Distal retinal ganglion cell axon transport loss and activation of p38 MAPK stress pathway following VEGF-A antagonism.

There is increasing evidence that VEGF-A antagonists may be detrimental to neuronal health following ocular administration. Here we investigated firstly the effects of VEGF-A neutralization on retinal neuronal survival in the Ins2(Akita) diabetic and JR5558 spontaneous choroidal neovascularization (CNV) mice, and then looked at potential mechanisms contributing to cell death. We detected elevated apoptosis in the ganglion cell layer in both these models following VEGF-A antagonism, indicating that even when vascular pathologies respond to treatment, neurons are still vulnerable to reduced VEGF-A levels. We observed that retinal ganglion cells (RGCs) seemed to be the cells most susceptible to VEGF-A antagonism, so we looked at anterograde transport in these cells, due to their long axons requiring optimal protein and organelle trafficking. Using cholera toxin B-subunit tracer studies, we found a distal reduction in transport in the superior colliculus following VEGF-A neutralization, which occurred prior to net RGC loss. This phenomenon of distal transport loss has been described as a feature of early pathological changes in glaucoma, Alzheimer's and Parkinson's disease models. Furthermore, we observed increased phosphorylation of p38 MAPK and downstream Hsp27 stress pathway signaling in the retinas from these experiments, potentially providing a mechanistic explanation for our findings. These experiments further highlight the possible risks of using VEGF-A antagonists to treat ocular neovascular disease, and suggest that VEGF-A may contribute to the maintenance and function of axonal transport in neurons of the retina.This work was funded by the Medical Research Council (G0901303) of the UK. We also wish to thank the Cambridge Eye Trust for their support.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/cddis.2016.11

Multi-Zone Modeling of The Pulsar Wind Nebula HESS J1825-137

The pulsar wind nebula associated with PSR J1826-1334, HESS J1825-137, is a bright very high energy source with an angular extent of ~1 degree and spatially-resolved spectroscopic TeV measurements. The gamma-ray spectral index is observed to soften with increasing distance from the pulsar, likely the result of cooling losses as electrons traverse the nebula. We describe analysis of X-ray data of the extended nebula, as well as 3-D time-dependent spectral energy distribution modeling, with emphasis on the spatial variations within HESS J1825-137. The multi-wavelength data places significant constraints on electron injection, transport, and cooling within the nebula. The large size and high nebular energy budget imply a relatively rapid initial pulsar spin period of 13 \pm 7 ms and an age of 40 \pm 9 kyr. The relative fluxes of each VHE zone can be explained by advective particle transport with a radially decreasing velocity profile with $v(r) \propto r^{-0.5}$. The evolution of the cooling break requires an evolving magnetic field which also decreases radially from the pulsar, $B(r,t) \propto r^{-0.7} \dot{E}(t)^{1/2}$. Detection of 10 TeV flux ~80 pc from the pulsar requires rapid diffusion of high energy particles with $\tau_{esc} \approx 90 (R / 10 pc)^2 (E_e/100 TeV)^{-1}$ year, contrary to the common assumption of toroidal magnetic fields with strong magnetic confinement. The model predicts a rather uniform Fermi LAT surface brightness out to ~1 degree from the pulsar, in good agreement with the recently discovered LAT source centered 0.5 degree southwest of PSR J1826-1334 with extension 0.6 \pm 0.1 degree.Comment: Updated to published versio

Argumentation in school science : Breaking the tradition of authoritative exposition through a pedagogy that promotes discussion and reasoning

The value of argumentation in science education has become internationally recognised and has been the subject of many research studies in recent years. Successful introduction of argumentation activities in learning contexts involves extending teaching goals beyond the understanding of facts and concepts, to include an emphasis on cognitive and metacognitive processes, epistemic criteria and reasoning. The authors focus on the difficulties inherent in shifting a tradition of teaching from one dominated by authoritative exposition to one that is more dialogic, involving small-group discussion based on tasks that stimulate argumentation. The paper builds on previous research on enhancing the quality of argument in school science, to focus on how argumentation activities have been designed, with appropriate strategies, resources and modelling, for pedagogical purposes. The paper analyses design frameworks, their contexts and lesson plans, to evaluate their potential for enhancing reasoning through foregrounding the processes of argumentation. Examples of classroom dialogue where teachers adopt the frameworks/plans are analysed to show how argumentation processes are scaffolded. The analysis shows that several layers of interpretation are needed and these layers need to be aligned for successful implementation. The analysis serves to highlight the potential and limitations of the design frameworks

Dimensionality and dynamics in the behavior of C. elegans

A major challenge in analyzing animal behavior is to discover some underlying simplicity in complex motor actions. Here we show that the space of shapes adopted by the nematode C. elegans is surprisingly low dimensional, with just four dimensions accounting for 95% of the shape variance, and we partially reconstruct "equations of motion" for the dynamics in this space. These dynamics have multiple attractors, and we find that the worm visits these in a rapid and almost completely deterministic response to weak thermal stimuli. Stimulus-dependent correlations among the different modes suggest that one can generate more reliable behaviors by synchronizing stimuli to the state of the worm in shape space. We confirm this prediction, effectively "steering" the worm in real time.Comment: 9 pages, 6 figures, minor correction

The role of multiple marks in epigenetic silencing and the emergence of a stable bivalent chromatin state

We introduce and analyze a minimal model of epigenetic silencing in budding yeast, built upon known biomolecular interactions in the system. Doing so, we identify the epigenetic marks essential for the bistability of epigenetic states. The model explicitly incorporates two key chromatin marks, namely H4K16 acetylation and H3K79 methylation, and explores whether the presence of multiple marks lead to a qualitatively different systems behavior. We find that having both modifications is important for the robustness of epigenetic silencing. Besides the silenced and transcriptionally active fate of chromatin, our model leads to a novel state with bivalent (i.e., both active and silencing) marks under certain perturbations (knock-out mutations, inhibition or enhancement of enzymatic activity). The bivalent state appears under several perturbations and is shown to result in patchy silencing. We also show that the titration effect, owing to a limited supply of silencing proteins, can result in counter-intuitive responses. The design principles of the silencing system is systematically investigated and disparate experimental observations are assessed within a single theoretical framework. Specifically, we discuss the behavior of Sir protein recruitment, spreading and stability of silenced regions in commonly-studied mutants (e.g., sas2, dot1) illuminating the controversial role of Dot1 in the systems biology of yeast silencing.Comment: Supplementary Material, 14 page

Exploring nursing students’ perceptions on usefulness, ease of use, and acceptability of using a simulated Electronic Medical Record: A descriptive study

Background: Modernisation in the healthcare landscape has seen the spread of the integration of health information technology to replace paper-based systems with electronic medical record systems. Although this technology has become accessible in most health care settings globally, its adoption into nursing school curricula as a teaching tool and learning strategy is slow. Universities are now faced with a number of challenges to ensure nursing and midwifery students are well equipped to use this new technology upon graduation and to determine how best to integrate this new technology into undergraduate health education curricula. Objective: The purpose of this study was to develop an Interactive Simulated Electronic Medical Record (ISEMR) as a learning tool and assess students’ acceptability and intention to use the tool in their nursing education. Methods: A quantitative descriptive study was conducted in the cohort of second-year undergraduate nursing students enrolled in a clinical course in a Bachelor of Nursing program in Australia. This study was guided by the Technology Acceptance Model (TAM). Data were collected over one semester using a validated questionnaire to measure the students’ perceived ease of use, perceived usefulness, intention to use, and acceptability. Results: Of the 530 students enrolled in the course, 433 (82%) participated in the study. In accordance with the TAM the findings showed that perceived usefulness of the ISEMR in providing learning and experience for the future was significant in determining students’ intention to use it. Students who perceived the ISEMR easy to use were more likely to perceive usefulness. Conclusion: Integrating the Electronic Medical Record into the nursing curriculum will be beneficial in providing undergraduate nursing students with the opportunity to enhance critical thinking, improve documentation and enhance understanding and nursing skill. Findings from this study will drive learning and teaching approaches that will lead to growth in capability with health information technology

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Chirality transfer in metal-­‐catalysed intermolecular addition reactions involving allenes

Allene chemistry in the presence of transition metal complexes is nowadays a very important topic that underpins many challenges and advances in organic synthesis. The amount of research articles covering new transformations of allenes is vast and the development of enantioselective reactions involving allenes has flourished in the last 10-15 years. In this review we cover three important topics in allene chemistry that we feel are timely appropriate for this special issue celebrating the work of Prof Trost: the metal-catalysed reactions involving chirality transfer from chiral allenes to products; the analysis of the possible racemization processes that have been observed in the interaction of some metals with allenes; and the chirality transfer using racemic allenes in reactions catalysed by metal complexes bearing chiral ligands to produce enantioriched products. We have focussed the review on intermolecular addition reactions as they are still much less explored than the intramolecular version

Game Theoretical Analysis of a Multi-MNO MVNO Business Model in 5G Networks

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