bluuebunny/crossref_metadata_2025 huggingface dataset:
Metastable Walking Machines
Authors: Byl Katie , Tedrake Russ
Published: June 2009

Legged robots that operate in the real world are inherently subject to stochasticity in their dynamics and uncertainty about the terrain. Owing to limited energy budgets and limited control authority, these “disturbances” cannot always be canceled out with high-gain feedback. Minimally actuated walking machines subject to stochastic disturbances no longer satisfy strict conditions for limit-cycle stability; however, they can still demonstrate impressively long-living periods of continuous walking. Here, we employ tools from stochastic processes to examine the “stochastic stability” of idealized rimless-wheel and compass-gait walking on randomly generated uneven terrain. Furthermore, we employ tools from numerical stochastic optimal control to design a controller for an actuated compass gait model which maximizes a measure of stochastic stability—the mean first-passage time—and compare its performance with a deterministic counterpart. Our results demonstrate that walking is well characterized as a metastable process, and that the stochastic dynamics of walking should be accounted for during control design in order to improve the stability of our machines.
Distal Biceps Tendon Rupture
Authors: Fenton Paul , Qureshi Ford , Ali Amjid , Potter David
Published: June 2009

Background

Distal biceps tendon ruptures are uncommon injuries. Operative treatment has been shown to improve functional outcomes. A variety of surgical repair techniques have been described for distal biceps ruptures.

Purpose

The authors present their experience with a new technique to anatomically repair distal biceps tendon ruptures through a single-incision approach that they believe is a safe and reliable method of achieving repair.

Study Design

Case series; Level of evidence, 4.

Materials and Methods

Fourteen patients with 14 biceps tendon ruptures underwent a repair with a bioabsorbable Biotenodesis screw. All 14 patients underwent clinical assessment using the Mayo Elbow Performance Score, measurement of range of motion, and flexion strength testing. Mean follow-up was 29.1 months.

Results

Three patients had a good result and 11 patients had an excellent result. The mean elbow flexion arc was 141.4° (range, 125°–155°; standard deviation, 7.19°) with no flexion contractures in the operated side compared with the unaffected elbow. All patients achieved an equal range of pronation/supination to the unaffected side. The mean flexion strength in the injured arm was 25.7 kg, compared with 26.9 kg in the uninjured side. No complications were noted about the elbow.

Conclusion

The authors believe this new technique gives a good functional outcome with reproducible results.
Comparative Studies of Mechanical and Interfacial Properties Between Jute and E-glass Fiber-reinforced Polypropylene Composites
Authors: Khan Ruhul A. , Khan Mubarak A. , Zaman Haydar U. , Pervin Shamim , Khan Nuruzzaman , Sultana Sabrina , Saha M. , Mustafa A.I.
Published: June 2009

Jute fiber (hessian cloth)-reinforced polypropylene matrix composites (50 wt% fiber) were fabricated by compression molding. Tensile strength, tensile modulus, bending strength, bending modulus, and impact strength of the composites were found to be 48 MPa, 2.5 GPa, 56 MPa, 4.5 GPa, and 18 kJ/m2, respectively. Then E-glass fiber (woven)-reinforced polypropylene-based composites (50 wt% fiber) were fabricated and the mechanical properties were compared with those of the jute-based composites. It was revealed that E-glass fiber-based composites had almost double the mechanical properties as compared to jute composites. The interfacial shear strength of the jute and E-glass fiber-based systems was investigated and found to be 2.13 and 4.66 MPa, respectively, measured using the single-fiber fragmentation test. Fracture sides after flexural testing of both types of the composites were studied by scanning electron microscope and the results revealed poor fiber matrix adhesion for jute-based composites when compared to that of the E-glass fiber composites.
Preparation and Characterization of Polymer/Date Pits Composites
Authors: Alsewailem Fares D. , Binkhder Yazeed A.
Published: June 2009

This research reports the formulation and characterization of polymer/date pits composites. Polymers used in this study were high-density polyethylene (HDPE) and polystyrene (PS), while date pits used were locally called khlaas (K) and sekari (S), wastes of two types of date palm fruit grown in Saudi Arabia. Tensile strength (TS) and Izod impact strength (IIS) tests were conducted to assess the mechanical properties of the prepared composites. Thermal properties of the composites were measured and discussed in view of glass transition and melting temperatures, Tg and Tm, respectively, as well as the heat of fusion, which reflects the degree of crystallinity of the polymer/date pits composites. Generally, mechanical properties, i.e., TS and IIS, were reduced upon date pits incorporation in the composites. Results showed that IIS of HDPE/date pits composites drastically suffered from the addition of as low as 5 wt% of date pits. Addition of date pits regardless of the type, either S or K, tended to reduce Tg of the PS100/date pits composites and the heat of fusion of the HDPE/date pits composites at relatively higher date pits content, >10 wt%. The reduction in both degree of crystallinty represented by heat of fusion of the HDPE and mechanical properties of all composite systems used in this study at the high loading presence of date pits may be related to the anticipated coarse morphology of the composites evolved during the mixing of polymers, with date pits in the absence of an appropriate coupling agent system.
Tension and Compression Strength Evaluation of Composite Plates with Circular Holes
Authors: Kamala Kannan V. , Murali Vela , Rajadurai A. , Nageswara Rao B.
Published: June 2009

Modifications were made in the well-known inherent flaw model as well as in the stress fracture models namely, point stress criterion and average stress criterion for accurate prediction of notched tensile and compressive strength of composite laminates containing holes. The adequacy of these modified fracture models were examined by considering the fracture data of center-hole specimens made of carbon/epoxy composites, weft-knitted glass fiber composites, and pultruded composites. Any one of these three fracture models can be utilized to predict the notched strength.
Math Anxiety and Math Ability in Early Primary School Years
Authors: Krinzinger Helga , Kaufmann Liane , Willmes Klaus
Published: June 2009

Mathematical learning disabilities (MLDs) are often associated with math anxiety, yet until now, very little is known about the causal relations between calculation ability and math anxiety during early primary school years. The main aim of this study was to longitudinally investigate the relationship between calculation ability, self-reported evaluation of mathematics, and math anxiety in 140 primary school children between the end of first grade and the middle of third grade. Structural equation modeling revealed a strong influence of calculation ability and math anxiety on the evaluation of mathematics but no effect of math anxiety on calculation ability or vice versa—contrasting with the frequent clinical reports of math anxiety even in very young MLD children. To summarize, our study is a first step toward a better understanding of the link between math anxiety and math performance in early primary school years performance during typical and atypical courses of development.
Biopesticides, Regulatory Innovation and the Regulatory State
Authors: Greaves Justin
Published: June 2009

This article analyses regulatory innovation. It considers, in particular, how a regulatory environmental agency has been encouraged to innovate in the area of biopesticides. The literature on regulatory innovation is reviewed, the discussion situated within Moran's theory of the regulatory state. It considers to what extent innovation has occurred within the agency, looking at its proactive stance, and how unusually for a regulatory body it has negotiated new policy spaces in which to operate. The article looks at the contextual drivers and also the exogenous and endogenous pressures behind the innovation. It shows how the executive has intervened in order to promote more use of biopesticides and how pressure is also being exerted within the regulatory authority. By using the existing literature and empirical evidence a framework is outlined for explaining the likelihood of regulatory innovation occurring in regulatory agencies.
Changing Course
Authors: Roberge Ian
Published: June 2009

Policy reversals represent a particular type of policy change. Reversals refer specifically to instances when a policy is adopted or discontinued despite previously adopted positions. In cases of reversals, decision makers have reassessed their core values usually because of substantive events in the policy parameter. Although reversals represent a stark redirection, they could not take place without prior institutionalization in the field. We use Title III of the Patriot Act, which deals among other things with money laundering and terrorist financing, to illustrate our point.
Authentic Leadership
Authors: Eriksen Matthew
Published: June 2009

This assignment provides a process to facilitate student engagement in practical reflexivity and self-authorship through which students develop the self-awareness that is required to be an authentic and effective leader. It facilitates the development of students’ personal leadership principles, which help guide their decision making and actions, and provides criteria on which to evaluate their leadership effectiveness. This facilitation of the development of students’ personal leadership principles is accomplished by having students first identify and clarify their values and beliefs and to consider the impact of these on their day-to-day organizational lives and leadership. By explicitly defining themselves in the form of their values and beliefs, students have a clear sense of self on which to base their authentic leadership. Their beliefs are expressed in the form of self-narratives. These self-narratives are shared as audio recordings with fellow classmates to facilitate students’ learning, self-understanding, and empathy.
Theorizing the Dark Side of the Workplace Spirituality Movement
Authors: Lips-Wiersma Marjolein , Lund Dean Kathy , Fornaciari Charles J.
Published: June 2009

This article constructs an alternative analytic lens by which to consider the “everyone wins” conclusions drawn within most workplace spirituality (WPS) research. The article offers a critical 2 × 2 matrix that makes visible two potentially negative organizational dimensions of WPS: control and instrumentality. The article investigates into the four quadrants of WPS: seduction, evangelization, manipulation, and subjugation, through practical examples. It concludes with implications for the workplace and offers an agenda for future research.
A Confirmatory Factor Analysis of the California Verbal Learning Test—Second Edition (CVLT-II) in a Traumatic Brain Injury Sample
Authors: DeJong Joy , Donders Jacobus
Published: June 2009

The latent structure of the California Verbal Learning Test—Second Edition (CVLT-II) was examined in a clinical sample of 223 persons with traumatic brain injury that had been screened to remove individuals with complicating premorbid (e.g., psychiatric) or comorbid (e.g., financial compensation seeking) histories. Analyses incorporated the z scores from 12 CVLT-II variables. Maximum-likelihood confirmatory analyses were performed to test the fit and parsimony of four hypothetical models. A four-factor model, consisting of Attention Span, Learning Efficiency, Delayed Memory, and Inaccurate Memory, met all the a priori specified criteria for model fit and parsimony. This model was consistent with that identified previously in a confirmatory factor analysis of the CVLT-II standardization sample. The results support the construct validity of the CVLT-II in individuals with traumatic brain injury and indicate that a multifactorial interpretation is appropriate for clinical practice.
The Role of Immigration for Violent Deaths
Authors: Nielsen Amie L. , Martinez Ramiro
Published: June 2009

This article examines the role of community-level factors, including percentage immigrant, for Latino- and Black-specific homicides and suicides in Miami, Florida. Using medical examiner data for 1985-1995 violent deaths and 1990 Census data, this article examines the contexts under which ethnic-specific lethal violence occurs at the census tract level. The results indicate that immigrants are not disrupting communities or undermining social integration. Overall, the article illustrates the importance of considering immigration for understanding race- and ethnic-specific lethal violence as well as the utility of examining the community contexts in which both homicide and suicide tend to occur.
Reimbursement for drugs — a register study comparing economic outcome for five healthcare centres in areas with different socioeconomic conditions
Authors: Semark B. , Fredlund K. , Åstrand B. , Brudin L.
Published: June 2009

Aims: Previous studies have indicated the negative effects of socioeconomic deprivation on health status and morbidity. Nevertheless, the economic assignment systems for pharmaceutical benefits in Sweden do not take socioeconomic status (SES) into account. The aim of the study was, therefore, to compare reimbursement for subsidized drugs at primary healthcare centres (HCCs) with differing socioeconomic conditions in relation to real costs. The word reimbursement is used to denote economic compensation to the HCCs from the county council for drug benefit costs. Methods: The numbers of individuals dispensed drugs, total costs and reimbursement at five HCCs with different socioeconomic conditions were compared. A socioeconomic index was calculated for each HCC on the basis of information from the municipality registries on income (with negative sign), assistance allowance, education, foreign background, and unemployment. Register data on drug benefit costs were retrieved from the National Corporation of Pharmacies (Apoteket AB) and the Swedish Prescribed Drug Register at the National Board of Health and Welfare. Data on listed and unlisted citizens at the Kalmar County Council and on public statistics from registers at the HCC municipalities where the HCCs were situated were retrieved. Results: There was an almost inverse linear relationship between total cost compensation and the socioeconomic index (n = 5; r =-0.99; p = 0.001). The HCCs with the lowest SES received lower cost compensation. Conclusions: HCCs responsible for citizens with lower SES appeared to be disadvantaged by the prevalent reimbursement system in Sweden, thereby increasing differences in the state of health of the citizens. This, in turn, hampers health preventing programmes and lifestyle interventions. An HCC-specific standardized summary of socioeconomic burden is presented.
Experts at Play
Authors: Reeves Stuart , Brown Barry , Laurier Eric
Published: June 2009

Developing from David Sudnow's accounts of expertise, this article examines the gameplay of Counter-Strike, a popular online game. Although Counter-Strike at first may seem an unsophisticated pursuit, players display remarkable dexterity developed through many hours of play. Through participating in the game and analyzing videos of gameplay, we examine Counter-Strike as an example of expert technology use. As players move beyond the mere physical prowess of chaining their movements with the environment, they develop a sense of the terrain of play as a contingent tactically oriented understanding, rather than as static spatial knowledge. Relatedly, we provide the beginnings of an alternative account of both games and expertise which brings out something of what it is to play a specific game, as opposed to games in general. Moreover, rather than presenting a disengaged general model of skill, the article considers how we might access and describe the situated skills of gameplay.
Dragon Kill Points
Authors: Malone Krista-Lee
Published: June 2009

World of Warcraft (WoW) is a massively multi-player online role-playing game (MMORPG). The end-game consists of complex encounters requiring highly organized groups (raids). This complexity has caused the organizing of raiding guilds (self-governing player communities). Raiding guilds have hierarchical political structures in which leaders must legitimate their positions to demand participation. In a symbiotic relationship of political structure and individual desire, guilds must guarantee advancement in tandem with individuals' acquisition of items (loot); but game mechanics make this problematic. Each end-game encounter defeated offers less loot than players needed. To compensate for this raiding guilds use DKP (intra-guild economic systems). It is DKP, I argue, that generates the political cohesion necessary for guilds to successfully engage the end-game. DKP is guild specific, but important for its effects on value and reciprocity. It creates player obligation through a rationalized system measuring commitment.
An Experimental Device for the Measurement of Hygroscopic Inertia Influence on RH Variation
Authors: Ramos N.M.M. , De Freitas V.P.
Published: June 2009

This article reports the development of an innovative flux chamber that is specifically developed for the support of experimental work that is aiming at a systematic measurement of the hygroscopic inertia influence on relative humidity (RH) variation inside rooms. This flux chamber is a flexible infrastructure where different test configurations can be run. The precise control of vapor production, inside air renovation, and system temperature allow for the reproduction, in a small-scale room, of hygrothermal scenarios that can be fully repeated in an unlimited number of cycles. Results obtained are presented in this article, relating especially to the testing and calibration procedures and highlighting the limitations and possibilities of the facility. The hygroscopic inertia effect on RH variation is demonstrated. A discussion on the perfect mixing of the air inside a room is also addressed, based on the obtained results.
Surface RANKL of Toll-like receptor 4–stimulated human neutrophils activates osteoclastic bone resorption
Authors: Chakravarti Arpita , Raquil Marie-Astrid , Tessier Philippe , Poubelle Patrice E.
Published: June 2009

Inflammatory bone loss in septic and inflammatory conditions is due to increased activity of osteoclasts that requires receptor activator of NF-kappa B-ligand (RANKL). Neutrophils are the predominant infiltrating cells in these conditions. Although disease severity is linked to neutrophils, their role in evolution of bony lesions is not clear. We show that lipopolysaccharide (LPS), a toll-like receptor 4 ligand, up-regulated the expression of membrane RANKL in human blood neutrophils and murine air pouch–derived neutrophils. LPS-activated human and murine neutrophils, cocultured with human monocyte-derived osteoclasts and RAW 264.7 cells, respectively, stimulated bone resorption. Transfection of PLB-985 neutrophil-like cells with RANKL antisense RNA reduced osteoclastogenesis. Synovial fluid neutrophils of patients with exacerbation of rheumatoid arthritis strongly expressed RANKL and activated osteoclastogenesis in coculture systems. Osteoprotegerin, the RANKL decoy receptor, suppressed osteoclast activation by neutrophils from these different sources. Moreover, direct cell-cell contact between neutrophils and osteoclasts was visualized by confocal laser microscopy. Activation of neutrophil membrane-bound RANKL was linked to tyrosine phosphorylation of Src-homology domain–containing cytosolic phosphatase 1 with concomitant down-regulation of cytokine production. The demonstration of these novel functions of neutrophils highlights their potential role in osteoimmunology and in therapeutics of inflammatory bone disease.
Direct crosstalk between mast cell–TNF and TNFR1-expressing endothelia mediates local tissue inflammation
Authors: Kneilling Manfred , Mailhammer Reinhard , Hültner Lothar , Schönberger Tanja , Fuchs Kerstin , Schaller Martin , Bukala Daniel , Massberg Steffen , Sander Christian A. , Braumüller Heidi , Eichner Martin , Maier Konrad L. , Hallmann Rupert , Pichler Bernd J. , Haubner Roland , Gawaz Meinrad , Pfeffer Klaus , Biedermann Tilo , Röcken Martin
Published: June 2009

Signaling through tumor necrosis factor receptor 1 (TNFR1) controls bacterial infections and the induction of inflammatory Th1 cell–mediated autoimmune diseases. By dissecting Th1 cell–mediated delayed-type hypersensitivity responses (DTHRs) into single steps, we localized a central defect to the missing TNFR1 expression by endothelial cells (ECs). Adoptive transfer and mast cell knockin experiments into KitW/KitW-v, TNF−/−, and TNFR1−/− mice showed that the signaling defect exclusively affects mast cell–EC interactions but not T cells or antigen-presenting cells. As a consequence, TNFR1−/− mice had strongly reduced mRNA and protein expression of P-selectin, E-selectin, ICAM-1, and VCAM-1 during DTHR elicitation. In consequence, intravital fluorescence microscopy revealed up to 80% reduction of leukocyte rolling and firm adhesion in TNFR1−/− mice. As substitution of TNF−/− mice with TNF-producing mast cells fully restored DTHR in these mice, signaling of mast cell-derived TNF through TNFR1-expressing ECs is essential for the recruitment of leukocytes into sites of inflammation.
Foreword to the international workshop on major genes and QTL in sheep and goats
Authors: Elsen Jean Michel
Published: June 2009

This is the third international meeting dealing with major genes in small ruminants. The first was held in Armidale (NSW, Australia) in 1980, just after the discovery of the Booroola gene by B. Bindon and L. Piper. The discovery of a gene having such a large effect on ovulation rate and prolificacy in sheep was totally unsuspected at this time and a number of research teams all over the world concentrated their efforts to study its effects and identify the causal mutation. About 20 years were finally needed to obtain this information, which opened a new approach to the physiological regulation of reproduction.

The second meeting was organised in 1990 in Toulouse along the same lines. Although its main concern was the Booroola gene, other major genes influencing ovulation in sheep were also considered. Indeed, an increasing amount of evidence demonstrated that, on the contrary to the current opinion in quantitative genetics laboratories before 1980, prolificacy is not always controlled by a very large number of genes each exhibiting a very small effect, but may also be influenced by genes with large effects, generalising the Booroola situation to other populations.

Since then, mixed inheritance was also found for other production traits such as body conformation, seasonality or milk composition. However, the major evolution has been the inexpensive large-scale access to molecular genetic information, using PCR, microsatellites and SNP technologies. QTL detection experiments are performed in all domestic species, including sheep and goats, and the identification of genes having an average effect on the performance trait variability is now possible. The utilisation of these polymorphisms should also be a great help for a better management of populations, either through the selection of breeders or through the preservation of genetic diversity.

This third meeting on major genes and QTL in sheep and goats was a unique occasion for the researchers involved in this area of Animal Science to present their latest results, exchange their experiences and progress in the organisation of scientific co-operation.
Altered effector function of peripheral cytotoxic cells in COPD
Authors: Urbanowicz Richard A , Lamb Jonathan R , Todd Ian , Corne Jonathan M , Fairclough Lucy C
Published: June 2009

Background

There is mounting evidence that perforin and granzymes are important mediators in the lung destruction seen in COPD. We investigated the characteristics of the three main perforin and granzyme containing peripheral cells, namely CD8+ T lymphocytes, natural killer (NK; CD56+CD3-) cells and NKT-like (CD56+CD3+) cells.

Methods

Peripheral blood mononuclear cells (PBMCs) were isolated and cell numbers and intracellular granzyme B and perforin were analysed by flow cytometry. Immunomagnetically selected CD8+ T lymphocytes, NK (CD56+CD3-) and NKT-like (CD56+CD3+) cells were used in an LDH release assay to determine cytotoxicity and cytotoxic mechanisms were investigated by blocking perforin and granzyme B with relevant antibodies.

Results

The proportion of peripheral blood NKT-like (CD56+CD3+) cells in smokers with COPD (COPD subjects) was significantly lower (0.6%) than in healthy smokers (smokers) (2.8%, p < 0.001) and non-smoking healthy participants (HNS) (3.3%, p < 0.001). NK (CD56+CD3-) cells from COPD subjects were significantly less cytotoxic than in smokers (16.8% vs 51.9% specific lysis, p < 0.001) as were NKT-like (CD56+CD3+) cells (16.7% vs 52.4% specific lysis, p < 0.001). Both cell types had lower proportions expressing both perforin and granzyme B. Blocking the action of perforin and granzyme B reduced the cytotoxic activity of NK (CD56+CD3-) and NKT-like (CD56+CD3+) cells from smokers and HNS.

Conclusion

In this study, we show that the relative numbers of peripheral blood NK (CD56+CD3-) and NKT-like (CD56+CD3+) cells in COPD subjects are reduced and that their cytotoxic effector function is defective.
A strategy for enrichment of claudins based on their affinity to Clostridium perfringens enterotoxin
Authors: Lohrberg Dörte , Krause Eberhard , Schümann Michael , Piontek Jörg , Winkler Lars , Blasig Ingolf E , Haseloff Reiner F
Published: June 2009

Background

Claudins, a family of protein localized in tight junctions, are essential for the control of paracellular permeation in epithelia and endothelia. The interaction of several claudins with Clostridium perfringens enterotoxin (CPE) has been exploited for an affinity-based enrichment of CPE-binding claudins from lysates of normal rat cholangiocytes.

Results

Immunoblotting and mass spectrometry (MS) experiments demonstrate strong enrichment of the CPE-binding claudins -3, -4 and -7, indicating specific association with glutathione-S-transferase (GST)-CPE116–319 fusion protein. In parallel, the co-elution of (non-CPE-binding) claudin-1 and claudin-5 was observed. The complete set of co-enriched proteins was identified by MS after electrophoretic separation. Relative mass spectrometric protein quantification with stable isotope labeling with amino acids in cell culture (SILAC) made it possible to discriminate specific binding from non-specific association to GST and/or matrix material.

Conclusion

CPE116–319 provides an efficient tool for single step enrichment of different claudins from cell lysates. Numerous proteins were shown to be co-enriched with the CPE-binding claudins, but there are no indications (except for claudins -1 and -5) for an association with tight junctions.
Subcellular localization of the antidepressant-sensitive norepinephrine transporter
Authors: Matthies Heinrich JG , Han Qiao , Shields Angela , Wright Jane , Moore Jessica L , Winder Danny G , Galli Aurelio , Blakely Randy D
Published: June 2009

Background

Reuptake of synaptic norepinephrine (NE) via the antidepressant-sensitive NE transporter (NET) supports efficient noradrenergic signaling and presynaptic NE homeostasis. Limited, and somewhat contradictory, information currently describes the axonal transport and localization of NET in neurons.

Results

We elucidate NET localization in brain and superior cervical ganglion (SCG) neurons, aided by a new NET monoclonal antibody, subcellular immunoisolation techniques and quantitative immunofluorescence approaches. We present evidence that axonal NET extensively colocalizes with syntaxin 1A, and to a limited degree with SCAMP2 and synaptophysin. Intracellular NET in SCG axons and boutons also quantitatively segregates from the vesicular monoamine transporter 2 (VMAT2), findings corroborated by organelle isolation studies. At the surface of SCG boutons, NET resides in both lipid raft and non-lipid raft subdomains and colocalizes with syntaxin 1A.

Conclusion

Our findings support the hypothesis that SCG NET is segregated prior to transport from the cell body from proteins comprising large dense core vesicles. Once localized to presynaptic boutons, NET does not recycle via VMAT2-positive, small dense core vesicles. Finally, once NET reaches presynaptic plasma membranes, the transporter localizes to syntaxin 1A-rich plasma membrane domains, with a portion found in cholera toxin-demarcated lipid rafts. Our findings indicate that activity-dependent insertion of NET into the SCG plasma membrane derives from vesicles distinct from those that deliver NE. Moreover, NET is localized in presynaptic membranes in a manner that can take advantage of regulatory processes targeting lipid raft subdomains.
A covalent peptide inhibitor of RGS4 identified in a focused one-bead, one compound library screen
Authors: Roof Rebecca A , Roman David L , Clements Samuel T , Sobczyk-Kojiro Katarzyna , Blazer Levi L , Ota Shodai , Mosberg Henry I , Neubig Richard R
Published: June 2009

Background

Regulators of G protein signaling (RGSs) accelerate GTP hydrolysis by Gα subunits and profoundly inhibit signaling by G protein-coupled receptors (GPCRs). The distinct expression patterns and pathophysiologic regulation of RGS proteins suggest that inhibitors may have therapeutic potential. We recently described a focused one-bead, one-compound (OBOC) library screen to identify peptide inhibitors of RGS4. Here we extend our observations to include another peptide with a different mechanism of action.

Results

Peptide 5nd (Tyr-Trp-c [Cys-Lys-Gly-Leu-Cys]-Lys-NH2, S-S) blocks the RGS4-Gαo interaction with an IC50 of 28 μM. It forms a covalent, dithiothreitol (DTT) sensitive adduct with a mass consistent with the incorporation of one peptide per RGS. Peptide 5nd activity is abolished by either changing its disulfide bridge to a methylene dithioether bridge, which cannot form disulfide bridges to the RGS, or by removing all cysteines from the RGS protein. However, no single cysteine in RGS4 is completely necessary or sufficient for 5nd activity.

Conclusion

Though it has some RGS selectivity, 5nd appears to be a partially random cysteine modifier. These data suggest that it inhibits RGS4 by forming disulfide bridges with the protein.
The TrueBlue study: Is practice nurse-led collaborative care effective in the management of depression for patients with heart disease or diabetes?
Authors: Morgan Mark , Dunbar James , Reddy Prasuna , Coates Michael , Leahy Robert
Published: June 2009

Background

In the presence of type 2 diabetes (T2DM) or coronary heart disease (CHD), depression is under diagnosed and under treated despite being associated with worse clinical outcomes. Our earlier pilot study demonstrated that it was feasible, acceptable and affordable for practice nurses to extend their role to include screening for and monitoring of depression alongside biological and lifestyle risk factors. The current study will compare the clinical outcomes of our model of practice nurse-led collaborative care with usual care for patients with depression and T2DM or CHD.

Methods

This is a cluster-randomised intervention trial. Eighteen general practices from regional and metropolitan areas agreed to join this study, and were allocated randomly to an intervention or control group. We aim to recruit 50 patients with co-morbid depression and diabetes or heart disease from each of these practices. In the intervention group, practice nurses (PNs) will be trained for their enhanced roles in this nurse-led collaborative care study. Patients will be invited to attend a practice nurse consultation every 3 months prior to seeing their usual general practitioner. The PN will assess psychological, physiological and lifestyle parameters then work with the patient to set management goals. The outcome of this assessment will form the basis of a GP Management Plan document. In the control group, the patients will continue to receive their usual care for the first six months of the study before the PNs undergo the training and switch to the intervention protocol. The primary clinical outcome will be a reduction in the depression score. The study will also measure the impact on physiological measures, quality of life and on patient attitude to health care delivered by practice nurses.

Conclusion

The strength of this programme is that it provides a sustainable model of chronic disease management with monitoring and self-management assistance for physiological, lifestyle and psychological risk factors for high-risk patients with co-morbid depression, diabetes or heart disease. The study will demonstrate whether nurse-led collaborative care achieves better outcomes than usual care.
Cytometric detection of antigen-specific IFN-γ/IL-2 secreting cells in the diagnosis of tuberculosis
Authors: Sargentini Valeria , Mariotti Sabrina , Carrara Stefania , Gagliardi Maria Cristina , Teloni Raffaela , Goletti Delia , Nisini Roberto
Published: June 2009

Background

The purpose of this study was to further characterize the immune response toMycobacterium tuberculosis(Mtb) antigens, in order to provide new insight into host-pathogen interactions in tuberculosis (TB), and to offer tools for a more accurate diagnosis of the different stages of TB.

Methods

T-cell responses to Bacillus Calmette-Guérin (BCG), purified protein derivative (PPD), early secretory antigenic target-6 (ESAT-6) protein and culture filtrate protein-10 kDa (CFP-10) were measured in terms of interferon (IFN)-γ and interleukin (IL)-2 release, using a novel flow cytometric cell-secreting cytokine detection technique. The study was conducted on peripheral blood mononuclear cells (PBMC) obtained from active TB patients, latently TB infected individuals, and healthy donors. IL-10 and IL-17 were also measured to test their possible role as indicators of disease activity.

Results

We confirmed that the enumeration of IFN-γ releasing cells upon Mtb-specific stimulation is sufficient to identify TB patients and that CD8+ T cells concur to IFN-γ secretion. IL-2 secreting cells were more frequently observed in latent TB infected individuals compared to active TB patients, suggesting that measurement of cells secreting this cytokine could be a marker of disease stage. No discriminating role was associated to IL-10 and IL-17 release in TB patients.

Conclusion

Our data indicate that the flow cytometric cytokine-secreting cell detection technique may be envisaged as an additional tool for TB diagnosis allowing the analysis of the immune response toM. tuberculosis-related antigens in the different stages of TB.
Type-1 Collagen differentially alters β-catenin accumulation in primary Dupuytren's Disease cord and adjacent palmar fascia cells
Authors: Vi Linda , Njarlangattil Anna , Wu Yan , Gan Bing Siang , O'Gorman David B
Published: June 2009

Background

Dupuytren's Disease (DD) is a debilitating contractile fibrosis of the palmar fascia characterised by excess collagen deposition, contractile myofibroblast development, increased Transforming Growth Factor-β levels and β-catenin accumulation. The aim of this study was to determine if a collagen-enriched environment, similar to in vivo conditions, altered β-catenin accumulation by primary DD cells in the presence or absence of Transforming Growth Factor-β.

Methods

Primary DD and patient matched, phenotypically normal palmar fascia (PF) cells were cultured in the presence or absence of type-1 collagen and Transforming Growth Factor-β1. β-catenin and α-smooth muscle actin levels were assessed by western immunoblotting and immunofluorescence microscopy.

Results

DD cells display a rapid depletion of cellular β-catenin not evident in patient-matched PF cells. This effect was not evident in either cell type when cultured in the absence of type-1 collagen. Exogenous addition of Transforming Growth Factor-β1 to DD cells in collagen culture negates the loss of β-catenin accumulation. Transforming Growth Factor-β1-induced α-smooth muscle actin, a marker of myofibroblast differentiation, is attenuated by the inclusion of type-1 collagen in cultures of DD and PF cells.

Conclusion

Our findings implicate type-1 collagen as a previously unrecognized regulator of β-catenin accumulation and a modifier of TGF-β1 signaling specifically in primary DD cells. These data have implications for current treatment modalities as well as the design of in vitro models for research into the molecular mechanisms of DD.
Modelling substrate specificity and enantioselectivity for lipases and esterases by substrate-imprinted docking
Authors: Juhl P Benjamin , Trodler Peter , Tyagi Sadhna , Pleiss Jürgen
Published: June 2009

Background

Previously, ways to adapt docking programs that were developed for modelling inhibitor-receptor interaction have been explored. Two main issues were discussed. First, when trying to model catalysis a reaction intermediate of the substrate is expected to provide more valid information than the ground state of the substrate. Second, the incorporation of protein flexibility is essential for reliable predictions.

Results

Here we present a predictive and robust method to model substrate specificity and enantioselectivity of lipases and esterases that uses reaction intermediates and incorporates protein flexibility. Substrate-imprinted docking starts with covalent docking of reaction intermediates, followed by geometry optimisation of the resulting enzyme-substrate complex. After a second round of docking the same substrate into the geometry-optimised structures, productive poses are identified by geometric filter criteria and ranked by their docking scores. Substrate-imprinted docking was applied in order to model (i) enantioselectivity of
Candida antarctica
lipase B and a W104A mutant, (ii) enantioselectivity and substrate specificity of
Candida rugosa
lipase and
Burkholderia cepacia
lipase, and (iii) substrate specificity of an acetyl- and a butyrylcholine esterase toward the substrates acetyl- and butyrylcholine.

Conclusion

The experimentally observed differences in selectivity and specificity of the enzymes were reproduced with an accuracy of 81%. The method was robust toward small differences in initial structures (different crystallisation conditions or a co-crystallised ligand), although large displacements of catalytic residues often resulted in substrate poses that did not pass the geometric filter criteria.
A case for using grid architecture for state public health informatics: the Utah perspective
Authors: Staes Catherine J , Xu Wu , LeFevre Samuel D , Price Ronald C , Narus Scott P , Gundlapalli Adi , Rolfs Robert , Nangle Barry , Samore Matthew , Facelli Julio C
Published: June 2009

This paper presents the rationale for designing and implementing the next-generation of public health information systems using grid computing concepts and tools. Our attempt is to evaluate all grid types including data grids for sharing information and computational grids for accessing computational resources on demand. Public health is a broad domain that requires coordinated uses of disparate and heterogeneous information systems. System interoperability in public health is limited. The next-generation public health information systems must overcome barriers to integration and interoperability, leverage advances in information technology, address emerging requirements, and meet the needs of all stakeholders. Grid-based architecture provides one potential technical solution that deserves serious consideration. Within this context, we describe three discrete public health information system problems and the process by which the Utah Department of Health (UDOH) and the Department of Biomedical Informatics at the University of Utah in the United States has approached the exploration for eventual deployment of a Utah Public Health Informatics Grid. These three problems are: i) integration of internal and external data sources with analytic tools and computational resources; ii) provide external stakeholders with access to public health data and services; and, iii) access, integrate, and analyze internal data for the timely monitoring of population health status and health services. After one year of experience, we have successfully implemented federated queries across disparate administrative domains, and have identified challenges and potential solutions concerning the selection of candidate analytic grid services, data sharing concerns, security models, and strategies for reducing expertise required at a public health agency to implement a public health grid.
Losartan counteracts the hyper-reactivity to angiotensin II and ROCK1 over-activation in aortas isolated from streptozotocin-injected diabetic rats
Authors: Failli Paola , Alfarano Chiara , Franchi-Micheli Sergio , Mannucci Edoardo , Cerbai Elisabetta , Mugelli Alessandro , Raimondi Laura
Published: June 2009

Background

In streptozotocin-injected rats (STZ-rats), we previously demonstrated a role for angiotensin II (AT-II) in cardiac remodelling and insulin resistance partially counteracted byin vivotreatment with losartan, an AT-II receptor antagonist.

We now aimed to investigate the effect of treating diabetic STZ-rats with losartan on diabetes vascular response to vasoconstrictors.

Methods

Male Wistar rats were randomly divided in four groups, two of them were assigned to receive losartan in the drinking water (20 mg/kg/day) until the experiment ending (3 weeks afterward). After 1 week, two groups, one of which receiving losartan, were injected in the tail vein with citrate buffer (normoglycemic, N and normoglycemic, losartan-treated, NL). The remaining received a single injection of streptozotocin (50 mg/kg in citrate i.v.) thus becoming diabetic (D) and diabetic losartan-treated (DL). Plasma glycaemia and blood pressure were measured in all animals before the sacrifice (15 days after diabetes induction).

In aortic strips isolated from N, NL, D and DL rats we evaluated i) the isometric concentration-dependent contractile response to phenylephrine (Phe) and to AT-II; ii) the RhoA-kinase (ROCK1) activity and expression by enzyme-immunoassay and Western blot respectively.

Key results

The concentration-dependent contractile effect of Phe was similar in aortas from all groups, whereas at all concentrations tested, AT-II contraction efficacy was 2 and half and 1 and half times higher in D and DL respectively in comparison with N and NL. AT-II contracture was similarly reduced in all groups by AT-II receptor antagonists, irbesartan or irbesartan plus PD123319. HA-1077 (10 μM), an inhibitor of ROCK1 activity, reduced AT-II efficacy (Δmg/mg tissue w.w.) by -3.5 ± 1.0, -4.6 ± 1.9, -22.1 ± 2.2 and -11.4 ± 1.3 in N, NL, D and DL respectively). ROCK1 activity and expression were higher in D than in N/NL and DL aortas.

Conclusion and implications

Aortas isolated from STZ-rats present hyper-contracture to AT-II mainly dependent on the up-regulation of ROCK1 expression/activity. In vivo losartan treatment partially corrects AT-II hyper-contracture, limiting the increase in ROCK1 expression/activity. These data offer a new molecular mechanism supporting the rationale for using losartan in the prevention of diabetic vascular complications.
Combined effects of obesity and type 2 diabetes contribute to increased breast cancer risk in premenopausal women
Authors: Alokail Majed S , Al-Daghri Nasser M , Al-Attas Omar S , Hussain Tajamul
Published: June 2009

Background

Both obesity and type 2 diabetes are among the risk factors for breast cancer development. Combined effect of these metabolic abnormalities on breast cancer risk however, has not been examined in premenopausal women. We tested this association in type 2 diabetic women, categorized as obese, overweight and normal body weight groups based on BMI.

Design and methods

A total of 101 subjects were included in this study. Serum levels of IL-6, TNF-α, C reactive protein, leptin, TGF-α, adiponectin and insulin were measured by ELISA. Data were logarithmically transformed for variables not normally distributed. Analysis of variance with post-hoc Bonferroni was applied to compare the data between the groups. Simple and partial correlation coefficients between the variables were determined and a stepwise multiple linear regression analysis was performed to determine the relationships between the variables of interest.

Results

Significantly increased levels of IL-6, C reactive protein, leptin and significantly decreased levels of adiponectin were found in obese group, while the levels of TNF-α and TGF-α were unaltered. A positive correlation between waist circumference and IL-6 was found in obese group. Similarly, C reactive protein, waist and hip circumferences were linearly correlated with BMI in obese group. Stepwise multiple linear regression analysis revealed several significant predictors for breast cancer risk.

Conclusion

Obesity and type 2 diabetes, owing to their effects on adipocytokines and inflammatory mediators, contribute to increased breast cancer risk in premenopausal women. This study emphasizes healthy life style and better management of these metabolic disorders to avoid the pathogenesis of breast cancer and of other chronic diseases.
Marked differences in CRP genotype frequencies between the Fulani and sympatric ethnic groups in Africa
Authors: Israelsson Elisabeth , Ekström Mattias , Nasr Amre , Dolo Amagana , Kearsley Susannah , Arambepola Gishanthi , Homann Manijeh Vafa , Maiga Bakary , Doumbo Ogobara K , ElGhazali Gehad , Giha Hayder A , Troye-Blomberg Marita , Berzins Klavs , Tornvall Per
Published: June 2009

Background

C-reactive protein (CRP) is an acute phase protein that can activate various immune cells and bind to certain Fcγ receptors. The latter may compete with the binding of IgG antibodies to these receptors and could thereby interfere with the antigen-specific immune response. Polymorphisms in the promoter region of theCRPgene have been strongly associated with the plasma concentration of CRP. The known lower susceptibility to malaria in the Fulani ethnic group, as compared to their sympatric neighbours in Africa, has been linked to different genetic backgrounds. The present study was performed to investigate if polymorphisms in the CRP gene could contribute to the lower susceptibility to malaria seen in the Fulani ethnic group.

Methods

The CRP -717 T>C, -286 C>T>A, and +1444 C>T polymorphisms were analysed in asymptomatic Fulani and non-Fulani individuals from Mali and Sudan using Pyrosequencing T and TaqMan r MGB probes.

Results

The rare -286 A allele, previously shown to be associated with increased CRP expression and plasma levels, was shown to be more frequent in the non-Fulani ethnic groups as compared to the sympatric Fulani ethnic group both in Mali and Sudan. The common -717 T allele was more prevalent in the non-Fulani ethnic group compared to the sympatric Fulani ethnic group, but only in Mali. The parasite prevalence was increased for the -286 A allele, but not for the -717 T allele. No differences regarding genotype frequency or parasite prevalence were seen for +1444 C>T.

Conclusion

This study indicate that CRP may play an important role in the immune responses to malaria, and that the -286 C/T/A CRP polymorphism may be a contributing factor to the lower susceptibility to malaria seen in the Fulani.