Spatiotemporal release of VEGF from biodegradable polylactic-co-glycolic acid microspheres induces angiogenesis in chick chorionic allantoic membrane assay

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.While vascular endothelial growth factor (VEGF) is an acknowledged potent pro-angiogenic agent there is a need to deliver it at an appropriate concentration for several days to achieve angiogenesis. The aim of this study was to produce microspheres of biodegradable polylactic-co-glycolic acid (PLGA) tailored to achieve sustained release of VEGF at an appropriate concentration over seven days, avoiding excessive unregulated release of VEGF that has been associated with the formation of leaky blood vessels. Several formulations were examined to produce microspheres loaded with both human serum albumin (HSA) and VEGF to achieve release of VEGF between 3 and 10 ng per ml for seven days to match the therapeutic window desired for angiogenesis. In vitro experiments showed an increase in endothelial cell proliferation in response to microspheres bearing VEGF. Similarly, when microspheres containing VEGF were added to the chorionic membrane of fertilised chicken eggs, there was an increase in the development of blood vessels over seven days in response, which was significant for microspheres bearing VEGF and HSA, but not VEGF alone. There was an increase in both blood vessel density and branching – both signs of proangiogenic activity. Further, there was clearly migration of cells to the VEGF loaded microspheres. In summary, we describe the development of an injectable delivery vehicle to achieve spatiotemporal release of physiologically relevant levels of VEGF for several days and demonstrate the angiogenic response to this. We propose that such a treatment vehicle would be suitable for the treatment of ischemic tissue or wounds

Radial evolution of sunward strahl electrons in the inner heliosphere

The heliospheric magnetic field (HMF) exhibits local inversions, in which the field apparently “bends back” upon itself. Candidate mechanisms to produce these inversions include various configurations of upstream interchange reconnection; either in the heliosphere, or in the corona where the solar wind is formed. Explaining the source of these inversions, and how they evolve in time and space, is thus an important step towards explaining the origins of the solar wind. Inverted heliospheric magnetic field lines can be identified by the anomalous sunward (i.e. inward) streaming of the typically anti-sunward propagating, field aligned (or anti-aligned), beam of electrons known as the “strahl”. We test if the pitch angle distribution (PAD) properties of sunward-propagating strahl are different from those of outward strahl.We perform a statistical study of strahl observed by the Helios spacecraft, over heliocentric distances spanning ≈ 0.3 – 1 AU. We find that sunward strahl PADs are broader and less intense than their outward directed counterparts; particularly at distances 0.3 – 0.75 AU. This is consistent with sunward strahl being subject to additional, path-length dependent, scattering in comparison to outward strahl.We conclude that the longer and more variable path from the Sun to the spacecraft, along inverted magnetic field, leads to this additional scattering. The results also suggest that the relative importance of scattering along this additional path length drops off with heliocentric distance. These results can be explained by a relatively simple, constant-rate, scattering process

The evolution of inverted magnetic fields through the inner heliosphere

Local inversions are often observed in the heliospheric magnetic field (HMF), but their origins and evolution are not yet fully understood.Parker Solar Probe has recently observed rapid, Alfvénic, HMF inversions in the inner heliosphere, known as ‘switchbacks’, which have been interpreted as the possible remnants of coronal jets. It has also been suggested that inverted HMF may be produced by near-Sun interchange reconnection; a key process in mechanisms proposed for slow solar wind release. These cases suggest that the source of inverted HMF is near the Sun, and it follows that these inversions would gradually decay and straighten as they propagate out through the heliosphere. Alternatively, HMF inversions could form during solar wind transit, through phenomena such velocity shears, draping over ejecta, or waves and turbulence. Such processes are expected to lead to a qualitatively radial evolution of inverted HMF structures. Using Helios measurements spanning 0.3–1 AU, we examine the occurrence rate of inverted HMF, as well as other magnetic field morphologies, as a function of radial distance r, and find that it continually increases. This trend may be explained by inverted HMF observed between 0.3–1 AU being primarily driven by one or more of the above in-transit processes, rather than created at the Sun. We make suggestions as to the relative importance of these different processes based on the evolution of the magnetic field properties associated with inverted HMF. We also explore alternative explanations outside of our suggested driving processes which may lead to the observed trend

How Does a Responsible Leader Win in a Competitive World?

Competitiveness demonstrates a firm’s effectiveness in achieving an advantage over others. A leader’s competitiveness can facilitate higher profits and growth. It can also lead to unethical and irresponsible corporate dealings. This paper suggests competitiveness can be responsible. Responsible Leadership defines two main responsible leaders (RL), integrative and instrumental. Integrators are linked to social responsibility and multiple stakeholders, while Instrumentalists are associated with competitive advantage and shareholders. Missing from extant research frameworks is how the two RLs experience competitiveness. We examined the lived experience of a group of Top 100 Leaders in Canada, finding that both RLs practiced responsible competitiveness. A more nuanced group, they shared characteristics and personal values that seemed to curb the overreach or hyper-competitiveness associated with irresponsibility

Food, pathogen, signal: The multifaceted nature of a bacterial diet

C. elegans, both in the wild and in the lab, live on a diet of live bacteria. The bacterial diet provides nutrients for C. elegans, but can also play a number of other roles in C. elegans physiology. Recently, we compared the effects of different bacterial diets on life history traits and gene expression. Here, we discuss our recent findings in the context of other dietary studies and highlight challenges in understanding dietary effects. For instance, since bacteria can be pathogenic it can be difficult to disentangle pathogenic from dietary effects. Here we summarize different bacterial diets used for C. elegans and how they affect the animal

Parker Solar Probe observations of suprathermal electron flux enhancements originating from coronal hole boundaries

Reconnection between pairs of solar magnetic flux elements, one open and the other a closed loop, is theorised to be a crucial process for both maintaining the structure of the corona and producing the solar wind. This 'interchange reconnection' is expected to be particularly active at the open-closed boundaries of coronal holes (CHs). Previous analysis of solar wind data at 1AU indicated that peaks in the flux of suprathermal electrons at slow-fast stream interfaces may arise from magnetic connection to the CH boundary, rather than dynamic effects such as compression. Further, offsets between the peak and stream interface locations are suggested to be the result of interchange reconnection at the source. As a preliminary test of these suggestions, we analyse two solar wind streams observed during the first Parker Solar Probe (PSP) perihelion encounter, each associated with equatorial CH boundaries (one leading and one trailing with respect to rotation). Each stream features a peak in suprathermal electron flux, the locations and associated plasma properties of which are indicative of a solar origin, in agreement with previous suggestions from 1AU observations. Discrepancies between locations of the flux peaks and other features suggest these peaks may too be shifted by source region interchange reconnection. Our interpretation of each event is compatible with a global pattern of open flux transport, although random footpoint motions or other explanations remain feasible. These exploratory results highlight future opportunities for statistical studies regarding interchange reconnection and flux transport at CH boundaries with modern near-Sun missions

UK-India Centre for Advanced Technology for Minimizing Indiscriminate Use of Antibiotics:"Exploring biology of antibiotic resistance and potential targets for early diagnosis and effective management of infectious diseases”

YesDuring January 15th – 17th, 2017 a group of scientists met, under the auspices of the UK-India Centre for Advanced Technology for Minimizing Indiscriminate Use of Antibiotics, to discuss the further developments and potential solutions to antimicrobial resistance. This was the third work shop under this funding stream held in Hyderabad. The presentations and outcomes of the workshop are released here. Key out comes included the need to address improved treatment and detection of TB, delivery of antimicrobial peptides, potential strategies for combating beta-lactam resistance.Medical Research Counci

Generation of inverted heliospheric magnetic flux by coronal loop opening and slow solar wind release

In situ spacecraft observations provide much-needed constraints on theories of solar wind formation and release, particularly the highly variable slow solar wind, which dominates near-Earth space. Previous studies have shown an association between local inversions in the heliospheric magnetic field (HMF) and solar wind released from the vicinity of magnetically closed coronal structures. We here show that in situ properties of inverted HMF are consistent with the same hot coronal source regions as the slow solar wind. We propose that inverted HMF is produced by solar wind speed shear, which results from interchange reconnection between a coronal loop and open flux tube, and introduces a pattern of fast–slow–fast wind along a given HMF flux tube. This same loop-opening process is thought to be central to slow solar wind formation. The upcoming Parker Solar Probe and Solar Orbiter missions provide a unique opportunity to directly observe these processes and thus determine the origin of the slow solar wind

Tamoxifen, 17beta-oestradiol and the calmodulin antagonist J8 inhibit human melanoma cell invasion through fibronectin.

Invasion through stromal extracellular matrix (ECM) is part of the complex, multistep process of tumour cell invasion and metastasis. Our group has previously demonstrated that calcium and calmodulin are important in another step in the metastatic cascade - that of attachment of cells to ECM. Interestingly, the non-steroidal anti-oestrogen tamoxifen (which also has calmodulin antagonist activity), used in the treatment of breast cancer and now in metastatic cutaneous melanoma, can inhibit the attachment of normal and neoplastic cells to ECM. In this study, we investigated whether such drugs, known to inhibit cell attachment, could also subsequently reduce their invasion through a layer of human fibronectin. We examined the ability of the specific calmodulin antagonist J8, tamoxifen and its two major metabolites, N-desmethyltamoxifen (N-des) and 4-hydroxytamoxifen (4-OH), as well as the pure anti-oestrogen ICI 182,780 and 17beta-oestradiol to inhibit invasion of the human cutaneous melanoma cell line, A375-SM, uveal melanoma cells and uveal melanocytes. A375-SM cells and uveal melanoma cells showed a high level of invasion (15.2% and 33.7% respectively) compared with melanocytes (around 5%) under the experimental conditions used. Submicromolar concentrations of N-des, tamoxifen, J8 and 17beta-oestradiol significantly reduced the invasiveness of the A375-SM cell line. The uveal melanoma cells also showed similar inhibition, although at higher concentrations of these agents. 4-OH and ICI 182, 780 had little or no effect on invasion of A375-SM cells (these were not tested on uveal melanoma cells). All cells used in this study were found to be negative for type I nuclear oestrogen receptors, reinforcing the possibility that tamoxifen and 17beta-oestradiol can act via mechanisms unrelated to binding to classical oestrogen receptors to inhibit tumour cell invasion

Factors of resilience in informal caregivers of people with dementia from integrative international data analysis

Background/Aims: Although caring for a person with dementia can be stressful, some caregivers appear to experience few negative consequences to their well-being. This study aimed to examine what proportion of caregivers demonstrates resilience under different challenging circumstances and to identify factors related to their resilience. Methods: Baseline data from 4 studies from the Netherlands and UK among informal caregivers of people with dementia were harmonized and integrated. Caregiver resilience was defined as high levels of psychological well-being despite different types of high caregiving demands. Multivariate regression analyses identified factors significantly related to caregiver resilience. Results: The integrated data set included 15 harmonized variables with data from 1,048 caregivers facing a high care demand. The prevalence of resilience varied between 35 and 43%, depending on the demand for high care. Being a male caregiver, caring for a female, living apart from your relative, and low caregiver burden were positively related to caregiver resilience. Conclusion: Caregivers have the capacity to demonstrate resilience despite significant challenges. This study demonstrates how harmonization of data from multiple existing studies can be used to increase power and explore the consistency of findings. This contributes to a better understanding of which factors are likely to facilitate caregiver resilience and offers insights for developing services