Search Results (12)

Atopic dermatitis (AD) is a chronic inflammatory skin disease featuring skin barrier dysfunction and immune dysregulation. Previously, we reported that the retinoid-related orphan nuclear receptor RORα was highly expressed in the epidermis of normal skin. We also found that it positively regulated the expression of differentiation markers and skin barrier-related genes in human keratinocytes. In contrast, epidermal RORα expression was downregulated in the skin lesions of several inflammatory skin diseases, including AD. In this study, we generated mouse strains with epidermis-specific Rora ablation to understand the roles of epidermal RORα in regulating AD pathogenesis. Although Rora deficiency did not cause overt macroscopic skin abnormalities at the steady state, it greatly amplified MC903-elicited AD-like symptoms by intensifying skin scaliness, increasing epidermal hyperproliferation and barrier impairment, and elevating dermal immune infiltrates, proinflammatory cytokines, and chemokines. Despite the normal appearance at the steady state, Rora-deficient skin showed microscopic abnormalities, including mild epidermal hyperplasia, increased TEWL, and elevated mRNA expression of Krt16, Sprr2a, and Tslp genes, indicating subclinical impairment of epidermal barrier functions. Our results substantiate the importance of epidermal RORα in partially suppressing AD development by maintaining normal keratinocyte differentiation and skin barrier function. Full article

Left ventricular contractile dysfunction and arrhythmias frequently occur in patients with sleep-disordered breathing (SDB). The CaMKII-dependent dysregulation of cellular Ca homeostasis has recently been described in SDB patients, but these studies only partly explain the mechanism and are limited by the patients’ heterogeneity. Here, we analyzed contractile function and Ca homeostasis in a mouse model of obstructive sleep apnea (OSA) that is not limited by confounding comorbidities. OSA was induced by artificial tongue enlargement with polytetrafluorethylene (PTFE) injection into the tongue of wildtype mice and mice with a genetic ablation of the oxidative activation sites of CaMKII (MMVV knock-in). After eight weeks, cardiac function was assessed with echocardiography. Reactive oxygen species (ROS) and Ca transients were measured using confocal and epifluorescence microscopy, respectively. Wildtype PTFE mice exhibited an impaired ejection fraction, while MMVV PTFE mice were fully protected. As expected, isolated cardiomyocytes from PTFE mice showed increased ROS production. We further observed decreased levels of steady-state Ca transients, decreased levels of caffeine-induced Ca transients, and increased pro-arrhythmic activity (defined as deviations from the diastolic Ca baseline) only in wildtype but not in MMVV PTFE mice. In summary, in the absence of any comorbidities, OSA was associated with contractile dysfunction and pro-arrhythmic activity and the inhibition of the oxidative activation of CaMKII conveyed cardioprotection, which may have therapeutic implications. Full article

Predicting the surface morphology of materials during steady-state ablation is important in rocket motor nozzles and the heat shields of vehicles performing atmospheric re-entry. When designing ablative materials, a high number of calculations is required for analyzing surface morphology. To effectively design these materials and reduce the number of experiments, a fast, effective, and simple calculation method is required. Although a fundamental theory for ablation has been established, quick and effective prediction of the morphology of the composites remains a challenge. In this study, we propose a fast, effective, and simple numerical calculation method to predict the surface morphology of steady-state ablation based on the geometric characteristics of the materials. The results obtained in this study were consistent with the experimental observations. The calculation time was significantly reduced. In addition, our method was found to be useful for analyzing the physical and chemical properties and surface roughness of ablative materials. Full article

Metal machining is one of the most important manufacturing processes in today’s production sector. The tools used in machining have been developed over the years to improve their performance, by reducing the cutting forces, the friction coefficient, and the heat generated during the cutting process. Several cooling systems have emerged as an effective way to remove the excessive heat generated from the chip-tool contact region. In recent years, the introduction of nano and micro-textures on the surface of tools has allowed to further improve their overall performance. However, there is not sufficient scientific data to clearly show how surface texturing can contribute to the reduction of tool temperature and identify its mechanisms. Therefore, this work proposes an experimental setup to study the tool surface characteristics’ impact on the heat transfer rate from the tools’ surface to the cooling fluid. Firstly, a numerical model is developed to mimic the heat energy flow from the tool. Next, the design variables were adjusted to get a linear system response and to achieve a fast steady-state thermal condition. Finally, the experimental device was implemented based on the optimized numerical model. A good agreement was obtained between the experimental tests and numerical simulations, validating the concept and the implementation of the experimental setup. A square grid pattern of 100 μm × 100 μm with grooves depths of 50, 100, and 150 μm was introduced on cutting insert surfaces by laser ablation. The experimental results show that there is a linear increase in heat transfer rate with the depth of the grooves relatively to a standard surface, with an increase of 3.77% for the depth of 150 μm. This is associated with the increase of the contact area with the coolant, the generation of greater fluid turbulence near the surface, and the enhancement of the surface wettability. Full article

A disintegrin and metalloproteinase 15 (ADAM15) is a member of the ADAM family of sheddases. Its genetic ablation in mice suggests that ADAM15 plays an important role in a wide variety of biological functions, including cartilage homeostasis. Nevertheless, while the substrate repertoire of other members of the ADAM family, including ADAM10 and ADAM17, is largely established, little is known about the substrates of ADAM15 and how it exerts its biological functions. Herein, we used unbiased proteomics to identify ADAM15 substrates and proteins regulated by the proteinase in chondrocyte-like HTB94 cells. ADAM15 silencing did not induce major changes in the secretome composition of HTB94 cells, as revealed by two different proteomic approaches. Conversely, overexpression of ADAM15 remodeled the secretome, with levels of several secreted proteins being altered compared to GFP-overexpressing controls. However, the analysis did not identify potential substrates of the sheddase, i.e., transmembrane proteins released by ADAM15 in the extracellular milieu. Intriguingly, secretome analysis and immunoblotting demonstrated that ADAM15 overexpression increased secreted levels of tissue inhibitor of metalloproteinases 3 (TIMP-3), a major regulator of extracellular matrix turnover. An inactive form of ADAM15 led to a similar increase in the inhibitor, indicating that ADAM15 regulates TIMP-3 secretion by an unknown mechanism independent of its catalytic activity. In conclusion, high-resolution quantitative proteomics of HTB94 cells manipulated to have increased or decreased ADAM15 expression did not identify canonical substrates of the proteinase in the steady state, but it revealed that ADAM15 can modulate the secretome in a catalytically-independent manner. Full article

Photodynamic therapy (PDT) is a promising treatment option that ablates cancerous cells and tumors via photoinduced sensitization of singlet oxygen. Over the last few decades, much work has been devoted to the development of new photochemotherapeutic agents for PDT. A wide variety of macrocyclic tetrapyrrole based photosensitizers have been designed, synthesized and characterized as PDT agents. Many of these complexes have a variety of issues that pose a barrier to their use in humans, including biocompatibility, inherent toxicity, and synthetic hurdles. We have developed a non-traditional, non-cyclic, and non-aromatic tetrapyrrole ligand scaffold, called the biladiene (DMBil1), as an alternative to these traditional photosensitizer complexes. Upon insertion of a heavy atom such as Pd²⁺ center, Pd[DMBil1] generates singlet oxygen in substantial yields (Φ_Δ = 0.54, λ_exc = 500 nm) when irradiated with visible light. To extend the absorption profile for Pd[DMBil1] deeper into the phototherapeutic window, the tetrapyrrole was conjugated with alkynyl phenyl groups at the 2- and 18-positions (Pd[DMBil2-PE]) resulting in a significant redshift while also increasing singlet oxygen generation (Φ_Δ = 0.59, 600 nm). To further modify the dialkynyl-biladiene scaffold, we conjugated a 1,8-diethynylanthracene with to the Pd[DMBil1] tetrapyrrole in order to further extend the compound’s π-conjugation in a cyclic loop that spans the entire tetrapyrrole unit. This new compound (Pd[DMBil2-P61]) is structurally reminiscent of the P61 Black Widow aircraft and absorbs light into the phototherapeutic window (600–900 nm). In addition to detailing the solid-state structure and steady-state spectroscopic properties for this new biladiene, photochemical sensitization studies demonstrated that Pd[DMBil2-P61] can sensitize the formation of ¹O₂ with quantum yields of Φ_Δ = 0.84 upon irradiation with light λ = 600 nm. These results distinguish the Pd[DMBil2-P61] platform as the most efficient biladiene-based singlet oxygen photosensitizer developed to date. When taken together, the improved absorption in the phototherapeutic window and high singlet oxygen sensitization efficiency of Pd[DMBil2-P61] mark this compound as a promising candidate for future study as an agent of photodynamic cancer therapy. Full article

Environmentally-mediated drug resistance in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) significantly contributes to relapse. Stromal cells in the bone marrow environment protect leukemia cells by secretion of chemokines as cues for BCP-ALL migration towards, and adhesion to, stroma. Stromal cells and BCP-ALL cells communicate through stromal galectin-3. Here, we investigated the significance of stromal galectin-3 to BCP-ALL cells. We used CRISPR/Cas9 genome editing to ablate galectin-3 in stromal cells and found that galectin-3 is dispensable for steady-state BCP-ALL proliferation and viability. However, efficient leukemia migration and adhesion to stromal cells are significantly dependent on stromal galectin-3. Importantly, the loss of stromal galectin-3 production sensitized BCP-ALL cells to conventional chemotherapy. We therefore tested novel carbohydrate-based small molecule compounds (Cpd14 and Cpd17) with high specificity for galectin-3. Consistent with results obtained using galectin-3-knockout stromal cells, treatment of stromal-BCP-ALL co-cultures inhibited BCP-ALL migration and adhesion. Moreover, these compounds induced anti-leukemic responses in BCP-ALL cells, including a dose-dependent reduction of viability and proliferation, the induction of apoptosis and, importantly, the inhibition of drug resistance. Collectively, these findings indicate galectin-3 regulates BCP-ALL cell responses to chemotherapy through the interactions between leukemia cells and the stroma, and show that a combination of galectin-3 inhibition with conventional drugs can sensitize the leukemia cells to chemotherapy. Full article

Atrial fibrillation (AF) is the most common cardiac arrhythmia. At present, cardiac ablation is the main treatment procedure for AF. To guide and plan this procedure, it is essential for clinicians to obtain patient-specific 3D geometrical models of the atria. For this, there is an interest in automatic image segmentation algorithms, such as deep learning (DL) methods, as opposed to manual segmentation, an error-prone and time-consuming method. However, to optimize DL algorithms, many annotated examples are required, increasing acquisition costs. The aim of this work is to develop automatic and high-performance computational models for left and right atrium (LA and RA) segmentation from a few labelled MRI volumetric images with a 3D Dual U-Net algorithm. For this, a supervised domain adaptation (SDA) method is introduced to infer knowledge from late gadolinium enhanced (LGE) MRI volumetric training samples (80 LA annotated samples) to a network trained with balanced steady-state free precession (bSSFP) MR images of limited number of annotations (19 RA and LA annotated samples). The resulting knowledge-transferred model SDA outperformed the same network trained from scratch in both RA (Dice equals 0.9160) and LA (Dice equals 0.8813) segmentation tasks. Full article

Eosinophils are implicated in the pathophysiology of a spectrum of eosinophil-associated diseases, including gastrointestinal eosinophilic diseases (EGIDs). Biologics that target the IL-5 pathway and are intended to ablate eosinophils have proved beneficial in severe eosinophilic asthma and may offer promise in treating some endotypes of EGIDs. However, destructive effector functions of eosinophils are only one side of the coin; eosinophils also play important roles in immune and tissue homeostasis. A growing body of data suggest tissue eosinophils represent a plastic and heterogeneous population of functional sub-phenotypes, shaped by environmental (systemic and local) pressures, which may differentially impact disease outcomes. This may be particularly relevant to the GI tract, wherein the highest density of eosinophils reside in the steady state, resident immune cells are exposed to an especially broad range of external and internal environmental pressures, and greater eosinophil longevity may uniquely enrich for co-expression of eosinophil sub-phenotypes. Here we review the growing evidence for functional sub-phenotypes of intestinal tissue eosinophils, with emphasis on the multifactorial pressures that shape and diversify eosinophil identity and potential targets to inform next-generation eosinophil-targeting strategies designed to restrain inflammatory eosinophil functions while sustaining homeostatic roles. Full article

A general method for solving a linear stability problem of an interface with a continuous internal structure is described. Such interfaces or fronts are commonly found in various branches of physics, such as combustion and plasma physics. It extends simplified analysis of an infinitely thin discontinuous front by means of numerical integration along the steady-state solution. Two examples are presented to demonstrate the application of the method for 1D pulsating instability in magnetic deflagration and 2D Darrieus–Landau instability in a laser ablation wave. Full article

The effect of thermal and chemical boundary conditions on the structure and chemical composition of the wake behind a 3D Mach 7 sphere-cone at an angle of attack of 5 degrees and an altitude of roughly 30,000 m is explored. A special emphasis is placed on determining the number density of chemical species which might lead to detection via the electromagnetic spectrum. The use of non-ablating cold-wall, adiabatic, and radiative equilibrium wall boundary conditions are used to simulate extremes in potential thermal protection system designs. Non-ablating, as well as an ablating boundary condition using the “steady-state ablation” assumption to compute a surface energy balance on the wall are used in order to determine the impacts of ablation on wake composition. On-body thermal boundary conditions downstream of an ablating nose are found to significantly affect wake temperature and composition, while the role of catalysis is found to change the composition only marginally except at very high temperatures on the cone’s surface for the flow regime considered. Ablation is found to drive the extensive production of detectable species otherwise unrelated to ablation, whereas if ablation is not present at all, air-species which would otherwise produce detectable spectra are minimal. Studies of afterbody cooling techniques, as well as shape, are recommended for further analysis. Full article

In situ laser ablation quadrupole inductively coupled plasma mass spectrometry was used to measure Pb isotopes in galena. Data acquisition was optimized by adjusting spot size, energy density, and ablation time to obtain near steady-state low relative standard deviation (%RSD) signals. Standard-sample bracketing using in-house Broken Hill galena as external reference standard was used and offline data reduction was carried out using VizualAge for Iolite3. Using this methodology, galena grain in polished thin sections from selected massive sulphide deposits of the Bathurst Mining Camp, Canada, were tested and compared to previously published data. Absolute values and errors on the weighted mean of ~20 individual analyses from each sample compared favourably with whole-rock Pb-Pb isotope data. This approach provides a mean to obtain rapid, accurate, and moderately (0.1% 2σ) precise Pb isotope measurements in galena and is particularly well suited for exploratory or reconnaissance studies. Further refinement of this approach may be useful in exploration for volcanogenic massive sulphides deposits and might be a useful vectoring tool when complemented with other conventional exploration techniques. Full article