A bioprinted cardiac patch composed of cardiac-specific extracellular matrix and progenitor cells for heart repair

Congenital heart defects are present in 8 of 1000 newborns and palliative surgical therapy has increased survival. Despite improved outcomes, many children develop reduced cardiac function and heart failure requiring transplantation. Human cardiac progenitor cell (hCPC) therapy has potential to repair the pediatric myocardium through release of reparative factors, but therapy suffers from limited hCPC retention and functionality. Decellularized cardiac extracellular matrix hydrogel (cECM) improves heart function in animals, and human trials are ongoing. In the present study, a 3D-bioprinted patch containing cECM for delivery of pediatric hCPCs is developed. Cardiac patches are printed with bioinks composed of cECM, hCPCs, and gelatin methacrylate (GelMA). GelMA-cECM bioinks print uniformly with a homogeneous distribution of cECM and hCPCs. hCPCs maintain >75% viability and incorporation of cECM within patches results in a 30-fold increase in cardiogenic gene expression of hCPCs compared to hCPCs grown in pure GelMA patches. Conditioned media from GelMA-cECM patches show increased angiogenic potential (>2-fold) over GelMA alone, as seen by improved endothelial cell tube formation. Finally, patches are retained on rat hearts and show vascularization over 14 d in vivo. This work shows the successful bioprinting and implementation of cECM-hCPC patches for potential use in repairing damaged myocardium

Receptor-Independent Interaction of Bacterial Lipopolysaccharide with Lipid and Lymphocyte Membranes; the Role of Cholesterol

Lipopolysaccharide (LPS) is a major constituent of bacterial outer membranes where it makes up the bulk of the outer leaflet and plays a key role as determinant of bacterial interactions with the host. Membrane-free LPS is known to activate T-lymphocytes through interactions with Toll-like receptor 4 via multiprotein complexes. In the present study, we investigate the role of cholesterol and membrane heterogeneities as facilitators of receptor-independent LPS binding and insertion, which underpin bacterial interactions with the host in symbiosis, pathogenesis and cell invasion. We use fluorescence spectroscopy to investigate the interactions of membrane-free LPS from intestinal Gram-negative organisms with cholesterol-containing model membranes and with T-lymphocytes. LPS preparations from Klebsiella pneumoniae and Salmonella enterica were found to bind preferentially to mixed lipid membranes by comparison to pure PC bilayers. The same was observed for LPS from the symbiote Escherichia coli but with an order of magnitude higher dissociation constant. Insertion of LPS into model membranes confirmed the preference for sphimgomyelin/cholesterol-containing systems. LPS insertion into Jurkat T-lymphocyte membranes reveals that they have a significantly greater LPS-binding capacity by comparison to methyl-β-cyclodextrin cholesterol-depleted lymphocyte membranes, albeit at slightly lower binding rates

Intrauterine exposure to preeclampsia does not impair vascular health in children

Background and objectives: Preeclampsia is a serious multisystem blood pressure disorder during pregnancy that is associated with increased long-term risk of cardiovascular disease to the mother and offspring. We investigated the vascular health of children exposed to intrauterine preeclampsia. Materials and methods: This was a cross-sectional study of offspring in a prospective cohort of women with complications during pregnancy. Children aged between 2 and 5 years [median age 4.7 (2.8, 5.1) years] exposed to intrauterine preeclampsia (n = 26) or normotensive controls (n = 34), were recruited between July 2020 and April 2021. Vascular health was assessed by measuring aortic intima-media thickness and pulse wave velocity. Univariate generalized linear regression models were used to explore associations between vascular measurements and explanatory variables. Results: Children exposed to preeclampsia had a lower body mass index at assessment (15.5 vs. 16.2 kg/m2, p = 0.04), birth weight (2.90 vs. 3.34 kg, p = 0.004), gestational age at birth (37.5 vs. 39.4 weeks, p < 0.001) and higher frequency of preterm birth (27% vs. 6%, p = 0.02). There were no differences in vascular health between children exposed to preeclampsia vs. controls (mean aortic intima-media thickness 0.575 mm vs. 0.563 mm, p = 0.51, pulse wave velocity 4.09 vs. 4.18 m/s, p = 0.54) and there were no significant associations in univariate analyses. Conclusions: There were no major adverse differences in vascular health which contrasts with existing studies. This suggests exposure to intrauterine preeclampsia may result in a less severe cardiovascular phenotype in young children. While reassuring, longitudinal studies are required to determine if and when exposure to intrauterine preeclampsia affects vascular health in children

Modeling Ice Shelf/Ocean Interaction in Antarctica: A Review

The most rapid loss of ice from the Antarctic Ice Sheet is observed where ice streams flow into the ocean and begin to float, forming the great Antarctic ice shelves that surround much of the continent. Because these ice shelves are floating, their thinning does not greatly influence sea level. However, they also buttress the ice streams draining the ice sheet, and so ice shelf changes do significantly influence sea level by altering the discharge of grounded ice. Currently, the most significant loss of mass from the ice shelves is from melting at the base (although iceberg calving is a close second). Accessing the ocean beneath ice shelves is extremely difficult, so numerical models are invaluable for understanding the processes governing basal melting. This paper describes the different ways in which ice shelf/ocean interactions are modeled and discusses emerging directions that will enhance understanding of how the ice shelves are melting now and how this might change in the future

Cognitive Performance Across the Life Course of Bolivian Forager-Farmers With Limited Schooling

Cognitive performance is characterized by at least two distinct life course trajectories. Many cognitive abilities (e.g. “effortful processing” abilities including fluid reasoning, and processing speed) improve throughout early adolescence and start declining in early adulthood, while other abilities (e.g. “crystallized” abilities like vocabulary breadth) improve throughout adult life, remaining robust even at late ages. Although schooling may impact performance and cognitive “reserve”, it has been argued that these age patterns of cognitive performance are human universals. Here we examine age patterns of cognitive performance among Tsimane forager-horticulturalists of Bolivia, and test whether schooling is related to differences in cognitive performance over the life course to assess models of active vs. passive cognitive reserve. We used a battery of eight tasks to assess a range of latent cognitive traits reflecting attention, processing speed, verbal declarative memory and semantic fluency (n=919 individuals, 49.9% female). Tsimane cognitive abilities show similar age-related differences as observed in industrialized populations: higher throughout adolescence and only slightly lower in later adulthood for semantic fluency, but substantially lower performance beginning in early adulthood for all other abilities. Schooling is associated with greater cognitive abilities at all ages controlling for sex, but has no attenuating effect on cognitive performance in late adulthood, consistent with models of passive cognitive reserve. We interpret the minimal attenuation of semantic fluency late in life in light of evolutionary theories of post-reproductive lifespan, which emphasize indirect fitness contributions of older adults through the transfer of information, labor and food to descendant kin

Forecast-Based Interference : Modelling Multicore Interference from Observable Factors

While there is significant interest in the use of COTS multicore platforms for Real-time Systems, there has been very little in terms of practical methods to calculate the interference multiplier (i.e. the increase in execution time due to interference) between tasks on such systems. COTS multicore platforms present two distinct challenges: firstly, the variable interference between tasks competing for shared resources such as cache, and secondly the complexity of the hardware mechanisms and policies used, which may result in a system which is very difficult if not impossible to analyse; assuming that the exact details of the hardware are even disclosed! This paper proposes a new technique, Forecast-Based Interference analysis, which mitigates both of these issues by combining measurement-based techniques with statistical techniques and forecast modelling to enable the prediction of an interference multiplier for a given set of tasks, in an automated and reliable manner. The combination of execution times and interference multipliers can be used both in the design, e.g. for specifying timing watchdogs, and analysis, e.g. verifying schedulability

On the analysis of random replacement caches using static probabilistic timing methods for multi-path programs

Probabilistic hard real-time systems, based on hardware architectures that use a random replacement cache, provide a potential means of reducing the hardware over-provision required to accommodate pathological scenarios and the associated extremely rare, but excessively long, worst-case execution times that can occur in deterministic systems. Timing analysis for probabilistic hard real-time systems requires the provision of probabilistic worst-case execution time (pWCET) estimates. The pWCET distribution can be described as an exceedance function which gives an upper bound on the probability that the execution time of a task will exceed any given execution time budget on any particular run. This paper introduces a more effective static probabilistic timing analysis (SPTA) for multi-path programs. The analysis estimates the temporal contribution of an evict-on-miss, random replacement cache to the pWCET distribution of multi-path programs. The analysis uses a conservative join function that provides a proper over-approximation of the possible cache contents and the pWCET distribution on path convergence, irrespective of the actual path followed during execution. Simple program transformations are introduced that reduce the impact of path indeterminism while ensuring sound pWCET estimates. Evaluation shows that the proposed method is efficient at capturing locality in the cache, and substantially outperforms the only prior approach to SPTA for multi-path programs based on path merging. The evaluation results show incomparability with analysis for an equivalent deterministic system using an LRU cache. For some benchmarks the performance of LRU is better, while for others, the new analysis techniques show that random replacement has provably better performance