Three-dimensional reconstruction and NURBS-based structured meshing of coronary arteries from the conventional X-ray angiography projection images

Despite its two-dimensional nature, X-ray angiography (XRA) has served as the gold standard imaging technique in the interventional cardiology for over five decades. Accordingly, demands for tools that could increase efficiency of the XRA procedure for the quantitative analysis of coronary arteries (CA) are constantly increasing. The aim of this study was to propose a novel procedure for three-dimensional modeling of CA from uncalibrated XRA projections. A comprehensive mathematical model of the image formation was developed and used with a robust genetic algorithm optimizer to determine the calibration parameters across XRA views. The frames correspondences between XRA acquisitions were found using a partial-matching approach. Using the same matching method, an efficient procedure for vessel centerline reconstruction was developed. Finally, the problem of meshing complex CA trees was simplified to independent reconstruction and meshing of connected branches using the proposed nonuniform rational B-spline (NURBS)-based method. Because it enables structured quadrilateral and hexahedral meshing, our method is suitable for the subsequent computational modelling of CA physiology (i.e. coronary blood flow, fractional flow reverse, virtual stenting and plaque progression). Extensive validations using digital, physical, and clinical datasets showed competitive performances and potential for further application on a wider scale

Radiomics-Based Assessment of Primary Sjögren's Syndrome From Salivary Gland Ultrasonography Images

Salivary gland ultrasonography (SGUS) has shown good potential in the diagnosis of primary Sjögren's syndrome (pSS). However, a series of international studies have reported needs for improvements of the existing pSS scoring procedures in terms of inter/intra observer reliability before being established as standardized diagnostic tools. The present study aims to solve this problem by employing radiomics features and artificial intelligence (AI) algorithms to make the pSS scoring more objective and faster compared to human expert scoring. The assessment of AI algorithms was performed on a two-centric cohort, which included 600 SGUS images (150 patients) annotated using the original SGUS scoring system proposed in 1992 for pSS. For each image, we extracted 907 histogram-based and descriptive statistics features from segmented salivary glands. Optimal feature subsets were found using the genetic algorithm based wrapper approach. Among the considered algorithms (seven classifiers and five regressors), the best preforming was the multilayer perceptron (MLP) classifier (κ = 0.7). The MLP over-performed average score achieved by the clinicians (κ = 0.67) by the considerable margin, whereas its reliability was on the level of human intra-observer variability (κ = 0.71). The presented findings indicate that the continuously increasing HarmonicSS cohort will enable further advancements in AI-based pSS scoring methods by SGUS. In turn, this may establish SGUS as an effective noninvasive pSS diagnostic tool, with the final goal to supplement current diagnostic tests

Growth Factors Regulate Expression of Osteoblast‐Associated Genes

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141995/1/jper1345.pd

In Vivo Delivery of Gremlin siRNA Plasmid Reveals Therapeutic Potential against Diabetic Nephropathy by Recovering Bone Morphogenetic Protein-7

Diabetic nephropathy is a complex and poorly understood disease process, and our current treatment options are limited. It remains critical, then, to identify novel therapeutic targets. Recently, a developmental protein and one of the bone morphogenetic protein antagonists, Gremlin, has emerged as a novel modulator of diabetic nephropathy. The high expression and strong co-localization with transforming growth factor- β1 in diabetic kidneys suggests a role for Gremlin in the pathogenesis of diabetic nephropathy. We have constructed a gremlin siRNA plasmid and have examined the effect of Gremlin inhibition on the progression of diabetic nephropathy in a mouse model. CD-1 mice underwent uninephrectomy and STZ treatment prior to receiving weekly injections of the plasmid. Inhibition of Gremlin alleviated proteinuria and renal collagen IV accumulation 12 weeks after the STZ injection and inhibited renal cell proliferation and apoptosis. In vitro experiments, using mouse mesangial cells, revealed that the transfect ion of gremlin siRNA plasmid reversed high glucose induced abnormalities, such as increased cell proliferation and apoptosis and increased collagen IV production. The decreased matrix metalloprotease level was partially normalized by transfection with gremlin siRNA plasmid. Additionally, we observed recovery of bone morphogenetic protein-7 signaling activity, evidenced by increases in phosphorylated Smad 5 protein levels. We conclude that inhibition of Gremlin exerts beneficial effects on the diabetic kidney mainly through maintenance of BMP-7 activity and that Gremlin may serve as a novel therapeutic target in the management of diabetic nephropathy

The Interaction between the First Transmembrane Domain and the Thumb of ASIC1a Is Critical for Its N-Glycosylation and Trafficking

Acid-sensing ion channel-1a (ASIC1a), the primary proton receptor in the brain, contributes to multiple diseases including stroke, epilepsy and multiple sclerosis. Thus, a better understanding of its biogenesis will provide important insights into the regulation of ASIC1a in diseases. Interestingly, ASIC1a contains a large, yet well organized ectodomain, which suggests the hypothesis that correct formation of domain-domain interactions at the extracellular side is a key regulatory step for ASIC1a maturation and trafficking. We tested this hypothesis here by focusing on the interaction between the first transmembrane domain (TM1) and the thumb of ASIC1a, an interaction known to be critical in channel gating. We mutated Tyr71 and Trp287, two key residues involved in the TM1-thumb interaction in mouse ASIC1a, and found that both Y71G and W287G decreased synaptic targeting and surface expression of ASIC1a. These defects were likely due to altered folding; both mutants showed increased resistance to tryptic cleavage, suggesting a change in conformation. Moreover, both mutants lacked the maturation of N-linked glycans through mid to late Golgi. These data suggest that disrupting the interaction between TM1 and thumb alters ASIC1a folding, impedes its glycosylation and reduces its trafficking. Moreover, reducing the culture temperature, an approach commonly used to facilitate protein folding, increased ASIC1a glycosylation, surface expression, current density and slowed the rate of desensitization. These results suggest that correct folding of extracellular ectodomain plays a critical role in ASIC1a biogenesis and function

Screening out irrelevant cell-based models of disease

The common and persistent failures to translate promising preclinical drug candidates into clinical success highlight the limited effectiveness of disease models currently used in drug discovery. An apparent reluctance to explore and adopt alternative cell-and tissue-based model systems, coupled with a detachment from clinical practice during assay validation, contributes to ineffective translational research. To help address these issues and stimulate debate, here we propose a set of principles to facilitate the definition and development of disease-relevant assays, and we discuss new opportunities for exploiting the latest advances in cell-based assay technologies in drug discovery, including induced pluripotent stem cells, three-dimensional (3D) co-culture and organ-on-a-chip systems, complemented by advances in single-cell imaging and gene editing technologies. Funding to support precompetitive, multidisciplinary collaborations to develop novel preclinical models and cell-based screening technologies could have a key role in improving their clinical relevance, and ultimately increase clinical success rates

OpenMandible: An open-source framework for highly realistic numerical modelling of lower mandible physiology

Objective Computer modeling of lower mandible physiology remains challenging because prescribing realistic material characteristics and boundary conditions from medical scans requires advanced equipment and skill sets. The objective of this study is to provide a framework that could reduce simplifications made and inconsistency (in terms of geometry, materials, and boundary conditions) among further studies on the topic. Methods The OpenMandible framework offers: 1) the first publicly available multiscale model of the mandible developed by combining cone beam computerized tomography (CBCT) and μCT imaging modalities, and 2) a C++ software tool for the generation of simulation-ready models (tet4 and hex8 elements). In addition to the application of conventional (Neumann and Dirichlet) boundary conditions, OpenMandible introduces a novel geodesic wave propagation - based approach for incorporating orthotropic micromechanical characteristics of cortical bone, and a unique algorithm for modeling muscles as uniformly directed vectors. The base intact model includes the mandible (spongy and compact bone), 14 teeth (comprising dentin, enamel, periodontal ligament, and pulp), simplified temporomandibular joints, and masticatory muscles (masseter, temporalis, medial, and lateral pterygoid). Results The complete source code, executables, showcases, and sample data are freely available on the public repository: https://github.com/ArsoVukicevic/OpenMandible. It has been demonstrated that by slightly editing the baseline model, one can study different “virtual” treatments or diseases, including tooth restoration, placement of implants, mandible bone degradation, and others. Significance OpenMandible eases the community to undertake a broad range of studies on the topic, while increasing their consistency and reproducibility. At the same time, the needs for dedicated equipment and skills for developing realistic simulation models are significantly reduced

BMP7 activates brown adipose tissue and reduces diet-induced obesity only at subthermoneutrality

BACKGROUND/AIMS: Brown adipose tissue (BAT) dissipates energy stored in triglycerides as heat via the uncoupling protein UCP-1 and is a promising target to combat hyperlipidemia and obesity. BAT is densely innervated by the sympathetic nervous system, which increases BAT differentiation and activity upon cold exposure. Recently, Bone Morphogenetic Protein 7 (BMP7) was identified as an inducer of BAT differentiation. We aimed to elucidate the role of sympathetic activation in the effect of BMP7 on BAT by treating mice with BMP7 at varying ambient temperature, and assessed the therapeutic potential of BMP7 in combating obesity. ----- METHODS AND RESULTS: High-fat diet fed lean C57Bl6/J mice were treated with BMP7 via subcutaneous osmotic minipumps for 4 weeks at 21 °C or 28 °C, the latter being a thermoneutral temperature in which sympathetic activation of BAT is largely diminished. At 21 °C, BMP7 increased BAT weight, increased the expression of Ucp1, Cd36 and hormone-sensitive lipase in BAT, and increased total energy expenditure. BMP7 treatment markedly increased food intake without affecting physical activity. Despite that, BMP7 diminished white adipose tissue (WAT) mass, accompanied by increased expression of genes related to intracellular lipolysis in WAT. All these effects were blunted at 28 °C. Additionally, BMP7 resulted in extensive 'browning' of WAT, as evidenced by increased expression of BAT markers and the appearance of whole clusters of brown adipocytes via immunohistochemistry, independent of environmental temperature. Treatment of diet-induced obese C57Bl6/J mice with BMP7 led to an improved metabolic phenotype, consisting of a decreased fat mass and liver lipids as well as attenuated dyslipidemia and hyperglycemia. ----- CONCLUSION: Together, these data show that BMP7-mediated recruitment and activation of BAT only occurs at subthermoneutral temperature, and is thus likely dependent on sympathetic activation of BAT, and that BMP7 may be a promising tool to combat obesity and associated disorders