Implantation of a rotary blood pump (RBP) can cause non-physiological flow fields in the left ventricle (LV) which may trigger thrombosis. Different inflow cannula geometry can affect LV flow fields. ...The aim of this study was to determine the effect of inflow cannula geometry on intraventricular flow under full LV support in a patient specific model.
Computed tomography angiography imaging of the LV was performed on a RBP candidate to develop a patient-specific model. Five inflow cannulae were evaluated, which were modelled on those used clinically or under development. The inflow cannulae are described as a crown like tip, thin walled tubular tip, large filleted tip, trumpet like tip and an inferiorly flared cannula. Placement of the inflow cannula was at the LV apex with the central axis intersecting the centre of the mitral valve. Full support was simulated by prescribing 5 l/min across the mitral valve. Thrombus risk was evaluated by identifying regions of stagnation. Rate of LV washout was assessed using a volume of fluid model. Relative haemolysis index and blood residence time was calculated using an Eulerian approach.
The inferiorly flared inflow cannula had the lowest thrombus risk due to low stagnation volumes. All cannulae had similar rates of LV washout and blood residence time. The crown like tip and thin walled tubular tip resulted in relatively higher blood damage indices within the LV.
Changes in intraventricular flow due to variances in cannula geometry resulted in different stagnation volumes. Cannula geometry does not appreciably affect LV washout rates and blood residence time. The patient specific, full support computational fluid dynamic model provided a repeatable platform to investigate the effects of inflow cannula geometry on intraventricular flow.
The growth and characterisation of a non-planar phthalocyanine (vanadyl phthalocyanine, VOPc) on a complete monolayer (ML) of a planar phthalocyanine (Iron(II) phthalocyanine, FePc) on an Au(111) ...surface, has been investigated using ultra-high vacuum (UHV) scanning tunnelling microscopy (STM) and low energy electron diffraction (LEED). The surface mesh of the initial FePc monolayer has been determined and shown to correspond to an incommensurate overlayer, not commensurate as previously reported. Ordered islands of VOPc, with (1 × 1) epitaxy, grow on the FePc layer at submonolayer coverages. The individual VOPc molecules occupy sites directly atop the underlying FePc molecules, indicating that significant intermolecular bonding must occur. It is proposed that this interaction implies that the Vdouble bond, length as m-dashO points down into the surface, allowing a Fe-O bond to form. The detailed appearance of the STM images of the VOPc molecules is consistent with previous studies in other VOPc growth studies in which this molecular orientation has been proposed.
•DL-based VOI predictions can be used as a basis for radiomic feature extraction.•DL-based VOI predictions showed high radiomic feature stability.•The VOI predictions showed good accordance with ...independent manual segmentations.•The DL-based VOI predictions achieved clinical feasibility in a subset of patients.•A specific retraining is necessary to apply the model for clinical GTV prediction.
Volume of interest (VOI) segmentation is a crucial step for Radiomics analyses and radiotherapy (RT) treatment planning. Because it can be time-consuming and subject to inter-observer variability, we developed and tested a Deep Learning-based automatic segmentation (DLBAS) algorithm to reproducibly predict the primary gross tumor as VOI for Radiomics analyses in extremity soft tissue sarcomas (STS).
A DLBAS algorithm was trained on a cohort of 157 patients and externally tested on an independent cohort of 87 patients using contrast-enhanced MRI. Manual tumor delineations by a radiation oncologist served as ground truths (GTs). A benchmark study with 20 cases from the test cohort compared the DLBAS predictions against manual VOI segmentations of two residents (ERs) and clinical delineations of two radiation oncologists (ROs). The ROs rated DLBAS predictions regarding their direct applicability.
The DLBAS achieved a median dice similarity coefficient (DSC) of 0.88 against the GTs in the entire test cohort (interquartile range (IQR): 0.11) and a median DSC of 0.89 (IQR 0.07) and 0.82 (IQR 0.10) in comparison to ERs and ROs, respectively. Radiomics feature stability was high with a median intraclass correlation coefficient of 0.97, 0.95 and 0.94 for GTs, ERs, and ROs, respectively. DLBAS predictions were deemed clinically suitable by the two ROs in 35% and 20% of cases, respectively.
The results demonstrate that the DLBAS algorithm provides reproducible VOI predictions for radiomics feature extraction. Variability remains regarding direct clinical applicability of predictions for RT treatment planning.
There remains a substantial shortfall in the treatment of severe skeletal injuries. The current gold standard of autologous bone grafting from the same patient has many undesirable side effects ...associated such as donor site morbidity. Tissue engineering seeks to offer a solution to this problem. The primary requirements for tissue-engineered scaffolds have already been well established, and many materials, such as polyesters, present themselves as potential candidates for bone defects; they have comparable structural features, but they often lack the required osteoconductivity to promote adequate bone regeneration. By combining these materials with biological growth factors, which promote the infiltration of cells into the scaffold as well as the differentiation into the specific cell and tissue type, it is possible to increase the formation of new bone. However due to the cost and potential complications associated with growth factors, controlling the rate of release is an important design consideration when developing new bone tissue engineering strategies. This paper will cover recent research in the area of encapsulation and release of growth factors within a variety of different polymeric scaffolds.
An immunosuppressive microenvironment causes poor tumor T cell infiltration and is associated with reduced patient overall survival in colorectal cancer. How to improve treatment responses in these ...tumors is still a challenge. Using an integrated screening approach to identify cancer-specific vulnerabilities, we identified complement receptor C5aR1 as a druggable target, which when inhibited improved radiotherapy, even in tumors displaying immunosuppressive features and poor CD8+ T cell infiltration. While C5aR1 is well-known for its role in the immune compartment, we found that C5aR1 is also robustly expressed on malignant epithelial cells, highlighting potential tumor cell-specific functions. C5aR1 targeting resulted in increased NF-κB-dependent apoptosis specifically in tumors and not normal tissues, indicating that, in malignant cells, C5aR1 primarily regulated cell fate. Collectively, these data revealed that increased complement gene expression is part of the stress response mounted by irradiated tumors and that targeting C5aR1 could improve radiotherapy, even in tumors displaying immunosuppressive features.
In the conventional model of transcriptional activation, transcription factors bind to response elements and recruit co-factors, including histone acetyltransferases. Contrary to this model, we show ...that the histone acetyltransferase KAT7 (HBO1/MYST2) is required genome wide for histone H3 lysine 14 acetylation (H3K14ac). Examining neural stem cells, we find that KAT7 and H3K14ac are present not only at transcribed genes but also at inactive genes, intergenic regions, and in heterochromatin. KAT7 and H3K14ac were not required for the continued transcription of genes that were actively transcribed at the time of loss of KAT7 but indispensable for the activation of repressed genes. The absence of KAT7 abrogates neural stem cell plasticity, diverse differentiation pathways, and cerebral cortex development. Re-expression of KAT7 restored stem cell developmental potential. Overexpression of KAT7 enhanced neuron and oligodendrocyte differentiation. Our data suggest that KAT7 prepares chromatin for transcriptional activation and is a prerequisite for gene activation.
Display omitted
•KAT7 is essential for H3K14 acetylation, neuron, and oligodendrocyte differentiation•KAT7 and H3K14ac are distributed widely in the genome, including in H3K9me3+ domains•Neuronal gene expression program fails to be activated in the absence of KAT7•KAT7 creates a permissive chromatin state for transcriptional activation
The role of acetylation of specific histone lysine residues remains unclear. Kueh et al. find that the absence of the lysine acetyltransferase KAT7 in neural stem cells causes loss of H3K14 acetylation, a failure to activate the neuron differentiation gene expression program, and neuronal differentiation.
A novel strategy is reported to produce biodegradable microfiber‐scaffolds layered with high densities of microparticles encapsulating a model protein. Direct electrospraying on highly porous melt ...electrospun scaffolds provides a reproducible scaffold coating throughout the entire architecture. The burst release of protein is significantly reduced due to the immobilization of microparticles on the surface of the scaffold and release mechanisms are dependent on protein‐polymer interactions. The composite scaffolds have a positive biological effect in contact with precursor osteoblast cells up to 18 days in culture. The scaffold design achieved with the techniques presented here endorses these new composite scaffolds as promising templates for growth factor delivery.
A novel platform for protein delivery is established here. Highly porous microfiber constructs are homogeneously coated by direct electrospraying of biodegradable microparticles loaded with proteins. Control over porosity, scaffold coating, and characteristics of particles are obtained with the processing parameters for tailored protein delivery required in tissue engineering.
Formation and regulation of excitatory glutamatergic synapses is essential for shaping neural circuits throughout development. In a Drosophila genetic screen for synaptogenesis mutants, we identified ...mind the gap (mtg), which encodes a secreted, extracellular N-glycosaminoglycan-binding protein. MTG is expressed neuronally and detected in the synaptic cleft, and is required to form the specialized transsynaptic matrix that links the presynaptic active zone with the post-synaptic glutamate receptor (GluR) domain. Null mtg embryonic mutant synapses exhibit greatly reduced GluR function, and a corresponding loss of localized GluR domains. All known post-synaptic signaling/scaffold proteins functioning upstream of GluR localization are also grossly reduced or mislocalized in mtg mutants, including the dPix-dPak-Dock cascade and the Dlg/PSD-95 scaffold. Ubiquitous or neuronally targeted mtg RNA interference (RNAi) similarly reduce post-synaptic assembly, whereas post-synaptically targeted RNAi has no effect, indicating that presynaptic MTG induces and maintains the post-synaptic pathways driving GluR domain formation. These findings suggest that MTG is secreted from the presynaptic terminal to shape the extracellular synaptic cleft domain, and that the cleft domain functions to mediate transsynaptic signals required for post-synaptic development.
Helminth infections in children are associated with impaired cognitive development; however, the biological mechanisms for this remain unclear. Using a murine model of gastrointestinal helminth ...infection, we demonstrate that early-life exposure to helminths promotes local and systemic inflammatory responses and transient changes in the gastrointestinal microbiome. Behavioral and cognitive analyses performed 9-months postinfection revealed deficits in spatial recognition memory and an anxiety-like behavioral phenotype in worm-infected mice, which was associated with neuropathology and increased microglial activation within the brain. This study demonstrates a previously unrecognized mechanism through which helminth infections may influence cognitive function, via perturbations in the gut-immune-brain axis.
PDF
