How Blood Vessel Networks Are Made and Measured

Tissue and organ viability depends on the proper systemic distribution of cells, nutrients, and oxygen through blood vessel networks. These networks arise in part via angiogenic sprouting. Vessel sprouting involves the precise coordination of several endothelial cell processes including cell-cell communication, cell migration, and proliferation. In this review, we discuss zebrafish and mammalian models of blood vessel sprouting and the quantification methods used to assess vessel sprouting and network formation in these models. We also review the mechanisms involved in angiogenic sprouting, and we propose that the process consists of distinct stages. Sprout initiation involves endothelial cell interactions with neighboring cells and the environment to establish a specialized tip cell responsible for leading the emerging sprout. Furthermore, local sprout guidance cues that spatially regulate this outward migration are discussed. We also examine subsequent events, such as sprout fusion and lumenization, that lead to maturation of a nascent sprout into a patent blood vessel

Regulation of blood vessel sprouting

Blood vessels are essential conduits of nutrients and oxygen throughout the body. The formation of these vessels involves angiogenic sprouting, a complex process entailing highly integrated cell behaviors and signaling pathways. In this review, we discuss how endothelial cells initiate a vessel sprout through interactions with their environment and with one another, particularly through lateral inhibition. We review the composition of the local environment, which contains an initial set of guidance cues to facilitate the proper outward migration of the sprout as it emerges from a parent vessel. The long-range guidance and sprout stability cues provided by soluble molecules, extracellular matrix components, and interactions with other cell types are also discussed. We also examine emerging evidence for mechanisms that govern sprout fusion with its target and lumen formation

Distributed System Contract Monitoring

The use of behavioural contracts, to specify, regulate and verify systems, is particularly relevant to runtime monitoring of distributed systems. System distribution poses major challenges to contract monitoring, from monitoring-induced information leaks to computation load balancing, communication overheads and fault-tolerance. We present mDPi, a location-aware process calculus, for reasoning about monitoring of distributed systems. We define a family of Labelled Transition Systems for this calculus, which allow formal reasoning about different monitoring strategies at different levels of abstractions. We also illustrate the expressivity of the calculus by showing how contracts in a simple contract language can be synthesised into different mDPi monitors.Comment: In Proceedings FLACOS 2011, arXiv:1109.239

Novel polyvinylpyrrolidones to improve delivery of poorly-water soluble drugs; from design to synthesis and evaluation

Polyvinylpyrrolidone is a widely used in tablet formulations with the linear form acting as a wetting agent and disintegrant whereas the cross-linked form is a super-disintegrant. We have previously reported that simply mixing the commercial cross-linked polymer with ibuprofen disrupted drug crystallinity with consequent improvements in drug dissolution behavior. In this study, we have designed and synthesized novel cross-linking agents containing a range of oligoether moieties which have then be polymerized with vinylpyrrolidone to generate a suite of novel excipients with enhanced hydrogen-bonding capabilities. The polymers have a porous surface and swell in most common solvents and in water; properties which suggest their value as disintegrants. The polymers were evaluated in simple physical mixtures with ibuprofen as a model poorly-water soluble drug. The results show that the novel PVPs induce the drug to become “X-ray amorphous”, which increased dissolution to a greater extent than that seen with commercial cross-linked PVP. The polymers stabilize the amorphous drug with no evidence for recrystallization seen after 20 weeks storage

Partisan Profiles in Presidential Policies: an Extension of Presidential Preferences for Inflation versus Unemployment

In a recent article, Zaleski does not find any clear difference between the political preferences of Republican and Democratic administrations with respect to the choice between unemployment and inflation. This paper provides empirical support for the opposite conclusion in a generalization of Zaleski's approach allowing for instrument costs

Evidence and recommendations on the use of telemedicine for the management of arterial hypertension:an international expert position paper

Telemedicine allows the remote exchange of medical data between patients and healthcare professionals. It is used to increase patients’ access to care and provide effective healthcare services at a distance. During the recent coronavirus disease 2019 (COVID-19) pandemic, telemedicine has thrived and emerged worldwide as an indispensable resource to improve the management of isolated patients due to lockdown or shielding, including those with hypertension. The best proposed healthcare model for telemedicine in hypertension management should include remote monitoring and transmission of vital signs (notably blood pressure) and medication adherence plus education on lifestyle and risk factors, with video consultation as an option. The use of mixed automated feedback services with supervision of a multidisciplinary clinical team (physician, nurse, or pharmacist) is the ideal approach. The indications include screening for suspected hypertension, management of older adults, medically underserved people, high-risk hypertensive patients, patients with multiple diseases, and those isolated due to pandemics or national emergencies

Schizont transcriptome variation among clinical isolates and laboratory-adapted clones of the malaria parasite Plasmodium falciparum

Background: Malaria parasites are genetically polymorphic and phenotypically plastic. In studying transcriptome variation among parasites from different infections, it is challenging to overcome potentially confounding technical and biological variation between samples. We investigate variation in the major human parasite Plasmodium falciparum, generating RNA-seq data on multiple independent replicate sample preparations of merozoite-containing intra-erythrocytic schizonts from a panel of clinical isolates and from long-term laboratory-adapted clones, with a goal of robustly identifying differentially expressed genes. Results: Analysis of biological sample replicates shows that increased numbers improve the true discovery rate of differentially expressed genes, and that six independent replicates of each parasite line allowed identification of most differences that could be detected with larger numbers. For highly expressed genes, focusing on the top quartile at schizont stages, there was more power to detect differences. Comparing cultured clinical isolates and laboratory-adapted clones, genes more highly expressed in the laboratory-adapted clones include those encoding an AP2 transcription factor (PF3D7_0420300), a ubiquitin-binding protein and two putative methyl transferases. In contrast, higher expression in clinical isolates was seen for the merozoite surface protein gene dblmsp2, proposed to be a marker of schizonts forming merozoites committed to sexual differentiation. Variable expression was extremely strongly, but not exclusively, associated with genes known to be targeted by Heterochromatin Protein 1. Clinical isolates show variable expression of several known merozoite invasion ligands, as well as other genes for which new RT-qPCR assays validate the quantitation and allow characterisation in samples with more limited material. Expression levels of these genes vary among schizont preparations of different clinical isolates in the first ex vivo cycle in patient erythrocytes, but mean levels are similar to those in continuously cultured clinical isolates. Conclusions: Analysis of multiple biological sample replicates greatly improves identification of genes variably expressed between different cultured parasite lines. Clinical isolates recently established in culture show differences from long-term adapted clones in transcript levels of particular genes, and are suitable for analyses requiring biological replicates to understand parasite phenotypes and variable expression likely to be relevant in nature

Multifractal Scaling, Geometrical Diversity, and Hierarchical Structure in the Cool Interstellar Medium

Multifractal scaling (MFS) refers to structures that can be described as a collection of interwoven fractal subsets which exhibit power-law spatial scaling behavior with a range of scaling exponents (concentration, or singularity, strengths) and dimensions. The existence of MFS implies an underlying multiplicative (or hierarchical, or cascade) process. Panoramic column density images of several nearby star- forming cloud complexes, constructed from IRAS data and justified in an appendix, are shown to exhibit such multifractal scaling, which we interpret as indirect but quantitative evidence for nested hierarchical structure. The relation between the dimensions of the subsets and their concentration strengths (the "multifractal spectrum'') appears to satisfactorily order the observed regions in terms of the mixture of geometries present: strong point-like concentrations, line- like filaments or fronts, and space-filling diffuse structures. This multifractal spectrum is a global property of the regions studied, and does not rely on any operational definition of "clouds.'' The range of forms of the multifractal spectrum among the regions studied implies that the column density structures do not form a universality class, in contrast to indications for velocity and passive scalar fields in incompressible turbulence, providing another indication that the physics of highly compressible interstellar gas dynamics differs fundamentally from incompressible turbulence. (Abstract truncated)Comment: 27 pages, (LaTeX), 13 figures, 1 table, submitted to Astrophysical Journa

Development and Application of Ultra-Performance Liquid Chromatography-TOF MS for Precision Large Scale Urinary Metabolic Phenotyping

To better understand the molecular mechanisms underpinning physiological variation in human populations, metabolic phenotyping approaches are increasingly being applied to studies involving hundreds and thousands of biofluid samples. Hyphenated ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) has become a fundamental tool for this purpose. However, the seemingly inevitable need to analyze large studies in multiple analytical batches for UPLC-MS analysis poses a challenge to data quality which has been recognized in the field. Herein, we describe in detail a fit-for-purpose UPLC-MS platform, method set, and sample analysis workflow, capable of sustained analysis on an industrial scale and allowing batch-free operation for large studies. Using complementary reversed-phase chromatography (RPC) and hydrophilic interaction liquid chromatography (HILIC) together with high resolution orthogonal acceleration time-of-flight mass spectrometry (oaTOF-MS), exceptional measurement precision is exemplified with independent epidemiological sample sets of approximately 650 and 1000 participant samples. Evaluation of molecular reference targets in repeated injections of pooled quality control (QC) samples distributed throughout each experiment demonstrates a mean retention time relative standard deviation (RSD) of <0.3% across all assays in both studies and a mean peak area RSD of <15% in the raw data. To more globally assess the quality of the profiling data, untargeted feature extraction was performed followed by data filtration according to feature intensity response to QC sample dilution. Analysis of the remaining features within the repeated QC sample measurements demonstrated median peak area RSD values of <20% for the RPC assays and <25% for the HILIC assays. These values represent the quality of the raw data, as no normalization or feature-specific intensity correction was applied. While the data in each experiment was acquired in a single continuous batch, instances of minor time-dependent intensity drift were observed, highlighting the utility of data correction techniques despite reducing the dependency on them for generating high quality data. These results demonstrate that the platform and methodology presented herein is fit-for-use in large scale metabolic phenotyping studies, challenging the assertion that such screening is inherently limited by batch effects. Details of the pipeline used to generate high quality raw data and mitigate the need for batch correction are provided