bluuebunny/crossref_metadata_2025 huggingface dataset:
Regulation of hematopoietic stem cell trafficking and mobilization by the endocannabinoid system
Authors: Jiang Shuxian , Fu Yigong , Avraham Hava Karsenty
Published: November 2011

The cannabinoid receptors CB1 and CB2 are seven‐transmembrane Gαi protein‐coupled receptors and are expressed in certain mature hematopoietic cells. We recently showed that these receptors are expressed in murine and human hematopoietic stem cells (HSCs) and that CB2 agonists induced chemotaxis, enhanced colony formation of marrow cells, as well as caused in vivo mobilization of murine HSCs with short‐ and long‐term repopulating abilities. Based on these observations, we have further explored the role of CB2 and its agonist AM1241 on hematopoietic recovery following sublethal irradiation in mice. Cannabinoid receptor 2 knockout mice (Cnr2−/− deficient mice) exhibited impaired recovery following sublethal irradiation as compared with irradiated wild‐type (WT) mice, as determined by low colony‐forming units and low peripheral blood counts. WT mice treated with CB2 agonist AM1241 following sublethal irradiation demonstrated accelerated marrow recovery and increased total marrow cells (approximately twofold) and total lineage– c‐kit+ cells (approximately sevenfold) as well as enhanced HSC survival as compared with vehicle control–treated mice. When the CB2 agonist AM1241 was administered to WT mice 12 days before their sublethal irradiation, analysis of hematopoiesis in these mice showed decreased apoptosis of HSCs, enhanced survival of HSCs, as well as increase in total marrow cells and c‐kit+ cells in the marrow. Thus, CB2 agonist AM1241 promoted recovery after sublethal irradiation by inhibiting apoptosis of HSCs and promoting survival, as well as enhancing the number of HSCs entering the cell cycle.
Advancing the preservation of cellular therapy products
Authors: Hubel Allison
Published: November 2011

Cell therapies are typically collected in one location, processed in a second location, and then administered in a third location. The ability to preserve the cells is critical to their clinical application. It improves patient access to therapies by increasing the genetic diversity of cells available. In addition, the ability to preserve cells improves the “manufacturability” of a cell therapy product by permitting the cells to be stored until the patient is ready for administration of the therapy, permitting inventory control of products, and improving management of staffing at cell therapy facilities. Finally, the ability to preserve cell therapies improves the safety of cell therapy products by extending the shelf life of a product and permitting completion of safety and quality control testing before release of the product for use. The support of the National Blood Foundation has been critical to our work on improving the quality of frozen and thawed cell therapy products through the development of a microfluidic device to remove dimethlysulfoxide (DMSO). We are also involved in research to replace DMSO with other agents that are less toxic to cells and patients. Finally, the need to advance the preservation of cell therapies was a driving force behind the development of the Biopreservation Core Resource (http://www.biocor.net), a national resource in biopreservation. New interest in translation of cell therapies from the bench to the patient's bedside has the potential to drive the transformation of preservation science, technology, and practice.
New platelet glycoprotein polymorphisms causing maternal immunization and neonatal alloimmune thrombocytopenia
Authors: Peterson Julie A. , Pechauer Shannon M. , Gitter Maria L. , Kanack Adam , Curtis Brian R. , Reese Jeff , Kamath Vasudeva M. , McFarland Janice G , Aster Richard H.
Published: November 2011

BACKGROUND: Maternal immunization against low‐frequency, platelet (PLT)‐specific antigens is being recognized with increasing frequency as a cause of neonatal alloimmune thrombocytopenia (NAIT).

STUDY DESIGN AND METHODS: Serologic and molecular studies were performed on PLTs and DNA from two families in which an infant was born with severe thrombocytopenia not attributable to maternal immunization against known PLT‐specific alloantigens.

RESULTS: Antibodies reactive only with paternal PLTs were identified in each mother using flow cytometry and solid‐phase assays. Unique mutations encoding amino acid substitutions K164T in glycoprotein (GP)IIb (Case 1) and R622W in GPIIIa (Case 2) were identified in paternal DNA and in DNA from the affected infants. Each maternal antibody recognized recombinant GPIIb/IIIa mutated to contain the polymorphisms identified in the corresponding father. None of 100 unselected normal subjects possessed these paternal mutations.

CONCLUSIONS: Severe NAIT observed in the affected infants was caused by maternal immunization against previously unrecognized, low‐frequency antigens created by amino acid substitutions in GPIIb/IIIa (αIIb/β3 integrin). A search should be conducted for novel paternal antigens in cases of apparent NAIT not explained on the basis of maternal‐fetal incompatibility for known human PLT antigens.
Influences of Social Norms and Context on Sexual Decision Making Among Adolescent Women
Authors: Fantasia Heidi Collins
Published: November 2011

Introduction: The aim of this study was to explore women's decisions to initiate and continue sexual activity in late adolescence.

Methods: Narrative inquiry was the qualitative methodology used to research the perceptions of factors that influence the sexual decision making of women in late adolescence. Single interviews were conducted with 10 late‐adolescence women between the ages of 18 and 22. Both purposive and snowball sampling were used, and recruitment ended when data saturation was achieved.

Results: The main findings that emerged as the story contained 3 distinct and influential components: the influence of social context provided the introduction to the story, perceptions of the expected social norm for sex and relationships formed the plot, and the narratives concluded with a discussion of how these adolescents’ decision‐making processes evolved in the years since coital debut.

Discussion: The results of this study provide evidence that adolescent sexual decision making is a multifaceted process with many layers of influence that reflect the complex world adolescents must navigate as they make decisions about their sexual behaviors. Detailed assessment of adolescent sexual activity and anticipatory guidance by health care providers will lay the foundation for risk reduction behavior and safer sexual encounters.
Hormonal Management of the Female‐to‐Male Transgender Patient
Authors: Steinle Kate
Published: November 2011

This article focuses on initiating and monitoring testosterone therapy for the female‐to‐male transgender person. For providers unfamiliar with the evaluation and treatment of the female‐to‐male transgender patient, this article offers an introduction to the diagnostic criteria for gender identity disorder as well as the eligibility and readiness criteria for hormonal treatment. Also included is information regarding screenings to be done before the initiation of testosterone therapy and during follow‐up visits, common side effects of testosterone, and basic testosterone regimens available.
Assessment of a Simulation Training Exercise to Teach Intrauterine Tamponade for the Treatment of Postpartum Hemorrhage
Authors: Stitely Michael L. , Cerbone Lena , Nixon Angelita , Bringman Jay J.
Published: November 2011

Introduction: Postpartum hemorrhage is a common complication of vaginal birth. Few midwives have experience in the performance of procedures to manage hemorrhage that fails to respond to initial management with medications and bimanual compression.

Methods: A simulation model was constructed by using a half‐pelvis birth simulator and a hollowed out cantaloupe. Practicing midwives and students participated in a simulation exercise by using uterine packing and placement of a uterine tamponade balloon. Pre‐exercise and post‐exercise self‐assessments were performed. Data were analyzed by using the Wilcoxon matched pairs signed rank test.

Results: A total of 25 learners participated in the training session. All 25 participants showed improvement in their self‐assessed competency level for the placement of the Bakri Postpartum Balloon (P < .001), and 24 of 25 showed improvement in self‐assessed competency levels for uterine packing (P < .001).

Discussion: An inexpensive simulation model can be used to effectively train midwives to treat postpartum hemorrhage by using methods of exerting direct pressure to the uterine cavity.
Buprenorphine for the Treatment of Perinatal Opioid Dependence: Pharmacology and Implications for Antepartum, Intrapartum, and Postpartum Care
Authors: Goodman Daisy
Published: November 2011

Opioid dependence during pregnancy is associated with significant health risks for both the mother and her fetus. Opioid maintenance therapy with methadone (Dolophine) is the current standard of care, reduces medical and social risks associated with illicit drug use, and decreases rates of prematurity and low birth weight. However, treatment with methadone is frequently associated with neonatal abstinence syndrome. Buprenorphine is an alternative to methadone that preliminary data indicates is equivalent in safety and efficacy to methadone and significantly increases access to treatment. The pharmacology of buprenorphine and its implications for the care of pregnant women with opioid dependence are described.
Use of Hyaluronidase to Prevent Perineal Trauma During Spontaneous Births: A Randomized, Placebo‐Controlled, Double‐blind, Clinical Trial
Authors: Colacioppo Priscila Maria , Gonzalez Riesco Maria Luiza , Koiffman Marcia Duarte
Published: November 2011

Introduction: The purpose of this study was to compare the frequency and severity of perineal trauma during spontaneous birth with or without perineal injections of hyaluronidase (HAase).

Methods: A randomized, placebo‐controlled, double‐blind clinical trial was conducted in a midwife‐led, in‐hospital birth center in São Paulo, Brazil. Primiparous women (N = 160) were randomly assigned to an experimental (n = 80) or control (n = 80) group. During the second stage of labor, women in the experimental group received an injection of 20.000 turbidity‐reducing units of HAase in the posterior region of the perineum, and those in the control group received a placebo injection. The assessment of perineal outcome was performed by 2 independent nurse‐midwives. A 1‐tailed Fisher exact test was performed, and a P value < .025 was considered statistically significant.

Results: Perineal integrity occurred in 34.2% of the experimental group and in 32.5% of the control group, which was not a statistically significant difference (P= .477). First‐degree laceration was the most common trauma in the posterior region of the perineum in women in both groups (experimental = 56%, control = 42.6%). Severe perineal trauma occurred in 28.9% of the experimental group and 38.8% of the control group, which also was not a statistically significant difference (P= .131). The depth of second‐degree perineal lacerations in the experimental and control groups, measured by the Peri‐Rule, was 1.9 cm and 2.3 cm, respectively. An episiotomy was performed in 11 women (experimental group = 3, control group = 8), and 4 (all in control group) had third‐degree lacerations.

Discussion: The use of injectable HAase did not increase the proportion of intact perineum and did not reduce the proportion of severe perineal trauma in our sample.
Basal Renal Tubular Epithelial Cell Vacuolization and Alcoholic Ketoacidosis
Authors: Zhou Chong , Byard Roger W.
Published: November 2011

Abstract:  Subnuclear renal tubular epithelial cell vacuolization is a marker for diabetic ketoacidosis. Whether it is because of hyperglycemia or of ketoacidosis is unclear. To examine the effect of ketoacidosis on renal cells in isolation, five cases of lethal alcoholic ketoacidosis without hyperglycemia were examined (vitreous humor β‐hydroxybutyrate: 6.42–8.75 mM, mean 7.66 mM; and glucose: 0.1–4.2 mM, mean 1.46 mM). Microscopic examination of the kidneys revealed basal vacuoles in three cases (60%). Seven control cases with acute alcohol toxicity without ketoacidosis (blood alcohol: 0.18–0.43%, mean 0.31%; and β‐hydroxybutyrate: 0.12–0.42 mM, mean 0.21 mM) did not have these changes. In this study, basal epithelial vacuolization was found only in cases with significant ketoacidosis. Although the numbers are small, the finding of basal renal tubular epithelial vacuolization in normoglycemic cases with elevated β‐hydroxybutyrate levels provide further evidence that disordered lipid metabolism may be involved in the pathogenesis of this phenomenon.
Impacts of price and productivity changes on banana‐growing households in Uganda
Authors: Komarek Adam M. , Ahmadi‐Esfahani Fredoun Z.
Published: November 2011

This article compares the effects of changing market prices and farm productivity on the welfare of banana‐growing households in the Ntungamo district of Uganda. A heterogeneous‐agent model is applied via a series of mathematical optimization problems, to simulate production and consumption responses of 70 farm households surveyed in 2006. Results show that a given increase in productivity has a greater impact on poverty alleviation than that same increase in market prices. Despite the effects of productivity gains being comparable across different types of household groups, price improvements primarily benefit the incomes of households who are involved in rural producer organizations, who are located closer to markets, and who sell at the market.
Profile of Inflammatory Mediators in Gestational Diabetes Mellitus: Phenotype and Genotype
Authors: Gueuvoghlanian‐Silva Bárbara Yasmin , Torloni Maria Regina , Mattar Rosiane , de Oliveira Lilian Silveira , Scomparini Flávia Burim , Nakamura Mary Uchiyama , Daher Silvia
Published: November 2011

Citation Gueuvoghlanian‐Silva BY, Torloni MR, Mattar R, de Oliveira LS, Scomparini FB, Nakamura MU, Daher S. Profile of inflammatory mediators in gestational diabetes mellitus: phenotype and genotype. Am J Reprod Immunol 2012; 67: 241–250

Problem  Our study aimed to assess in vitro production of IL‐10, IL‐6, TNF‐A, and adiponectin serum levels in pregnant women with and without gestational diabetes mellitus (GDM) and to investigate a possible association between GDM and IL‐10−1082 A>G (rs1800896), IL‐6−174 G>C (rs1800795), TNF‐A−308 G>A (rs1800629), adiponectin +45 T>G (rs2241766), and adiponectin−11377 C>G (rs266729) gene polymorphisms.

Method of study  This case–control study included 79 women with GDM and 169 healthy controls (C) grouped according to pre‐pregnancy BMI. IL‐10, IL‐6, and TNF‐A culture supernatant and adiponectin serum levels were assessed by ELISA. DNA genotype was performed by PCR‐RFLP.

Results  Adiponectin levels were significantly higher in C than GDM women, even within the same BMI category. Cytokines levels were similar between the groups. There were no associations between GDM and the analyzed gene polymorphisms.

Conclusions  Women with GDM have significantly lower adiponectin levels in the third trimester, regardless of BMI.
Responses of riparian guilds to flow alterations in a Mediterranean stream
Authors: Bejarano María Dolores , González del Tánago Marta , de Jalón Diego García , Marchamalo Miguel , Sordo‐Ward Álvaro , Solana‐Gutiérrez Joaquín
Published: November 2011

Questions

Do Mediterranean riparian guilds show distinct responses to stream water declines? If observed, which are the most sensitive and resilient guilds and their most affected attributes?

Location

Tiétar river below the Rosarito dam, central‐western Spain.

Methods

We identified riparian guilds based on key woody species features and species distribution within this Mediterranean river corridor, and evaluated similarity of their responses to long‐term flow alteration (i.e. stream water declines since dam construction in 1959). Hierarchical cluster analysis was used to group surveyed vegetation bands according to species composition. The groups were designated as riparian guilds where each vegetation group comprising a guild: (1) contains species sharing similar features (using PCA); and (2) shares a similar environment (using DCA). Changes in several guild attributes (i.e. dominance and species composition, diversity and establishment patterns) during the regulated period were compared statistically. We used pre‐ and post‐dam established vegetation bands identified based on old (1956) and modern (2006) aerial photographs and field measurements of woody species diameter.

Results

Responses to flow alterations varied between guilds according to ecological requirements of their species. The ability to survive water stress (i.e. ‘Xeric’ guilds) and drag forces caused by floods (‘Torrential’ guilds) allowed certain pioneer shrub‐dominated guilds (e.g. Flueggea tinctoria and Salix salviifolia) to spread on newly emerged surfaces downward to the main channel after flow alterations, although new shrubland had less species diversity than pre‐dam shrubland. In contrast, new hydromorphological conditions following damming limited recruitment of native late‐successional tree guilds sensitive to floods (to drag forces, inundation and anoxia; i.e. ‘Slow‐water’ and ‘Flood‐sensitive’, respectively) and those with greater water requirements (i.e. ‘Hydric’) (e.g. Alnus glutinosa and Celtis australis), although species diversity increased in this mature forest through co‐existence of remaining riparian species and new arrival of upland species.

Conclusions

Changes in several riparian attributes after flow alterations differed between guilds. Stream water declines after damming caused shifts in species‐poor pioneer shrubland downwards to the watered channel, resulting in severe declines of mature native forest. Understanding vegetation guild responses provides information about general trends in plant populations and assemblage structures expected to occur during river development and flow regulation, increasing our capacity to detect and synthesize complex flow alteration–riparian ecosystem response relationships, and anticipate irreversible impacts.
Self‐efficacy and physical activity in adolescent and parent dyads
Authors: Rutkowski Elaine M. , Connelly Cynthia D.
Published: November 2011

Purpose. The study examined the relationships between self‐efficacy and physical activity in adolescent and parent dyads.

Design and Methods. A cross‐sectional, correlational design was used to explore the relationships among levels of parent physical activity, parent–adolescent self‐efficacy, and adolescent physical activity. Descriptive and multivariate regression analyses were conducted in a purposive sample of 94 adolescent/parent dyads.

Results. Regression results indicated the overall model significantly predicted adolescent physical activity (R2= .20,R2adj= .14,F[5, 70]= 3.28,p= .01). Only one of the five predictor variables significantly contributed to the model. Higher levels of adolescent self‐efficacy was positively related to greater levels of adolescent physical activity (β= .29,p= .01).

Practice Implications. Practitioners are encouraged to examine the level of self‐efficacy and physical activity in families in an effort to develop strategies that impact these areas and ultimately to mediate obesity‐related challenges in families seeking care.
AFLATOXIN DETERMINATION IN BLACK TEA (CAMELLIA SINENSIS) – STATUS AND DEVELOPMENT OF A PROTOCOL
Authors: VISWANATH PREMA , NANJEGOWDA DIVYASHREE KALLENAHALLI , GOVINDEGOWDA HEMALATHA , DATTATREYA AKSHATHA MALEBENNUR , SIDDAPPA VINUTHA
Published: November 2011

Aflatoxins, toxic mold metabolites, are naturally contaminants of food and have been reported on tea (Camellia sinensis), but there are no validated methods published for its determination. A method has been standardized incorporating Tween‐20, a nonionic surfactant in the extraction solvent, with use of an immunoaffinity column for cleanup followed by postcolumn photochemical derivatization reversed‐phase high‐performance liquid chromatography. Acceptable recoveries of 76–100% were observed when spiked with aflatoxins B1, B2, G1 and G2. Analysis of market samples of black tea showed the presence of aflatoxigenic molds in 25.9% of samples, and aflatoxin B1 was detected in one sample at a level of 19.2 µg/kg. Aflatoxin production was observed in tea samples artificially inoculated with the conidia of an aflatoxigenic strain of Aspergillus flavus. Major portion of the aflatoxins added to the tea leaves remains in the residue when boiled with water, and 30.6% gets partitioned into the filtrate, which is the component used to prepare the beverage.

PRACTICAL APPLICATION

Tea (Camellia sinensis) beverage is widely consumed in the world. This manuscript discusses the prevalence and problems of aflatoxigenic molds and aflatoxins in black tea. A new protocol has been validated for determination of aflatoxins using a surfactant in the extraction solvent for better extraction, followed by column cleanup using immunoaffinity columns and quantification by postcolumn photochemical derivatization reversed‐phase high‐performance liquid chromatography. Aflatoxin production in tea artificially inoculated with the conidia of Aspergillus flavus (isolated in the laboratory) was also observed. The method of preparation of tea beverage by a large number of people in the country is by boiling the black tea leaves with water and using the filtrate to prepare the beverage with milk and sweetener. In the study on the partitioning of the aflatoxins added to black tea leaves before boiling, it was observed that about 30.6% of the added toxin is in the filtrate, a finding with relevance in risk assessment.
Sensory Characteristics and Consumer Acceptance and Purchase Intention Toward Fresh‐Cut Potatoes
Authors: Montouto‐Graña Mónica , Cabanas‐Arias Sonia , Porto‐Fojo Silvia , Vázquez‐Odériz Ma Lourdes , Romero‐Rodríguez Ma Angeles
Published: November 2011

Abstract:  For a new product to succeed in the market, it must be accepted by consumers. This study investigates consumer opinions on fresh‐cut potatoes packaged under vacuum and under a modified atmosphere using home use tests. The data obtained were related to demographic characteristics and patterns of consumption and to purchase intention toward potatoes and other vegetables. The sensory characteristics evaluated by a panel of assessors trained in the sensory evaluation of potato were also considered. The results indicate that although both products were accepted by the consumer, vacuum‐packed potatoes received slightly higher ratings and more consumers intended to purchase this product.

Practical Application:  The fresh‐cut potato packaged under vacuum is a product with all the sensory characteristics that will be accepted by the consumers. The adaptation to the productive process at the industrial level, it can be performed with enough guarantees that the product will definitely be purchased by the consumers.
Antioxidant, Antimicrobial, and Anticancer Activity of 3 Umbilicaria Species
Authors: Kosanić Marijana , Ranković Branislav , Stanojković Tatjana
Published: November 2011

Abstract:  The aim of this study is to investigate in vitro antioxidant, antimicrobial, and anticancer activity of the acetone extracts of the lichens Umbilicaria crustulosa, U. cylindrica, and U. polyphylla. Antioxidant activity was evaluated by 5 separate methods: free radical scavenging, superoxide anion radical scavenging, reducing power, determination of total phenolic compounds, and determination of total flavonoid content. Of the lichens tested, U. polyphylla had largest free radical scavenging activity (72.79% inhibition at a concentration of 1 mg/mL), which was similar as standard antioxidants in the same concentration. Moreover, the tested extracts had effective reducing power and superoxide anion radical scavenging. Total content of phenol and flavonoid in extracts was determined as pyrocatechol equivalent, and as rutin equivalent, respectively. The strong relationships between total phenolic and flavonoid contents and the antioxidant effect of tested extracts were observed. The antimicrobial activity was estimated by determination of the minimal inhibitory concentration by the broth microdilution method. The most active was extract of U. polyphylla with minimum inhibitory concentration values ranging from 1.56 to 12.5 mg/mL. Anticancer activity was tested against FemX (human melanoma) and LS174 (human colon carcinoma) cell lines using MTT method. All extracts were found to be strong anticancer activity toward both cell lines with IC50 values ranging from 28.45 to 97.82 μg/mL. The present study shows that tested lichen extracts demonstrated a strong antioxidant, antimicrobial, and anticancer effects. That suggests that lichens may be used as possible natural antioxidant, antimicrobial, and anticancer agents.
Managing Ambiguity in Reference Generation: The Role of Surface Structure
Authors: Khan Imtiaz H. , Deemter Kees van , Ritchie Graeme
Published: November 2011

This article explores the role of surface ambiguities in referring expressions, and how the risk of such ambiguities should be taken into account by an algorithm that generates referring expressions, if these expressions are to be optimally effective for a hearer. We focus on the ambiguities that arise when adjectives occur in coordinated structures. The central idea is to use statistical information about lexical co‐occurrence to estimate which interpretation of a phrase is most likely for human readers, and to avoid generating phrases where misunderstandings are likely. Various aspects of the problem were explored in three experiments in which responses by human participants provided evidence about which reading was most likely for certain phrases, which phrases were deemed most suitable for particular referents, and the speed at which various phrases were read. We found a preference for ‘‘clear’’ expressions to ‘‘unclear’’ ones, but if several of the expressions are ‘‘clear,’’ then brief expressions are preferred over non‐brief ones even though the brief ones are syntactically ambiguous and the non‐brief ones are not; the notion of clarity was made precise using Kilgarriff's Word Sketches. We outline an implemented algorithm that generates noun phrases conforming to our hypotheses.
Searching for General Principles in Cognitive Performance: Reply to Commentators
Authors: Stephen Damian G. , Van Orden Guy
Published: November 2011

The commentators expressed concerns regarding the relevance and value of non‐computational non‐symbolic explanations of cognitive performance. But what counts as an “explanation” depends on the pre‐theoretical assumptions behind the scenes of empirical science regarding the kinds of variables and relationships that are sought out in the first place, and some of the present disagreements stem from incommensurate assumptions. Traditional cognitive science presumes cognition to be a decomposable system of components interacting according to computational rules to generate cognitive performances (i.e., component‐dominant dynamics). We assign primacy to interaction‐dominant dynamics among components. Though either choice can be a good guess before the fact, the primacy of interactions is now supported by much recent empirical work in cognitive science. Consequently, in the main, the commentators have failed so far to address the growing evidence corroborating the theory‐driven predictions of complexity science.
Mechanisms of aggregation inhibition by aspirin and nitrate-aspirin prodrugs in human platelets
Authors: Harmon Shona , Inkielewicz-Stepniak Iwona , Jones Michael , Ledwidge Mark , Santos-Martinez Maria Jose , Medina Carlos , Radomski Marek W , Gilmer John F
Published: November 2011

Objectives

Aspirin is the mainstay of anti-platelet therapy in the secondary prevention of cardiovascular disease. However, problems with aspirin safety and resistance demand clinical strategies based on multiple pharmacological approaches. Prodrugs of aspirin may offer beneficial effects in terms of gastro-intestinal safety and multiple pharmacological approaches. However, the pharmacological profile of aspirin prodrugs in human platelets has not been completed yet. We aimed to compare the effects of aspirin and prodrugs of aspirin (1–5) on human platelet aggregation stimulated by ADP and collagen and associated receptor expression (GPIIb/IIIa and P-selectin) in platelet-rich plasma (PRP) and washed platelets (WP).

Methods

As aspirin is released from prodrugs following esterase hydrolysis we studied the expression and activity of butyrylcholineterase (BuChE) and carboxyesterase (CE) in plasma and platelets. The mechanism of prodrug-induced platelet aggregation inhibition was explored by studying the effects of plasma and purified human BuChE on aggregation. Finally, the relative contribution of nitric oxide (NO) bioactivity to nitrate-containing prodrugs of aspirin-induced inhibition of aggregation was determined using 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ,) a selective inhibitor of the soluble guanylyl cyclase.

Key findings

ST0702, 2, a nicotinic acid-aspirin codrug was equipotent with aspirin with respect to inhibition of collagen-induced platelet aggregation. Compound 4, a NO releasing aspirin was the most potent inhibitor of ADP-induced platelet aggregation, an effect partially reversed by ODQ. The platelet inhibitory effects of aspirin prodrugs were time-dependent as the maximal inhibitory effects against collagen-induced aggregation were achieved by aspirin at 2 min, 1 at 5 min and ST0702 at 15 min. The aspirin prodrugs were significantly less potent in WP than in PRP and the reverse was true of aspirin. In the presence of complete BuChE inhibition in PRP, there was almost complete loss of aspirin prodrug, but not aspirin anti-aggregatory activity. Interestingly, CE activity was observed in WP and platelet lysate with pNPA substrate. Accordingly, 1 and ST0702 retained 50% and 100% anti-aggregatory activity at maximal concentrations in WP, which was attenuated in the presence of esterase inhibitor phenylmethylsulphonyl fluoride.

Conclusions

The inhibitory effect of aspirin prodrugs in PRP is due to prodrug activation by BuChE. In contrast, the platelet-inhibitory effects of aspirin prodrugs in WP may be mediated through the activity of platelet CE. Compound 4, a NO-containing aspirin prodrug, may exert dual inhibitory effects in platelets. Thus, aspirin prodrugs effectively inhibit human platelet aggregation and as such may be an alternative to conventional aspirin.
Parameter estimation of multiple item response profile model
Authors: Cho Sun‐Joo , Partchev Ivailo , De Boeck Paul
Published: November 2011

Multiple item response profile (MIRP) models are models with crossed fixed and random effects. At least one between‐person factor is crossed with at least one within‐person factor, and the persons nested within the levels of the between‐person factor are crossed with the items within levels of the within‐person factor. Maximum likelihood estimation (MLE) of models for binary data with crossed random effects is challenging. This is because the marginal likelihood does not have a closed form, so that MLE requires numerical or Monte Carlo integration. In addition, the multidimensional structure of MIRPs makes the estimation complex. In this paper, three different estimation methods to meet these challenges are described: the Laplace approximation to the integrand; hierarchical Bayesian analysis, a simulation‐based method; and an alternating imputation posterior with adaptive quadrature as the approximation to the integral. In addition, this paper discusses the advantages and disadvantages of these three estimation methods for MIRPs. The three algorithms are compared in a real data application and a simulation study was also done to compare their behaviour.
Probing compositional disorder in vanadium oxide thin films grown on atomic layer deposited hafnia on silicon by capacitance spectroscopy
Authors: Ko Changhyun , Zhou You , Ramanathan Shriram
Published: November 2011

The authors investigate capacitance-voltage characteristics of HfO2/VOx/HfO2/n-Si metal-oxide semiconductor devices that include vanadium oxide (VOx) films of different composition. Temperature dependent capacitance-voltage measurements are reported spanning the metal-insulator transition boundary of VOx films. The measured trends in dielectric properties are cross-correlated with resistance ratio change and oxidation state in identical films. The results could be of relevance to advancing synthesis of correlated oxide films on dielectric layers and further utilizing capacitance spectroscopy as a way to probe oxide stoichiometry in gated heterostructures.
Liquid transfer imprint lithography: A new route to residual layer thickness control
Authors: Koo Namil , Wuk Kim Jung , Otto Martin , Moormann Christian , Kurz Heinrich
Published: November 2011

In this study, an extension of the soft UV nanoimprint process is presented with improved control of the residual layer thickness and significant reduction of the nanoimprint proximity effect. The process is based on the consecutive halving of the liquid resist layer by a liquid transfer process. In the initial stage, this liquid transfer process uses a thick initial resist layer to ensure complete filling of the stamp cavities. The thick residual layer is then thinned down to about half by peeling off the applied imprint stamp, a process that can be repeated until the desired residual layer thickness is achieved. The information carrying layer remaining on the stamp can be transferred conformally to any substrate even with nonplanar surfaces. The fabrication of silicon photonic waveguides and photovoltaic antireflection textures are two applications where the advantage of this process becomes particularly clear.
Seafood Eco-Label Grapples With Challenge of Proving Its Impact
Authors: Stokstad Erik
Published: November 2011

A new analysis, released last week, makes the most detailed case yet that certification by the Marine Stewardship Council, the world's biggest eco-label for sustainable seafood, does yield environmental benefits.
A Difficult View From Space for NOAA
Authors: Malakoff David
Published: November 2011

As the agency moves to get polar-orbiting satellites off the ground, ocean science programs could feel budget chill.
Polyfunctional T Cells Accumulate in Large Human Cytomegalovirus-Specific T Cell Responses
Authors: Lachmann Raskit , Bajwa Martha , Vita Serena , Smith Helen , Cheek Elizabeth , Akbar Arne , Kern Florian
Published: November 2011

Large cytomegalovirus (CMV)-specific CD8 T-cell responses are observed in both young and, somewhat more often, old people. Frequent CMV reactivation is thought to exhaust these cells and render them dysfunctional so that larger numbers of them are needed to control CMV. Expansions of CMV-specific CD4 T cells are also seen but are less well studied. In this study, we examined the T-cell response to the dominant CMV pp65 and IE-1 antigens in healthy CMV-infected people across a wide age range (20 to 84 years) by using multicolor flow cytometry. CMV-specific T cells were characterized by the activation markers CD40 ligand (CD40L), interleukin-2 (IL-2), tumor necrosis factor alpha (TNF-α), and gamma interferon (IFN-γ) and the memory markers CD27 and CD45RA. The proportions of effector memory T cells increased in large responses, as did the proportions of polyfunctional CD8 (IFN-γ+IL-2+/−TNF-α+) and CD4 (CD40L+/−IFN-γ+IL-2+TNF-α+) T-cell subsets, while the proportion of naïve T cells decreased. The bigger the CD4 or CD8 T-cell response to pp65, the larger was the proportion of T cells with an advanced memory phenotype in the entire (including non-CMV-specific) T-cell compartment. In addition, the number of activation markers per cell correlated with the degree of T-cell receptor downregulation, suggesting increased antigen sensitivity in polyfunctional cells. In summary, our findings show that polyfunctional CMV-specific T cells were not superseded by dysfunctional cells, even in very large responses. At the same time, however, the memory subset composition of the entire T-cell compartment correlated with the size of the T-cell response to CMV pp65, confirming a strong effect of CMV infection on the immune systems of some, but not all, infected people.
Ex Vivo
and
In Vivo
Inhibition of Human Rhinovirus Replication by a New Pseudosubstrate of Viral 2A Protease
Authors: Falah Nisrine , Violot Sébastien , Décimo Didier , Berri Fatma , Foucault-Grunenwald Marie-Laure , Ohlmann Théophile , Schuffenecker Isabelle , Morfin Florence , Lina Bruno , Riteau Béatrice , Cortay Jean-Claude
Published: November 2011

Human rhinoviruses (HRVs) remain a significant public health problem as they are the major cause of both upper and lower respiratory tract infections. Unfortunately, to date no vaccine or antiviral against these pathogens is available. Here, using a high-throughput yeast two-hybrid screening, we identified a 6-amino-acid hit peptide, LVLQTM, which acted as a pseudosubstrate of the viral 2A cysteine protease (2A
pro
) and inhibited its activity. This peptide was chemically modified with a reactive electrophilic fluoromethylketone group to form a covalent linkage with the nucleophilic active-site thiol of the enzyme.
Ex vivo
and
in vivo
experiments showed that thus converted, LVLQTM was a strong inhibitor of HRV replication in both A549 cells and mice. To our knowledge, this is the first report validating a compound against HRV infection in a mouse model.
Viral Adaptation to Host Immune Responses Occurs in Chronic Hepatitis B Virus (HBV) Infection, and Adaptation Is Greatest in HBV e Antigen-Negative Disease
Authors: Desmond Christopher P. , Gaudieri Silvana , James Ian R. , Pfafferott Katja , Chopra Abha , Lau George K. , Audsley Jennifer , Day Caroline , Chivers Sarah , Gordon Adam , Revill Peter A. , Bowden Scott , Ayres Anna , Desmond Paul V. , Thompson Alexander J. , Roberts Stuart K. , Locarnini Stephen A. , Mallal Simon A. , Lewin Sharon R.
Published: November 2011

Hepatitis B virus (HBV)-specific T-cell responses are important in the natural history of HBV infection. The number of known HBV-specific T-cell epitopes is limited, and it is not clear whether viral evolution occurs in chronic HBV infection. We aimed to identify novel HBV T-cell epitopes by examining the relationship between HBV sequence variation and the human leukocyte antigen (HLA) type in a large prospective clinic-based cohort of Asian patients with chronic HBV infection recruited in Australia and China (n= 119). High-resolution 4-digit HLA class I and II typing and full-length HBV sequencing were undertaken for treatment-naïve individuals (52% with genotype B, 48% with genotype C, 63% HBV e antigen [HBeAg] positive). Statistically significant associations between HLA types and HBV sequence variation were identified (n= 49) at 41 sites in the HBV genome. Using prediction programs, we determined scores for binding between peptides containing these polymorphisms and associated HLA types. Among the regions that could be tested, HLA binding was predicted for 14/18 (78%). We identified several HLA-associated polymorphisms involving likely known anchor residues that resulted in altered predicted binding scores. Some HLA-associated polymorphisms fell within known T-cell epitopes with matching HLA restriction. Enhanced viral adaptation (defined as the presence of the relevant HLA and the escaped amino acid) was independently associated with HBeAg-negative disease (P= 0.003). Thus, HBV appears to be under immune pressure in chronic HBV infection, particularly in HBeAg-negative disease.
Contributions of CTCF and DNA Methyltransferases DNMT1 and DNMT3B to Epstein-Barr Virus Restricted Latency
Authors: Hughes David J. , Marendy Elessa M. , Dickerson Carol A. , Yetming Kristen D. , Sample Clare E. , Sample Jeffery T.
Published: November 2011

Establishment of persistent Epstein-Barr virus (EBV) infection requires transition from a program of full viral latency gene expression (latency III) to one that is highly restricted (latency I and 0) within memory B lymphocytes. It is well established that DNA methylation plays a critical role in EBV gene silencing, and recently the chromatin boundary protein CTCF has been implicated as a pivotal regulator of latency via its binding to several loci within the EBV genome. One notable site is upstream of the common EBNA gene promoter Cp, at which CTCF may act as an enhancer-blocking factor to initiate and maintain silencing of EBNA gene transcription. It was previously suggested that increased expression of CTCF may underlie its potential to promote restricted latency, and here we also noted elevated levels of DNA methyltransferase 1 (DNMT1) and DNMT3B associated with latency I. Within B-cell lines that maintain latency I, however, stable knockdown of CTCF, DNMT1, or DNMT3B or of DNMT1 and DNMT3B in combination did not result in activation of latency III protein expression or EBNA gene transcription, nor did knockdown of DNMTs significantly alter CpG methylation within Cp. Thus, differential expression of CTCF and DNMT1 and -3B is not critical for maintenance of restricted latency. Finally, mutant EBV lacking the Cp CTCF binding site exhibited sustained Cp activity relative to wild-type EBV in a recently developed B-cell superinfection model but ultimately was able to transition to latency I, suggesting that CTCF contributes to but is not necessarily essential for the establishment of restricted latency.
Potent Autologous and Heterologous Neutralizing Antibody Responses Occur in HIV-2 Infection across a Broad Range of Infection Outcomes
Authors: de Silva Thushan I. , Aasa-Chapman Marlén , Cotten Matthew , Hué Stéphane , Robinson James , Bibollet-Ruche Frederic , Sarge-Njie Ramu , Berry Neil , Jaye Assan , Aaby Peter , Whittle Hilton , Rowland-Jones Sarah , Weiss Robin
Published: November 2011

Few studies have explored the role of neutralizing antibody (NAb) responses in controlling HIV-2 viremia and disease progression. Using a TZM-bl neutralization assay, we assessed heterologous and autologous NAb responses from a community cohort of HIV-2-infected individuals with a broad range of disease outcomes in rural Guinea-Bissau. All subjects (
n
= 40) displayed exceptionally high heterologous NAb titers (50% inhibitory plasma dilution or 50% inhibitory concentration [IC
50
], 1:7,000 to 1:1,000,000) against 5 novel primary HIV-2 envelopes and HIV-2 7312A, whereas ROD A and 3 primary envelopes were relatively resistant to neutralization. Most individuals also showed high autologous NAb against contemporaneous envelopes (78% of plasma-envelope combinations in 69 envelopes from 21 subjects), with IC
50
s above 1:10,000. No association between heterologous or autologous NAb titer and greater control of HIV-2 was found. A subset of envelopes was found to be more resistant to neutralization (by plasma and HIV-2 monoclonal antibodies). These envelopes were isolated from individuals with greater intrapatient sequence diversity and were associated with changes in potential N-linked glycosylation sites but not CD4 independence or CXCR4 use. Plasma collected from up to 15 years previously was able to potently neutralize recent autologous envelopes, suggesting a lack of escape from NAb and the persistence of neutralization-sensitive variants over time, despite significant NAb pressure. We conclude that despite the presence of broad and potent NAb responses in HIV-2-infected individuals, these are not the primary forces behind the dichotomous outcomes observed but reveal a limited capacity for adaptive selection and escape from host immunity in HIV-2 infection.
Arterivirus and Nairovirus Ovarian Tumor Domain-Containing Deubiquitinases Target Activated RIG-I To Control Innate Immune Signaling
Authors: van Kasteren Puck B. , Beugeling Corrine , Ninaber Dennis K. , Frias-Staheli Natalia , van Boheemen Sander , García-Sastre Adolfo , Snijder Eric J. , Kikkert Marjolein
Published: November 2011

The innate immune response constitutes the first line of defense against viral infection and is extensively regulated through ubiquitination. The removal of ubiquitin from innate immunity signaling factors by deubiquitinating enzymes (DUBs) therefore provides a potential opportunity for viruses to evade this host defense system. It was previously found that specific proteases encoded by the unrelated arteri- and nairoviruses resemble the ovarian tumor domain-containing (OTU) family of DUBs. In arteriviruses, this domain has been characterized before as a papain-like protease (PLP2) that is also involved in replicase polyprotein processing. In nairoviruses, the DUB resides in the polymerase protein but is not essential for RNA replication. Using both
in vitro
and cell-based assays, we now show that PLP2 DUB activity is conserved in all members of the arterivirus family and that both arteri- and nairovirus DUBs inhibit RIG-I-mediated innate immune signaling when overexpressed. The potential relevance of RIG-I-like receptor (RLR) signaling for the innate immune response against arterivirus infection is supported by our finding that in mouse embryonic fibroblasts, the production of beta interferon primarily depends on the recognition of arterivirus RNA by the pattern-recognition receptor MDA5. Interestingly, we also found that both arteri- and nairovirus DUBs inhibit RIG-I ubiquitination upon overexpression, suggesting that both MDA5 and RIG-I have a role in countering infection by arteriviruses. Taken together, our results support the hypothesis that arteri- and nairoviruses employ their deubiquitinating potential to inactivate cellular proteins involved in RLR-mediated innate immune signaling, as exemplified by the deubiquitination of RIG-I.
The impact of contraction velocity on amortisation and electromyographic activity during heavy-load resistance exercise
Authors: Sampson J A , McAndrew D , Taylor N A S , Groeller H
Published: November 2011

Heavy-load resistance exercise is not normally associated with stretch shortening muscle activation. Rapid lengthening, and a decreased period of time between lengthening and shortening phases of contraction (amortisation phase) has been associated with increased energy transfer from passive muscle structures (series elastic component, SEC), and gains in muscle efficiency during stretch shortening muscle activation. In this investigation, we sought to determine the effect of limb velocity on the amortisation phase and electromyographic (EMG) activity during heavy load (85%1RM) resistance exercise. Twelve healthy males performed 6RM unilateral elbow flexion-extension exercise during; rapid lengthening-shortening, rapid shortening and slow lengthening-shortening muscle activation. The amortisation phase and velocity of lengthening and shortening were determined using a shaft encoder and muscle activity was recorded at thebiceps brachiiusing intramuscular and surface EMG. A decrease (P<0.05) in time spent in amortisation was observed during rapid lengthening-shortening (0.10±0.00 ms), compared to rapid shortening (0.14±0.00 ms) and slow lengthening-shortening (0.19±0.00 ms). Intramuscular EMG was ∼25% (P<0.05) greater during the first, second and third repetition of rapid lengthening-shortening exercise compared to the other two conditions. A trend towards increased surface EMG activity was also noted during rapid lengthening-shortening, however significance (P<0.05) was only observed in the second repetition. In this investigation, the characteristics typical of a stretch shortening muscle activation were observed alongside elevated electromyographic activity during heavy-load rapid lengthening-shortening resistance exercise.