2 and B subunits for a tripartite adhesin-adhesin-toxoid fusion (FaeG-FedF-LT192A2:B). This fusion was used for immunizations in mice and pigs to assess the induction of antiadhesin and antitoxin antibodies. In addition, protection by the elicited antiadhesin and antitoxin antibodies against a porcine ETEC strain was evaluated in a gnotobiotic piglet challenge model. The data showed that this FaeG-FedF-LT192A2:B fusion elicited anti-K88, anti-F18, and anti-LT antibodies in immunized mice and pigs. In addition, the anti-porcine antibodies elicited neutralized cholera toxin and inhibited adherence against both K88 and F18 fimbriae. Moreover, immunized piglets were protected when challenged with ETEC strain 30302 (K88ac/LT/STb) and did not develop clinical disease. In contrast, all control nonvaccinated piglets developed severe diarrhea and dehydration after being challenged with the same ETEC strain. This study clearly demonstrated that this FaeG-FedF-LT192A2:B fusion antigen elicited antibodies that neutralized LT toxin and inhibited the adherence of K88 and F18 fimbrialE. colistrains and that this fusion could serve as an antigen for vaccines against porcine ETEC diarrhea. In addition, the adhesin-toxoid fusion approach used in this study may provide important information for developing effective vaccines against human ETEC diarrhea.
Gag Induces the Coalescence of Clustered Lipid Rafts and Tetraspanin-Enriched Microdomains at HIV-1 Assembly Sites on the Plasma Membrane
Authors: Hogue Ian B. , Grover Jonathan R. , Soheilian Ferri , Nagashima Kunio , Ono Akira
Published: August 2011

The HIV-1 structural protein Gag associates with two types of plasma membrane microdomains, lipid rafts and tetraspanin-enriched microdomains (TEMs), both of which have been proposed to be platforms for HIV-1 assembly. However, a variety of studies have demonstrated that lipid rafts and TEMs are distinct microdomains in the absence of HIV-1 infection. To measure the impact of Gag on microdomain behaviors, we took advantage of two assays: an antibody-mediated copatching assay and a Förster resonance energy transfer (FRET) assay that measures the clustering of microdomain markers in live cells without antibody-mediated patching. We found that lipid rafts and TEMs copatched and clustered to a greater extent in the presence of membrane-bound Gag in both assays, suggesting that Gag induces the coalescence of lipid rafts and TEMs. Substitutions in membrane binding motifs of Gag revealed that, while Gag membrane binding is necessary to induce coalescence of lipid rafts and TEMs, either acylation of Gag or binding of phosphatidylinositol-(4,5)-bisphosphate is sufficient. Finally, a Gag derivative that is defective in inducing membrane curvature appeared less able to induce lipid raft and TEM coalescence. A higher-resolution analysis of assembly sites by correlative fluorescence and scanning electron microscopy showed that coalescence of clustered lipid rafts and TEMs occurs predominately at completed cell surface virus-like particles, whereas a transmembrane raft marker protein appeared to associate with punctate Gag fluorescence even in the absence of cell surface particles. Together, these results suggest that different membrane microdomain components are recruited in a stepwise manner during assembly.
Immunization with a Vaccine Combining Herpes Simplex Virus 2 (HSV-2) Glycoprotein C (gC) and gD Subunits Improves the Protection of Dorsal Root Ganglia in Mice and Reduces the Frequency of Recurrent Vaginal Shedding of HSV-2 DNA in Guinea Pigs Compared to Immunization with gD Alone
Authors: Awasthi Sita , Lubinski John M. , Shaw Carolyn E. , Barrett Shana M. , Cai Michael , Wang Fushan , Betts Michael , Kingsley Susan , DiStefano Daniel J. , Balliet John W. , Flynn Jessica A. , Casimiro Danilo R. , Bryan Janine T. , Friedman Harvey M.
Published: August 2011

Attempts to develop a vaccine to prevent genital herpes simplex virus 2 (HSV-2) disease have been only marginally successful, suggesting that novel strategies are needed. Immunization with HSV-2 glycoprotein C (gC-2) and gD-2 was evaluated in mice and guinea pigs to determine whether adding gC-2 to a gD-2 subunit vaccine would improve protection by producing antibodies that block gC-2 immune evasion from complement. Antibodies produced by gC-2 immunization blocked the interaction between gC-2 and complement C3b, and passive transfer of gC-2 antibody protected complement-intact mice but not C3 knockout mice against HSV-2 challenge, indicating that gC-2 antibody is effective, at least in part, because it prevents HSV-2 evasion from complement. Immunization with gC-2 also produced neutralizing antibodies that were active in the absence of complement; however, the neutralizing titers were higher when complement was present, with the highest titers in animals immunized with both antigens. Animals immunized with the gC-2-plus-gD-2 combination had robust CD4
+
T-cell responses to each immunogen. Multiple disease parameters were evaluated in mice and guinea pigs immunized with gC-2 alone, gD-2 alone, or both antigens. In general, gD-2 outperformed gC-2; however, the gC-2-plus-gD-2 combination outperformed gD-2 alone, particularly in protecting dorsal root ganglia in mice and reducing recurrent vaginal shedding of HSV-2 DNA in guinea pigs. Therefore, the gC-2 subunit antigen enhances a gD-2 subunit vaccine by stimulating a CD4
+
T-cell response, by producing neutralizing antibodies that are effective in the absence and presence of complement, and by blocking immune evasion domains that inhibit complement activation.
HLA-DR+CD38+CD4+T Lymphocytes Have Elevated CCR5 Expression and Produce the Majority of R5-Tropic HIV-1 RNAInVivo
Authors: Meditz Amie L. , Haas Michelle K. , Folkvord Joy M. , Melander Kelsey , Young Russ , McCarter Martin , MaWhinney Samantha , Campbell Thomas B. , Lie Yolanda , Coakley Eoin , Levy David N. , Connick Elizabeth
Published: August 2011

Percentages of activated T cells correlate with HIV-1 disease progression, but the underlying mechanisms are not fully understood. We hypothesized that HLA-DR+CD38+(DR+38+) CD4+T cells produce the majority of HIV-1 due to elevated expression of CCR5 and CXCR4. In phytohemagglutinin (PHA)-stimulated CD8-depleted peripheral blood mononuclear cells (PBMC) infected with HIV-1 green fluorescent protein (GFP) reporter viruses, DR−38+T cells constituted the majority of CCR5 (R5)-tropic (median, 62%) and CXCR4 (X4)-tropic HIV-1-producing cells (median, 61%), although cell surface CCR5 and CXCR4 were not elevated in this subset of cells. In lymph nodes from untreated individuals infected with R5-tropic HIV-1, percentages of CCR5+cells were elevated in DR+38+CD4+T cells (median, 36.4%) compared to other CD4+T-cell subsets (median values of 5.7% for DR−38−cells, 19.4% for DR+38−cells, and 7.6% for DR−38+cells;n= 18;P< 0.001). In sorted CD8−lymph node T cells, median HIV-1 RNA copies/105cells was higher for DR+38+cells (1.8 × 106) than for DR−38−(0.007 × 106), DR−38+(0.064 × 106), and DR+38−(0.18 × 106) subsets (n= 8;P< 0.001 for all). After adjusting for percentages of subsets, a median of 87% of viral RNA was harbored by DR+38+cells. Percentages of CCR5+CD4+T cells and concentrations of CCR5 molecules among subsets predicted HIV-1 RNA levels among CD8−DR/38 subsets (P< 0.001 for both). Median HIV-1 DNA copies/105cells was higher in DR+38+cells (5,360) than in the DR−38−(906), DR−38+(814), and DR+38−(1,984) subsets (n= 7;P≤ 0.031). Thus, DR+38+CD4+T cells in lymph nodes have elevated CCR5 expression, are highly susceptible to infection with R5-tropic virus, and produce the majority of R5-tropic HIV-1. PBMC assays failed to recapitulatein vivofindings, suggesting limited utility. Strategies to reduce numbers of DR+38+CD4+T cells may substantially inhibit HIV-1 replication.
Crystal Structures of Enterovirus 71 3C Protease Complexed with Rupintrivir Reveal the Roles of Catalytically Important Residues
Authors: Wang Jing , Fan Tingting , Yao Xue , Wu Zhiqiang , Guo Li , Lei Xiaobo , Wang Jianwei , Wang Meitian , Jin Qi , Cui Sheng
Published: August 2011

EV71 is the primary pathogenic cause of hand-foot-mouth disease (HFMD), but an effective antiviral drug currently is unavailable. Rupintrivir, an inhibitor against human rhinovirus (HRV), has potent antiviral activities against EV71. We determined the high-resolution crystal structures of the EV71 3C
pro
/rupintrivir complex, showing that although rupintrivir interacts with EV71 3C
pro
similarly to HRV 3C
pro
, the C terminus of the inhibitor cannot accommodate the leaving-group pockets of EV71 3C
pro
. Our structures reveal that EV71 3C
pro
possesses a surface-recessive S2′ pocket that is not present in HRV 3C
pro
that contributes to the additional substrate binding affinity. Combined with mutagenic studies, we demonstrated that catalytic Glu71 is irreplaceable for maintaining the overall architecture of the active site and, most importantly, the productive conformation of catalytic His40. We discovered the role of a previously uncharacterized residue, Arg39 of EV71 3C
pro
, that can neutralize the negative charge of Glu71, which may subsequently assist deprotonation of His40 during proteolysis.
Mapping a Region of Hepatitis C Virus E2 That Is Responsible for Escape from Neutralizing Antibodies and a Core CD81-Binding Region That Does Not Tolerate Neutralization Escape Mutations
Authors: Keck Zhen-Yong , Saha Anasuya , Xia Jinming , Wang Yong , Lau Patrick , Krey Thomas , Rey Felix A. , Foung Steven K. H.
Published: August 2011

Understanding the interaction between broadly neutralizing antibodies and their epitopes provides a basis for the rational design of a preventive hepatitis C virus (HCV) vaccine. CBH-2, HC-11, and HC-1 are representatives of antibodies to overlapping epitopes on E2 that mediate neutralization by blocking virus binding to CD81. To obtain insights into escape mechanisms, infectious cell culture virus, 2a HCVcc, was propagated under increasing concentrations of a neutralizing antibody to isolate escape mutants. Three escape patterns were observed with these antibodies. First, CBH-2 escape mutants that contained mutations at D431G or A439E, which did not compromise viral fitness, were isolated. Second, under the selective pressure of HC-11, escape mutations progressed from a single L438F substitution at a low antibody concentration to double substitutions, L438F and N434D or L438F and T435A, at higher antibody concentrations. Escape from HC-11 was associated with a loss of viral fitness. An HCV pseudoparticle (HCVpp) containing the L438F mutation bound to CD81 half as efficiently as did wild-type (wt) HCVpp. Third, for HC-1, the antibody at a critical concentration completely suppressed viral replication and generated no escape mutants. Epitope mapping revealed contact residues for CBH-2 and HC-11 in two regions of the E2 glycoprotein, amino acids (aa) 425 to 443 and aa 529 to 535. Interestingly, contact residues for HC-1 were identified only in the region encompassing aa 529 to 535 and not in aa 425 to 443. Taken together, these findings point to a region of variability, aa 425 to 443, that is responsible primarily for viral escape from neutralization, with or without compromising viral fitness. Moreover, the region aa 529 to 535 is a core CD81 binding region that does not tolerate neutralization escape mutations.
Trends in home smoking bans in the USA, 1995–2007: prevalence, discrepancies and disparities
Authors: Zhang Xiao , Martinez-Donate Ana P , Kuo Daphne , Jones Nathan R , Palmersheim Karen A
Published: August 2011

Background

Home smoking bans significantly reduce the likelihood of secondhand smoke exposure among children and non-smoking adults. The purpose of this study was to examine national trends in (1) the adoption of home smoking bans, (2) discrepancies in parental smoking ban reports and (3) household and parental correlates of home smoking bans among households with underage children from 1995 to 2007.

Methods

The authors used data from the 1995–1996, 1998–1999, 2001–2002, 2003 and 2006–2007 Tobacco Use Supplement of the US Current Population Survey to estimate prevalence rates and logistic regression models of parental smoking ban reports by survey period.

Results

Overall, the prevalence of a complete home smoking bans increased from 58.1% to 83.8% (p<0.01), while discrepancies in parental reports decreased from 12.5% to 4.6% (p<0.01) from 1995 to 2007. Households with single parent, low income, one or two current smokers, parents with less than a college education or without infants were consistently less likely to report a home smoking ban over this period (p<0.05).

Conclusions

Despite general improvements in the adoption of home smoking bans and a reduction on parental discrepancies, disparities in the level of protection from secondhand smoke have persisted over time. Children living in households with single parents, low income, current smoker parents, less educated parents or without infants are less likely to be protected by a home smoking ban. These groups are in need of interventions promoting the adoption of home smoking bans to reduce disparities in tobacco-related diseases.
Solid-state 207Pb nuclear magnetic resonance studies of adducts of 1,10-phenanthroline with lead(II) halides
Authors: Glatfelter Alicia , Bai Shi , Dmitrenko Olga , Perry Dale L. , Van Bramer Scott E. , Dybowski Cecil
Published: August 2011

Experimental and predicted 207Pb nuclear magnetic resonance (NMR) parameters of solid-state coordination complexes of lead(II) bromide, lead(II) iodide, and lead(II) chloride with 1,10-phenanthroline are reported. Structural and electronic differences between the 1:1 and 1:2 adducts are reflected by the NMR parameters. The NMR chemical shieldings of the isostructural complexes indicate that the electronic state of the lead(II) center depends on the number of ligands and the halogen anion. The NMR results suggest that the 1:2 adduct may be more stereochemically active than the 1:1 adduct.
[Pt@Pb12]2– — A challenging system for relativistic density functional theory calculations of195Pt and207Pb NMR parameters
Authors: Le Guennic Boris , Autschbach Jochen
Published: August 2011

We report computations of NMR chemical shifts and indirect spin-spin coupling constants (J couplings) for the [Pt@Pb12]2–“superatom”. The system is strongly influenced by relativistic effects. The Pt–Pb coupling constant is predicted to be negative, with its magnitude being in reasonable agreement with experiment. Pt and Pb chemical shifts also agree reasonably well with experiment. The Pb shielding tensor is strongly anisotropic, with a large deshielding principal component dominated by magnetic coupling between frontier orbitals of the cluster that resemble atomic g orbitals. The NMR parameters are sensitive to approximations made in the computations and require the inclusion of spin-orbit coupling in the theoretical model to achieve reliable results. Computing the NMR parameters of the compact [Pt@Pb12]2–system with its many electrons proves to be a challenging test case for relativistic density functional methods.
Expression of a naturally occurring angiotensin AT1 receptor cleavage fragment elicits caspase-activation and apoptosis
Authors: Cook Julia L. , Singh Akannsha , deHaro Dawn , Alam Jawed , Re Richard N.
Published: August 2011

Several transmembrane receptors are documented to accumulate in nuclei, some as holoreceptors and others as cleaved receptor products. Our prior studies indicate that a population of the 7-transmembrane angiotensin type-1 receptor (AT1R) is cleaved in a ligand-augmented manner after which the cytoplasmic, carboxy-terminal cleavage fragment (CF) traffics to the nucleus. In the present report, we determine the precise cleavage site within the AT1R by mass spectrometry and Edman sequencing. Cleavage occurs between Leu(305) and Gly(306) at the junction of the seventh transmembrane domain and the intracellular cytoplasmic carboxy-terminal domain. To evaluate the function of the CF distinct from the holoreceptor, we generated a construct encoding the CF as an in-frame yellow fluorescent protein fusion. The CF accumulates in nuclei and induces apoptosis in CHO-K1 cells, rat aortic smooth muscle cells (RASMCs), MCF-7 human breast adenocarcinoma cells, and H9c2 rat cardiomyoblasts. All cell types show nuclear fragmentation and disintegration, as well as evidence for phosphotidylserine displacement in the plasma membrane and activated caspases. RASMCs specifically showed a 5.2-fold increase ( P < 0.001) in CF-induced active caspases compared with control and a 7.2-fold increase ( P < 0.001) in cleaved caspase-3 (Asp174). Poly(ADP-ribose)polymerase was upregulated 4.8-fold ( P < 0.001) in CF expressing cardiomyoblasts and colocalized with terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). CF expression also induces DNA laddering, the gold-standard for apoptosis in all cell types studied. CF-induced apoptosis, therefore, appears to be a general phenomenon as it is observed in multiple cell types including smooth muscle cells and cardiomyoblasts.
Exertional dyspnea in mitochondrial myopathy: clinical features and physiological mechanisms
Authors: Heinicke Katja , Taivassalo Tanja , Wyrick Phil , Wood Helen , Babb Tony G. , Haller Ronald G.
Published: August 2011

Exertional dyspnea limits exercise in some mitochondrial myopathy (MM) patients, but the clinical features of this syndrome are poorly defined, and its underlying mechanism is unknown. We evaluated ventilation and arterial blood gases during cycle exercise and recovery in five MM patients with exertional dyspnea and genetically defined mitochondrial defects, and in four control subjects (C). Patient ventilation was normal at rest. During exercise, MM patients had low V̇o2peak (28 ± 9% of predicted) and exaggerated systemic O2 delivery relative to O2 utilization (i.e., a hyperkinetic circulation). High perceived breathing effort in patients was associated with exaggerated ventilation relative to metabolic rate with high V̇e/V̇o2peak, (MM = 104 ± 18; C = 42 ± 8, P ≤ 0.001), and V̇e/V̇co2peak, (MM = 54 ± 9; C = 34 ± 7, P ≤ 0.01); a steeper slope of increase in ΔV̇e/ΔV̇co2 (MM = 50.0 ± 6.9; C = 32.2 ± 6.6, P ≤ 0.01); and elevated peak respiratory exchange ratio (RER), (MM = 1.95 ± 0.31, C = 1.25 ± 0.03, P ≤ 0.01). Arterial lactate was higher in MM patients, and evidence for ventilatory compensation to metabolic acidosis included lower PaCO2 and standard bicarbonate. However, during 5 min of recovery, despite a further fall in arterial pH and lactate elevation, ventilation in MM rapidly normalized. These data indicate that exertional dyspnea in MM is attributable to mitochondrial defects that severely impair muscle oxidative phosphorylation and result in a hyperkinetic circulation in exercise. Exaggerated exercise ventilation is indicated by markedly elevated V̇e/V̇o2, V̇e/V̇co2, and RER. While lactic acidosis likely contributes to exercise hyperventilation, the fact that ventilation normalizes during recovery from exercise despite increasing metabolic acidosis strongly indicates that additional, exercise-specific mechanisms are responsible for this distinctive pattern of exercise ventilation.
Adaptive mechanisms to compensate for overnutrition-induced cardiovascular abnormalities
Authors: Pulakat Lakshmi , DeMarco Vincent G. , Ardhanari Sivakumar , Chockalingam Anand , Gul Rukhsana , Whaley-Connell Adam , Sowers James R.
Published: August 2011

In conditions of overnutrition, cardiac cells must cope with a multitude of extracellular signals generated by changes in nutrient load (glucose, amino acids, and lipids) and the hormonal milieu [increased insulin (INS), ANG II, and adverse cytokine/adipokine profile]. Herein, we review the diverse compensatory/adaptive mechanisms that counter the deleterious effects of excess nutrients and growth factors. We largely focus the discussion on evidence obtained from Zucker obese (ZO) and Zucker diabetic fatty (ZDF) rats, which are useful models to evaluate adaptive and maladaptive metabolic, structural, and functional cardiac remodeling. One adaptive mechanism present in the INS-resistant ZO, but absent in the diabetic ZDF heart, involves an interaction between the nutrient sensor kinase mammalian target of rapamycin complex 1 (mTORC1) and ANG II-type 2 receptor (AT2R). Recent evidence supports a cardioprotective role for the AT2R; for example, suppression of AT2R activation interferes with antihypertrophic/antifibrotic effects of AT1R blockade, and AT2R agonism improves cardiac structure and function. We propose a scenario, whereby mTORC1-signaling-mediated increase in AT2R expression in the INS-resistant ZO heart is a cardioprotective adaptation to overnutrition. In contrast to the ZO rat, heart tissues of ZDF rats do not show activation of mTORC1. We posit that such a lack of activation of the mTOR↔AT2R integrative pathway in cardiac tissue under conditions of obesity-induced diabetes may be a metabolic switch associated with INS deficiency and clinical diabetes.
Serotonin nerve terminals in the dorsomedial medulla facilitate sympathetic and ventilatory responses to hemorrhage and peripheral chemoreflex activation
Authors: Kung Ling-Hsuan , Scrogin Karie E.
Published: August 2011

Serotonin neurons of the caudal raphe facilitate ventilatory and sympathetic responses that develop following blood loss in conscious rats. Here, we tested whether serotonin projections to the caudal portion of the dorsomedial brain stem (including regions of the nucleus tractus solitarius that receive cardiovascular and chemosensory afferents) contribute to cardiorespiratory compensation following hemorrhage. Injections of the serotonin neurotoxin 5,7-dihydroxytryptamine produced >90% depletion of serotonin nerve terminals in the region of injection. Withdrawal of ∼21% of blood volume over 10 min produced a characteristic three-phase response that included 1) a normotensive compensatory phase, 2) rapid sympathetic withdrawal and hypotension, and 3) rapid blood pressure recovery accompanied by slower recovery of heart rate and sympathetic activity. A gradual tachypnea developed throughout hemorrhage, which quickly reversed with the advent of sympathetic withdrawal. Subsequently, breathing frequency and neural minute volume (determined by diaphragmatic electromyography) declined below baseline following termination of hemorrhage but gradually recovered over time. Lesioned rats showed attenuated sympathetic and ventilatory responses during early compensation and later recovery from hemorrhage. Both ventilatory and sympathetic responses to chemoreceptor activation with potassium cyanide injection were attenuated by the lesion. In contrast, the gain of sympathetic and heart rate baroreflex responses was greater, and low-frequency oscillations in blood pressure were reduced after lesion. Together, the data are consistent with the view that serotonin innervation of the caudal dorsomedial brain stem contributes to sympathetic compensation during hypovolemia, possibly through facilitation of peripheral chemoreflex responses.
Inorganic phosphate homeostasis in sodium-dependent phosphate cotransporter Npt2b+/−mice
Authors: Ohi Akiko , Hanabusa Etsuyo , Ueda Otoya , Segawa Hiroko , Horiba Naoshi , Kaneko Ichiro , Kuwahara Shoji , Mukai Tomo , Sasaki Shohei , Tominaga Rieko , Furutani Junya , Aranami Fumito , Ohtomo Shuichi , Oikawa Yumiko , Kawase Yousuke , Wada Naoko A. , Tachibe Takanori , Kakefuda Mami , Tateishi Hiromi , Matsumoto Kaoru , Tatsumi Sawako , Kido Shinsuke , Fukushima Naoshi , Jishage Kou-ichi , Miyamoto Ken-ichi
Published: August 2011

An inorganic phosphate (Pi)-restricted diet is important for patients with chronic kidney disease and patients on hemodialysis. Phosphate binders are essential for preventing hyperphosphatemia and ectopic calcification. The sodium-dependent Pi(Na/Pi) transport system is involved in intestinal Piabsorption and is regulated by several factors. The type II sodium-dependent Pitransporter Npt2b is expressed in the brush-border membrane in intestinal epithelial cells and transports Pi. In the present study, we analyzed the phenotype of Npt2b−/−and hetero+/−mice. Npt2b−/−mice died in utero soon after implantation, indicating that Npt2b is essential for early embryonic development. At 4 wk of age, Npt2b+/−mice showed hypophosphatemia and low urinary Piexcretion. Plasma fibroblast growth factor 23 levels were significantly decreased and 1,25(OH)2D3levels were significantly increased in Npt2b+/−mice compared with Npt2b+/+mice. Npt2b mRNA levels were reduced to 50% that in Npt2b+/+mice. In contrast, renal Npt2a and Npt2c transporter protein levels were significantly increased in Npt2b+/−mice. At 20 wk of age, Npt2b+/−mice showed hypophosphaturia and reduced Na/Picotransport activity in the distal intestine. Npt2b+/+mice with adenine-induced renal failure had hyperphosphatemia and high plasma creatinine levels. Npt2b+/−mice treated with adenine had significantly reduced plasma Pilevels compared with Npt2b+/+mice. Intestinal Npt2b protein and Na+/Pitransport activity levels were significantly lower in Npt2b+/−mice than in the Npt2b+/+mice. The findings of the present studies suggest that Npt2b is an important target for the prevention of hyperphosphatemia.
Nonexistence Results for the Cauchy Problem for Nonlinear Ultraparabolic Equations
Authors: Kerbal Sebti , Kirane Mokhtar
Published: August 2011

Nonexistence of global solutions to ultraparabolic equations and systems is presented.
Our results fill a gap in the literature on ultraparabolic equations. The
method of proof we use relies on a choice of a suitable test function in the weak
formulation of the solutions of the problems under‐study.
Global Attractivity and Periodic Solution of a Discrete Multispecies Cooperation and Competition Predator‐Prey System
Authors: Zhou Zheyan
Published: August 2011

We propose a discrete multispecies cooperation and competition predator‐prey systems. For general nonautonomous case, sufficient conditions which ensure the permanence and the global stability of the system are obtained; for periodic case, sufficient conditions which ensure the existence of a globally stable positive periodic solution of the system are obtained.
Thrombotic Microangiopathy with Targeted Cancer Agents
Authors: Blake-Haskins John A. , Lechleider Robert J. , Kreitman Robert J.
Published: August 2011

Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are clinically similar disorders characterized by microvascular thrombosis, hemolysis, thrombocytopenia, and end-organ damage. Although they may present with overlapping symptoms, multiple etiologies have been proposed for these thrombotic microangiopathies (TMA). Chemotherapy-induced TMA, which has been described with the use of mitomycin, gemcitabine, and other drugs, has a poor prognosis. Recently, reports of TMA associated with targeted cancer agents have surfaced in the literature. We discuss the clinical presentation, outcome, and etiology of TMA reported with the use of immunotoxins, monoclonal antibodies, and tyrosine kinase inhibitors. A search of PubMed and meeting abstracts was conducted for cases of TMA with the use of targeted cancer agents. The defining symptoms, laboratory values, time to onset, and patient outcomes were compiled. Consistent definitions of TMA and grading of severity in these cases are lacking. However, presentation of TMA in these cases revealed the importance of monitoring for renal toxicity, hemolysis, and thrombocytopenia. Patient outcomes seem to differ from those seen in cases of chemotherapy-induced TMA and may reflect a different underlying etiology. Little is known about the pathogenesis of TMA with targeted cancer agents. In contrast to chemotherapy-induced TMA, partial to full reversibility may be a common outcome. However, further research is warranted into optimal management of patients diagnosed with TMA following treatment with targeted agents. Clin Cancer Res; 17(18); 5858–66. ©2011 AACR.