Growth differentiation factor 9: bone morphogenetic protein 15 synergism and the potential involvement of heterodimerization

LetterDavid G. Mottershead, Craig A. Harrison, Thomas D. Mueller, Peter G. Stanton, Robert B. Gilchrist and Kenneth P. McNatt

Patient satisfaction with community pharmacist-led anticoagulation management services and its relationship with patient characteristics in New Zealand

BACKGROUND: Community pharmacist-led anticoagulation management service (CPAMS) offers international normalised ratio point-of-care testing of warfarin in a community pharmacy setting. It has now expanded with 7,344 patients enrolled in the service across 164 pharmacies in New Zealand. The clinical benefit of CPAMS has been shown to be superior, but patient satisfaction with the service has not been fully explored. OBJECTIVE: To develop a questionnaire to assess patient satisfaction with CPAMS and evaluate its psychometric properties. Additionally, to determine the level of patient satisfaction with CPAMS and identify determinants of satisfaction with CPAMS. Settings 1071 patients enrolled in CPAMS across New Zealand invited to take part in the study. MAIN OUTCOME MEASURE: Satisfaction with CPAMS service. METHODS: Adult patients taking warfarin and currently enrolled in CPAMS were recruited through the national international normalised ratio online system and invited to complete a 36-item survey assessing satisfaction with CPAMS. To identify the most important dimensions of patient satisfaction, exploratory factor analysis was used. Multivariate linear regression models were used to examine the effect of independent variables on patient satisfaction. RESULTS: A total of 305 patients completed the survey. The mean overall satisfaction score was 94.5% ± 13.1 out of maximum possible points. Five dimensions of patient satisfaction were identified by factor analysis: patient-centred communication, confidence in pharmacist competence, patient-pharmacist relationship, confidence in CPAMS, and pharmacy environment. Being older and more frequent visits to a pharmacy were positively associated with patient satisfaction. Living more than 1 km away from a pharmacy, and ‘poor’ self-perceived health status were negative predictors of patient satisfaction. Being Māori or of other ethnic minority was also associated with lower satisfaction scores, exploratory analysis suggests patient-pharmacist relationship is an important driver of these differences. CONCLUSIONS: The high level of patient satisfaction further supports the effectiveness of CPAMS as a delivery model. Patient satisfaction is affected by age, frequency of pharmacy visits, ethnicity, travel distance to pharmacy, and perceived health status. Policy makers and practitioners should consider the characteristics of patients with low levels of satisfaction to improve and enhance CPAMS engagement

The 18 kDa translocator protein, microglia and neuroinflammation

The 18 kDa translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, is expressed in the injured brain. It has become known as an imaging marker of “neuroinflammation” indicating active disease, and is best interpreted as a nondiagnostic biomarker and disease staging tool that refers to histopathology rather than disease etiology. The therapeutic potential of TSPO as a drug target is mostly based on the understanding that it is an outer mitochondrial membrane protein required for the translocation of cholesterol, which thus regulates the rate of steroid synthesis. This pivotal role together with the evolutionary conservation of TSPO has underpinned the belief that any loss or mutation of TSPO should be associated with significant physiological deficits or be outright incompatible with life. However, against prediction, full Tspo knockout mice are viable and across their lifespan do not show the phenotype expected if cholesterol transport and steroid synthesis were significantly impaired. Thus, the “translocation” function of TSPO remains to be better substantiated. Here, we discuss the literature before and after the introduction of the new nomenclature for TSPO and review some of the newer findings. In light of the controversy surrounding the function of TSPO, we emphasize the continued importance of identifying compounds with confirmed selectivity and suggest that TSPO expression is analyzed within specific disease contexts rather than merely equated with the reified concept of “neuroinflammation.” © 2014 The Authors© 2014 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited

An optimized TOPS+ comparison method for enhanced TOPS models

This article has been made available through the Brunel Open Access Publishing Fund.Background Although methods based on highly abstract descriptions of protein structures, such as VAST and TOPS, can perform very fast protein structure comparison, the results can lack a high degree of biological significance. Previously we have discussed the basic mechanisms of our novel method for structure comparison based on our TOPS+ model (Topological descriptions of Protein Structures Enhanced with Ligand Information). In this paper we show how these results can be significantly improved using parameter optimization, and we call the resulting optimised TOPS+ method as advanced TOPS+ comparison method i.e. advTOPS+. Results We have developed a TOPS+ string model as an improvement to the TOPS [1-3] graph model by considering loops as secondary structure elements (SSEs) in addition to helices and strands, representing ligands as first class objects, and describing interactions between SSEs, and SSEs and ligands, by incoming and outgoing arcs, annotating SSEs with the interaction direction and type. Benchmarking results of an all-against-all pairwise comparison using a large dataset of 2,620 non-redundant structures from the PDB40 dataset [4] demonstrate the biological significance, in terms of SCOP classification at the superfamily level, of our TOPS+ comparison method. Conclusions Our advanced TOPS+ comparison shows better performance on the PDB40 dataset [4] compared to our basic TOPS+ method, giving 90 percent accuracy for SCOP alpha+beta; a 6 percent increase in accuracy compared to the TOPS and basic TOPS+ methods. It also outperforms the TOPS, basic TOPS+ and SSAP comparison methods on the Chew-Kedem dataset [5], achieving 98 percent accuracy. Software Availability: The TOPS+ comparison server is available at http://balabio.dcs.gla.ac.uk/mallika/WebTOPS/.This article is available through the Brunel Open Access Publishing Fun

Simulating quantum statistics with entangled photons: a continuous transition from bosons to fermions

In contrast to classical physics, quantum mechanics divides particles into two classes-bosons and fermions-whose exchange statistics dictate the dynamics of systems at a fundamental level. In two dimensions quasi-particles known as 'anyons' exhibit fractional exchange statistics intermediate between these two classes. The ability to simulate and observe behaviour associated to fundamentally different quantum particles is important for simulating complex quantum systems. Here we use the symmetry and quantum correlations of entangled photons subjected to multiple copies of a quantum process to directly simulate quantum interference of fermions, bosons and a continuum of fractional behaviour exhibited by anyons. We observe an average similarity of 93.6\pm0.2% between an ideal model and experimental observation. The approach generalises to an arbitrary number of particles and is independent of the statistics of the particles used, indicating application with other quantum systems and large scale application.Comment: 10 pages, 5 figure

Comparing the Effect of Concept Mapping and Conventional Methods on Nursing Students' Practical Skill Score

Background: Development of practical skills in the field of nursing education has remained a serious and considerable challenge in nursing education. Moreover, newly graduated nurses may have weak practical skills, which can be a threat to patients’ safety. Objectives: The present study was conducted to compare the effect of concept mapping and conventional methods on nursing students’ practical skills. Patients and Methods: This quasi-experimental study was conducted on 70 nursing students randomly assigned into two groups of 35 people. The intervention group was taught through concept mapping method, while the control group was taught using conventional method. A two-part instrument was used including a demographic information form and a checklist for direct observation of procedural skills. Descriptive statistics, chi-square, independent samples t-tests and paired t-test were used to analyze data. Results: Before education, no significant differences were observed between the two groups in the three skills of cleaning (P = 0.251), injection (P = 0.185) and sterilizing (P = 0.568). The students mean scores were significantly increased after the education and the difference between pre and post intervention of students mean scores were significant in the both groups (P < 0.001). However, after education, in all three skills the mean scores of the intervention group were significantly higher than the control group (P < 0.001). Conclusions: Concept mapping was superior to conventional skill teaching methods. It is suggested to use concept mapping in teaching practical courses such as fundamentals of nursing

Cumulin, an Oocyte-secreted Heterodimer of the Transforming Growth Factor-β Family, Is a Potent Activator of Granulosa Cells and Improves Oocyte Quality

Growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) are oocyte-specific growth factors with central roles in mammalian reproduction, regulating species-specific fecundity, ovarian follicular somatic cell differentiation, and oocyte quality. In the human, GDF9 is produced in a latent form, the mechanism of activation being an open question. Here, we produced a range of recombinant GDF9 and BMP15 variants, examined their in silico and physical interactions and their effects on ovarian granulosa cells (GC) and oocytes. We found that the potent synergistic actions of GDF9 and BMP15 on GC can be attributed to the formation of a heterodimer, which we have termed cumulin. Structural modeling of cumulin revealed a dimerization interface identical to homodimeric GDF9 and BMP15, indicating likely formation of a stable complex. This was confirmed by generation of recombinant heterodimeric complexes of pro/mature domains (pro-cumulin) and covalent mature domains (cumulin). Both pro-cumulin and cumulin exhibited highly potent bioactivity on GC, activating both SMAD2/3 and SMAD1/5/8 signaling pathways and promoting proliferation and expression of a set of genes associated with oocyte-regulated GC differentiation. Cumulin was more potent than pro-cumulin, pro-GDF9, pro-BMP15, or the two combined on GC. However, on cumulus-oocyte complexes, pro-cumulin was more effective than all other growth factors at notably improving oocyte quality as assessed by subsequent day 7 embryo development. Our results support a model of activation for human GDF9 dependent on cumulin formation through heterodimerization with BMP15. Oocyte-secreted cumulin is likely to be a central regulator of fertility in mono-ovular mammals

Meeple Centred Design: A Heuristic Toolkit for Evaluating the Accessibility of Tabletop Games

Evaluation of accessibility within a tabletop context is much more complicated than it is within a video game environment. There is a considerable amount of variation in game systems, game mechanisms, and interaction regimes. Games may be entirely verbal, or completely non-verbal. They might be real-time or turn based, or based on simultaneous actions. They can be competitive or co-operative, or shift from one to the other during a single game session. They might involve visual pattern recognition or force players to memorise game state without visual cues. They may involve touch, or smell. They might involve social deduction or betrayal. They can encompass all sensory faculties, in differing degrees. Almost all games have accessibility considerations that should be taken into account, but there is currently no comprehensive tool by which this can be done that encompasses the rich variety of tabletop gaming interaction metaphors. In this paper, the authors discuss the heuristic lens that is used by the Meeple Centred Design tabletop accessibility project. This is a tool that has been applied to one hundred and sixteen games to date, and the full results of these have been published for analysis and consideration within the wider tabletop gaming community

Dynamic cerebral autoregulation after intracerebral hemorrhage: A case-control study

<p>Abstract</p> <p>Background</p> <p>Dynamic cerebral autoregulation after intracerebral hemorrhage (ICH) remains poorly understood. We performed a case-control study to compare dynamic autoregulation between ICH patients and healthy controls.</p> <p>Methods</p> <p>Twenty-one patients (66 ± 15 years) with early (< 72 hours) lobar or basal ganglia ICH were prospectively studied and compared to twenty-three age-matched controls (65 ± 9 years). Continuous measures of mean flow velocity (MFV) in the middle cerebral artery and mean arterial blood pressure (MAP) were obtained over 5 min. Cerebrovascular resistance index (CVR_i) was calculated as the ratio of MAP to MFV. Dynamic cerebral autoregulation was assessed using transfer function analysis of spontaneous MAP and MFV oscillations in the low (0.03-0.15 Hz) and high (0.15-0.5 Hz) frequency ranges.</p> <p>Results</p> <p>The ICH group demonstrated higher CVR_icompared to controls (ipsilateral: 1.91 ± 1.01 mmHg·s·cm^-1, <it>p </it>= 0.04; contralateral: 2.01 ± 1.24 mmHg·s·cm^-1, <it>p </it>= 0.04; vs. control: 1.42 ± 0.45 mmHg·s·cm^-1). The ICH group had higher gains than controls in the low (ipsilateral: 1.33 ± 0.58%/mmHg, <it>p </it>= 0.0005; contralateral: 1.47 ± 0.98%/mmHg, <it>p </it>= 0.004; vs. control: 0.82 ± 0.30%/mmHg) and high (ipsilateral: 2.11 ± 1.31%/mmHg, <it>p </it>< 0.0001; contralateral: 2.14 ± 1.49%/mmHg, <it>p </it>< 0.0001; vs. control: 0.66 ± 0.26%/mmHg) frequency ranges. The ICH group also had higher coherence in the contralateral hemisphere than the control (ICH contralateral: 0.53 ± 0.38, <it>p </it>= 0.02; vs. control: 0.38 ± 0.15) in the high frequency range.</p> <p>Conclusions</p> <p>Patients with ICH had higher gains in a wide range of frequency ranges compared to controls. These findings suggest that dynamic cerebral autoregulation may be less effective in the early days after ICH. Further study is needed to determine the relationship between hematoma size and severity of autoregulation impairment.</p

Identification and Localization of Proteins Associated with Biomineralization in the Iron Deposition Vesicles of Honeybees (Apis mellifera)

Honeybees (Apis mellifera) form superparamagnetic magnetite to act as a magnetoreceptor for magnetoreception. Biomineralization of superparamagnetic magnetite occurs in the iron deposition vesicles of trophocytes. Even though magnetite has been demonstrated, the mechanism of magnetite biomineralization is unknown. In this study, proteins in the iron granules and iron deposition vesicles of trophocytes were purified and identified by mass spectrometry. Antibodies against such proteins were produced. The major proteins include actin, myosin, ferritin 2, and ATP synthase. Immunolabeling and co-immunoprecipitation studies suggest that iron is stored in ferritin 2 for the purpose of forming 7.5-nm diameter iron particles and that actin-myosin-ferritin 2 may serve as a transporter system. This system, along with calcium and ATP, conveys the iron particles (ferritin) to the center of iron deposition vesicles for iron granules formation. These proteins and reactants are included in iron deposition vesicles during the formation of iron deposition vesicles from the fusion of smooth endoplasmic reticulum. A hypothetical model for magnetite biomineralization in iron deposition vesicles is proposed for honeybees