An In Vitro Platform to Characterize Myocardial Wound Remodeling

Heart Failure, sometimes called Congestive Heart Failure, is a collection of pathological disruptions in which the heart is unable to pump blood properly. It affects over 6 million people in the United States, with the cost-per-patient at approximately $30,000 and the total cost estimated to be$160 billion by 2030. There is no single cause of heart failure, as it can manifest as a varying array of diseases, disorders, and syndromes. However, many of these underlying diseases result specifically from dysregulation of mechanically active cells called cardiac fibroblasts, which play a critical role in the remodeling of the extracellular matrix and provide a feedback mechanism to control force distributions within the myocardium via stiffening or softening the tissue. These forces, generated by cardiomyocytes, are then altered into one of many unique disease states. Cardiac fibrosis stimulates excessive collagen production, stiffening the ECM and resulting in Left Ventricle hypertrophy. Myocardial Infarction results in a localized region of dominant and activated fibroblasts, greatly upregulating ECM production to protect against loss of healthy tissue and disrupting electrical signaling propagation. The underlying mechanisms of fibroblast-mediated matrix remodeling and its effects on cardiomyocyte force generation are critical to our understanding of cardiovascular diseases. We have developed an in vitro 3D wound platform that can recreate biologically relevant mechanical conditions utilizing cardiac fibroblasts and cardiomyocytes. It does this by precisely balancing matrix stiffness properties, cell distributions, and electrical/mechanical stimulation. With the ability to create healthy left ventricular myocardial tissue, we also show the ability to produce diseased tissues that either mimic the mode of injury (MI) or upregulate fibroblast signaling pathways (cardiac fibrosis) to recreate an appropriate model of each pathology. This provides a unique platform that can create and characterize, with high precision, the biological and mechanical condition of diseased myocardial tissue for use in clinical or drug development applications

“Close but no cigar”: the measurement of corruption

The financial cost of corruption has recently been estimated at more than 5 per cent of global GDP. Yet, despite the widespread agreement that corruption is one of the most pressing policy challenges facing world leaders, it remains as widespread today, possibly even more so, as it was when concerted international attention began being devoted to the issue following the end of the Cold War. In reality, we still have a relatively weak understanding of how best to measure corruption and how to develop effective guides to action from such measurement. This paper provides a detailed review of existing approaches to measuring corruption, focusing in particular on perception-based and non- perceptual approaches. We highlight a gap between the conceptualisation of corruption and its measurement, and argue that there is a tension between the demands of policy-makers and anti-corruption activists on the one hand, and the motivations of academic researchers on the other. The search for actionable answers on the part of the former sits uncomfortably with the latter’s focus on the inherent complexity of corruption

Pulvinar Projections to the Striatum and Amygdala in the Tree Shrew

Visually guided movement is possible in the absence of conscious visual perception, a phenomenon referred to as “blindsight.” Similarly, fearful images can elicit emotional responses in the absence of their conscious perception. Both capabilities are thought to be mediated by pathways from the retina through the superior colliculus (SC) and pulvinar nucleus. To define potential pathways that underlie behavioral responses to unperceived visual stimuli, we examined the projections from the pulvinar nucleus to the striatum and amygdala in the tree shrew (Tupaia belangeri), a species considered to be a prototypical primate. The tree shrew brain has a large pulvinar nucleus that contains two SC-recipient subdivisions; the dorsal (Pd) and central (Pc) pulvinar both receive topographic (“specific”) projections from SC, and Pd receives an additional non-topographic (“diffuse”) projection from SC (Chomsung et al., 2008). Anterograde and retrograde tract tracing revealed that both Pd and Pc project to the caudate and putamen, and Pd, but not Pc, additionally projects to the lateral amygdala. Using immunocytochemical staining for substance P (SP) and parvalbumin (PV) to reveal the patch/matrix organization of tree shrew striatum, we found that SP-rich/PV-poor patches interlock with a PV-rich/SP-poor matrix. Confocal microscopy revealed that tracer-labeled pulvino-striatal terminals preferentially innervate the matrix. Electron microscopy revealed that the postsynaptic targets of tracer-labeled pulvino-striatal and pulvino-amygdala terminals are spines, demonstrating that the pulvinar nucleus projects to the spiny output cells of the striatum matrix and the lateral amygdala, potentially relaying: (1) topographic visual information from SC to striatum to aid in guiding precise movements, and (2) non-topographic visual information from SC to the amygdala alerting the animal to potentially dangerous visual images

Astronomy below the survey threshold in the SKA era

Astronomy at or below the 'survey threshold' has expanded significantly since the publication of the original 'Science with the Square Kilometer Array' in 1999 and its update in 2004. The techniques in this regime may be broadly (but far from exclusively) defined as 'confusion' or 'P(D)' analyses (analyses of one-point statistics), and 'stacking', accounting for the flux-density distribution of noise-limited images co-added at the positions of objects detected/isolated in a different waveband. Here we discuss the relevant issues, present some examples of recent analyses, and consider some of the consequences for the design and use of surveys with the SKA and its pathfinders

CWRML: representing crop wild relative conservation and use data in XML

Background Crop wild relatives are wild species that are closely related to crops. They are valuable as potential gene donors for crop improvement and may help to ensure food security for the future. However, they are becoming increasingly threatened in the wild and are inadequately conserved, both in situ and ex situ. Information about the conservation status and utilisation potential of crop wild relatives is diverse and dispersed, and no single agreed standard exists for representing such information; yet, this information is vital to ensure these species are effectively conserved and utilised. The European Community-funded project, European Crop Wild Relative Diversity Assessment and Conservation Forum, determined the minimum information requirements for the conservation and utilisation of crop wild relatives and created the Crop Wild Relative Information System, incorporating an eXtensible Markup Language (XML) schema to aid data sharing and exchange. Results Crop Wild Relative Markup Language (CWRML) was developed to represent the data necessary for crop wild relative conservation and ensure that they can be effectively utilised for crop improvement. The schema partitions data into taxon-, site-, and population-specific elements, to allow for integration with other more general conservation biology schemata which may emerge as accepted standards in the future. These elements are composed of sub-elements, which are structured in order to facilitate the use of the schema in a variety of crop wild relative conservation and use contexts. Pre-existing standards for data representation in conservation biology were reviewed and incorporated into the schema as restrictions on element data contents, where appropriate. Conclusion CWRML provides a flexible data communication format for representing in situ and ex situ conservation status of individual taxa as well as their utilisation potential. The development of the schema highlights a number of instances where additional standards-development may be valuable, particularly with regard to the representation of population-specific data and utilisation potential. As crop wild relatives are intrinsically no different to other wild plant species there is potential for the inclusion of CWRML data elements in the emerging standards for representation of biodiversity data

MeerKLASS: MeerKAT Large Area Synoptic Survey

We discuss the ground-breaking science that will be possible with a wide area survey, using the MeerKAT telescope, known as MeerKLASS (MeerKAT Large Area Synoptic Survey). The current specifications of MeerKAT make it a great fit for science applications that require large survey speeds but not necessarily high angular resolutions. In particular, for cosmology, a large survey over $\sim 4,000 \, {\rm deg}^2$ for $\sim 4,000$ hours will potentially provide the first ever measurements of the baryon acoustic oscillations using the 21cm intensity mapping technique, with enough accuracy to impose constraints on the nature of dark energy. The combination with multi-wavelength data will give unique additional information, such as exquisite constraints on primordial non-Gaussianity using the multi-tracer technique, as well as a better handle on foregrounds and systematics. Such a wide survey with MeerKAT is also a great match for HI galaxy studies, providing unrivalled statistics in the pre-SKA era for galaxies resolved in the HI emission line beyond local structures at z > 0.01. It will also produce a large continuum galaxy sample down to a depth of about 5\,$\mu$Jy in L-band, which is quite unique over such large areas and will allow studies of the large-scale structure of the Universe out to high redshifts, complementing the galaxy HI survey to form a transformational multi-wavelength approach to study galaxy dynamics and evolution. Finally, the same survey will supply unique information for a range of other science applications, including a large statistical investigation of galaxy clusters as well as produce a rotation measure map across a huge swathe of the sky. The MeerKLASS survey will be a crucial step on the road to using SKA1-MID for cosmological applications and other commensal surveys, as described in the top priority SKA key science projects (abridged).Comment: Larger version of the paper submitted to the Proceedings of Science, "MeerKAT Science: On the Pathway to the SKA", Stellenbosch, 25-27 May 201

A Multiplexed Urinary Biomarker Panel Has Potential for Alzheimer’s Disease Diagnosis Using Targeted Proteomics and Machine Learning

As disease-modifying therapies are now available for Alzheimer’s disease (AD), accessible, accurate and affordable biomarkers to support diagnosis are urgently needed. We sought to develop a mass spectrometry-based urine test as a high-throughput screening tool for diagnosing AD. We collected urine from a discovery cohort (n = 11) of well-characterised individuals with AD (n = 6) and their asymptomatic, CSF biomarker-negative study partners (n = 5) and used untargeted proteomics for biomarker discovery. Protein biomarkers identified were taken forward to develop a high-throughput, multiplexed and targeted proteomic assay which was tested on an independent cohort (n = 21). The panel of proteins identified are known to be involved in AD pathogenesis. In comparing AD and controls, a panel of proteins including MIEN1, TNFB, VCAM1, REG1B and ABCA7 had a classification accuracy of 86%. These proteins have been previously implicated in AD pathogenesis. This suggests that urine-targeted mass spectrometry has potential utility as a diagnostic screening tool in AD

How surgical Trainee Research Collaboratives achieve success: a mixed methods study to develop trainee engagement strategies

OBJECTIVES: This study aimed to understand the role of surgical Trainee Research Collaboratives (TRCs) in conducting randomised controlled trials and identify strategies to enhance trainee engagement in trials. DESIGN: This is a mixed methods study. We used observation of TRC meetings, semi-structured interviews and an online survey to explore trainees' motivations for engagement in trials and TRCs, including barriers and facilitators. Interviews were analysed thematically, alongside observation field notes. Survey responses were analysed using descriptive statistics. Strategies to enhance TRCs were developed at a workshop by 13 trial methodologists, surgical trainees, consultants and research nurses. SETTING: This study was conducted within a secondary care setting in the UK. PARTICIPANTS: The survey was sent to registered UK surgical trainees. TRC members and linked stakeholders across surgical specialties and UK regions were purposefully sampled for interviews. RESULTS: We observed 5 TRC meetings, conducted 32 semi-structured interviews and analysed 73 survey responses. TRCs can mobilise trainees thus gaining wider access to patients. Trainees engaged with TRCs to improve patient care, surgical evidence and to help progress their careers. Trainees valued the TRC infrastructure, research expertise and mentoring. Challenges for trainees included clinical and other priorities, limited time and confidence, and recognition, especially by authorship. Key TRC strategies were consultant support, initial simple rapid studies, transparency of involvement and recognition for trainees (including authorship policies) and working with Clinical Trials Units and research nurses. A 6 min digital story on YouTube disseminated these strategies. CONCLUSION: Trainee surgeons are mostly motivated to engage with trials and TRCs. Trainee engagement in TRCs can be enhanced through building relationships with key stakeholders, maximising multi-disciplinary working and offering training and career development opportunities