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In idiopathic pulmonary fibrosis (IPF), the normal delicate lung architecture is replaced with rigid extracellular matrix (ECM) as a result of the accumulation of activated myofibroblasts and excessive deposition of ECM. Lamins have a role in fostering mechanosignaling from the ECM to the nucleus. Although there is a growing number of studies on lamins and associated diseases, there are no prior reports linking aberrations in lamins with pulmonary fibrosis. Here, we discovered, through analysis of RNA sequencing data, a novel isoform of lamin A/C that is more highly expressed in IPF compared with control lung. This novel LMNA (lamin A/C) splice variant includes retained introns 10 and 11 and exons 11 and 12 as documented by rapid amplification of cDNA ends. We found that this novel isoform is induced by stiff ECM. To better clarify the specific effects of this novel isoform of lamin A/C and how it may contribute to the pathogenesis of IPF, we transduced the lamin transcript into primary lung fibroblasts and alveolar epithelial cells and found that it impacts several biological effects, including cell proliferation, senescence, cell contraction, and the transition of fibroblasts to myofibroblasts. We also observed that type II epithelial cells and myofibroblasts in the IPF lung exhibited wrinkled nuclei, and this is notable because this has not been previously described and is consistent with laminopathymediated cellular effects. [ABSTRACT FROM AUTHOR]

The article discusses a study which investigated whether megakaryocyte/platelet gene signatures are altered in idiopathic pulmonary fibrosis (IPF) by analysing publicly available transcriptome datasets with xCell, a novel computational method. Topics include analysis of National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) transcriptome datasets from patients with IPF and healthy control subjects, survival analysis in IDF cohort, and limitations of the study.

Fibrosis involving the lung may occur in many settings, including in association with known environmental agents, connective tissue diseases, and exposure to drugs or radiation therapy. The most common form is referred to as 'idiopathic' since a causal agent or specific association has not been determined; the strongest risk factor for idiopathic pulmonary fibrosis is aging. Emerging studies indicate that targeting certain components of aging biology may be effective in mitigating age-associated fibrosis. While transforming growth factor-ß1 (TGF-ß1) is a central mediator of fibrosis in almost all contexts, and across multiple organs, it is not feasible to target this canonical pathway at the ligand-receptor level due to the pleiotropic nature of its actions; importantly, its homeostatic roles as a tumor-suppressor and immune-modulator make this an imprudent strategy. However, defining targets downstream of its receptor(s) that mediate fibrogenesis, while relatively dispenable for tumor- and immune-suppressive functions may aid in developing safer and more effective therapies. In this review, we explore molecular targets that, although TGF-ß1 induced/activated, may be relatively more selective in mediating tissue fibrosis. Additionally, we explore epigenetic mechanisms with global effects on the fibrogenic process, as well as metabolic pathways that regulate aging and fibrosis. [ABSTRACT FROM AUTHOR]

This technical paper demonstrates the influence of the probe-tip surface smoothness of a bipolar electrostatic chuck (ESC) on electrostatic force. ESC, which has a silicon-based beam-array microstructure, aims to pick and place a dielectric object with a curved surface owing to the compliance of its elastically deformable beams. The ESC was fabricated using a lithography technique, specifically deep reactive ion etching (DRIE), to smooth the surface of the beam tip. The surface roughness of the beam tips was observed using a field-emission scanning electron microscope (FE-SEM), and the adhesional force was experimentally evaluated. The results show that by the smoothing process, the adhesional force per unit area is significantly increased compared to the previous study reported by Choi (one of the authors). This suggests that the proposed bipolar ESC device has great potential for use in various industries. [ABSTRACT FROM AUTHOR]

Rationale: Point-of-care ultrasonography is an invaluable asset for inpatient decision-making. Whether handheld ultrasound can be used in the outpatient management of pulmonary hypertension is unknown. Objectives: We investigated whether a handheld ultrasound estimate of right atrial pressure correlates with B-type natriuretic peptide (BNP) and clinical outcome over time in outpatients with pulmonary hypertension. Methods: This prospective study included outpatients in a Pulmonary Hypertension Comprehensive Care Center clinic who had a same-day BNP concentration. We used a handheld ultrasound to measure inferior vena cava size and collapsibility, which were used to estimate right atrial pressure (eRAP) and categorize it as normal, intermediate, or high. Correlation analysis was used to compare these ultrasound measurements with BNP at baseline and over time. Cox regression was used to determine whether these measurements were associated with time to clinical worsening. Results: Ninety patients (60% Group 1 pulmonary hypertension) were enrolled. Patients with an intermediate or high eRAP category at baseline had higher BNP concentrations than patients with normal eRAP. For every transition in eRAP category (e.g., from normal to intermediate) between clinic visits, BNP changed by an average of 155 pg/ml (95% confidence interval [CI], 84-227). Higher baseline eRAP category was independently associated with more than twofold increased risk for clinical worsening (hazard ratio, 2.44; 95% CI, 1.47-4.07). Conclusions: Right atrial pressure estimated by portable handheld ultrasound correlates with BNP at baseline and serially over time. Furthermore, eRAP is independently associated with clinical worsening. The use of portable handheld ultrasound to estimate right atrial pressure should be considered in pulmonary hypertension clinics. Clinical trial registered at clinicaltrials.gov (NCT02873039). [ABSTRACT FROM AUTHOR]

The article reports that emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–induced coronavirus disease dominated the year 2020. Topics include examines that IPF lungs are characterized by an emerging aberrant basaloid epithelial-cell population, which coexpresses basal epithelial, mesenchymal, senescence, and developmental markers.

Idiopathic pulmonary fibrosis (IPF) is a fibroproliferative lung disease, and fibroblast-myofibroblast differentiation (FMD) is thought to be a key event in the pathogenesis of IPF. Histone deacetylase-8 (HDAC8) has been shown to associate with α-smooth muscle actin (α-SMA; a marker of FMD) and regulates cell contractility in vascular smooth muscle cells. However, the role of HDAC8 in FMD or pulmonary fibrosis has never been reported. This study investigated the role of HDAC8 in pulmonary fibrosis with a focus on FMD. We observed that HDAC8 expression was increased in IPF lung tissue as well as transforming growth factor (TGF)β1-treated normal human lung fibroblasts (NHLFs). Immunoprecipitation experiments revealed that HDAC8 was associated with α-SMA in TGFβ1-treated NHLFs. HDAC8 inhibition with NCC170 (HDAC8-selective inhibitor) repressed TGFβ1-induced fibroblast contraction and α-SMA protein expression in NHLFs cultured in collagen gels. HDAC8 inhibition with HDAC8 siRNA also repressed TGFβ1-induced expression of profibrotic molecules such as fibronectin and increased expression of antifibrotic molecules such as peroxisome proliferator-activated receptor- (PPAR). Chromatin immunoprecipitation quantitative PCR using an antibody against H3K27ac (histone H3 acetylated at lysine 27; a known HDAC8 substrate and a marker for active enhancers) suggested that HDAC8 inhibition with NCC170 ameliorated TGFβ1- induced loss of H3K27ac at the PPAR gene enhancer. Furthermore, NCC170 treatment significantly decreased fibrosis measured by Ashcroft score as well as expression of type 1 collagen and fibronectin in bleomycin-treated mouse lungs. These data suggest that HDAC8 contributes to pulmonary fibrosis and that there is a therapeutic potential for HDAC8 inhibitors to treat IPF as well as other fibrotic lung diseases. [ABSTRACT FROM AUTHOR]

Myofibroblasts are important mediators of fibrogenesis; thus blocking fibroblast-to-myofibroblast differentiation (FMD) may be an effective strategy to treat pulmonary fibrosis (PF). Previously, we reported that histone deacetylase 4 (HDAC4) activity is necessary for transforming growth factor-β1 (TGF-β1)-induced human lung FMD. Here, we show that TGF-β1 increases NADPH oxidase 4 (NOX4) mRNA and protein expression in normal human lung fibroblasts (NHLFs) and causes nuclear export of HDAC4. Application of the NOX family inhibitor diphenyleneiodonium chloride reduces TGF-β1-induced HDAC4 nuclear export, expression of the myofibroblast marker α-smooth muscle actin (α-SMA), and α-SMA fiber formation. Inhibition of HDAC4 nucleus-to-cytoplasm translocation using leptomycin B (LMB) had little effect on α-SMA expression but blocked α-SMA fiber formation. A coimmunoprecipitation assay showed that HDAC4 associates with α-SMA. Moreover, LMB abolishes TGF-β1-induced α-SMA fiber formation and cell contraction. Relevant to human pulmonary fibrosis, idiopathic PF specimens showed significantly higher NOX4 RNA expression and scant HDAC4 staining within nuclei of fibroblast foci myofibroblasts. Taken together, these results indicate that reactive oxygen species promote TGF-β1-mediated myofibroblast differentiation and HDAC4 nuclear export. The physical association of HDAC4 with α-SMA suggests that HDAC4 has a role in regulating the α-SMA cytoskeleton arrangement. [ABSTRACT FROM AUTHOR]

A model with surface conductivity and adhesional force is proposed to investigate the mechanism for electrostatic micro manipulation of a dielectric object using a single probe. The manipulation system consists of three elements: a conductive probe as a manipulator, a conductive plate as a substrate, and a dielectric particle as the target object for manipulation. The particle can be successfully picked up/placed if a rectangular pulse voltage is applied between the probe and the plate. The reliability of the picking up/placing operation is improved by applying a pulse voltage that is determined by a theoretical model considering surface conductivity and adhesion. To verify the theoretical prediction, manipulation experiment is conducted using soda-lime glass particles with radii of 20 μm and 40 μm. [ABSTRACT FROM AUTHOR]

Fish have a complex self-defense mechanism against microbial invasion. Recently, L-lysine α-oxidases have been identified from a number of fish species as a novel type of antibacterial protein in the integument. These enzymes exhibit strict substrate specificity for L-lysine, but the underlying mechanisms and details of their catalytic properties remain unknown. In this study, a synthetic gene coding for Scomber japonicus L-lysine a-oxidase, originally termed AIP (for apoptosisinducing protein), was expressed in Pichia pastoris, and the recombinant enzyme (rAIP) was purified and characterized. rAIP exhibited essentially the same substrate specificity as the native enzyme, catalyzing the oxidative deamination of L-lysine as an exclusive substrate. rAIP was N-glycosylated and remained active over a wide range of pH, with an optimal pH of 7.5. The enzyme was stable in the pH range from 4.5 to 10.0 and was thermally stable up to 60°C. A molecular modelling of rAIP and a comparative structure/ sequence analysis with homologous enzymes indicate that Asp220 and Asp320 are the substrate-binding residues that are likely to confer exclusive substrate specificity for L-lysine on the fish enzymes. [ABSTRACT FROM AUTHOR]

Electrostatic gripper is a technology that has seen many advancements in the last few decades. Its popularity among researchers is due mainly to many advantages it offers, e.g. its ability of a simple force control by adjusting the applied voltage to the electrodes. The electrostatic gripper with voltages of positive and negative polarities is particularly deemed promising as it can handle various materials, especially dielectrics, by the principle of polarization due to the electric fields. In this work, an electrostatic gripper with a beam-array structure made of conductive polymeric fibers is considered. The structure of coaxial electrodes has been understood to sport a superior performance; however no comparative analysis has been reported so far. Thus, this work offers an empirical comparison between fibers consisting of coaxial and parallel electrodes by experiments which are validated by numerical simulations. Furthermore, utilizing numerical simulations, design guidelines, especially concerning the voltage polarity patterns are established. The results are expected to shed an insight toward the development of a full-fledged electrostatic gripper for industrial use. [ABSTRACT FROM AUTHOR]

In this paper, we propose a successful fabrication method for a bipolar electrostatic chuck (ESC) device with a beam-array assembly, in order to achieve a fairly flat surface on the beam’s tip. A fabricated bipolar ESC device is expected to clamp a curved dielectric object due to its elastically-deformable beams, which are compliant with an object’s surface. As a fabrication process, the lithography technique including multiple etching processes against a single etching mask was performed to etch a three-layer material (conductor–dielectric–conductor). Due to the fairly flat surface of the beam’s tip (figure 4(c)), sufficient adhesional contact area with the target object for a large adhesional force can be obtained. In order to understand the adhesion performance of the device, an experimental force curve was measured and partially compared with the theoretical adhesional force calculated using finite element analysis. The Pascal-expression for future work dealing with a large surface area was also calculated, corresponding to stacked prototype modules. [ABSTRACT FROM AUTHOR]

A compliant electrostatic gripper with bipolar voltage polarity for a pick-and-place manipulation is presented. The compliance, realized by the introduction of an array of micropillars which act as the electrode, extends the application of electrostatic-based gripper to manipulating fragile, rough-surfaced dielectric objects at macro scale. A prototype consisting of two arrays is developed by a chemical etching process. The experimental force is then compared with the theoretical force obtained from a simulation, showing a discrepancy between them. The sources of the discrepancy are analyzed to provide design insight for force improvement. To assess the reliability, the prototype is used for a manipulation demonstration of flat-surfaced paper. The result shows a good repeatability, and the necessary pick-up condition is confirmed. Subsequently, as the proof of the concept, another pick-up for rough-surfaced objects represented by a tissue paper with different roughness condition is also demonstrated. The effect of the rough surfaces to the generated forces is qualitatively discussed. [ABSTRACT FROM AUTHOR]

By clarifying the effect of surface conductivity and adhesivity on the electrostatic manipulation condition, a dielectric particle made of any material can be manipulated with surface conductivity. The manipulation system consists of three elements: a conductive probe as a manipulator, a conductive plate as a substrate, and a dielectric particle as the target object for manipulation. The particle can be successfully picked up/placed if a rectangular pulse voltage is applied between the probe and the plate. Four kinds of particle materials are used in the experiment: silica, soda-lime glass, polymethyl methacrylate coated by conductive polymer, and polystyrene coated by surfactant. The radius of each particle is 15 μm. A first-order resistor-capacitor (RC) circuit model is adopted to describe the effect of surface conductivity and adhesivity on the manipulation condition. The manipulation system is modeled as a series circuit consisting of a resistor and a capacitor by considering the surface conductivity. A detachment voltage is defined as the capacitance voltage to detach the particle adhered to the plate or probe. Parameters of the RC model, surface resistance, surface capacitance and detachment voltage are identified by a simulation and measurements. To verify the RC model, the particle’s behavior is observed by a high-speed camera, and the electrical current is measured by an electrometer. A manipulation experiment is demonstrated to show the effectiveness of the model. The particle reaction is observed for each duration and magnitude of the pulse voltage for the manipulation. The optimum pulse voltage for successful manipulation is determined by the parameters of the RC model as the standard. This knowledge is expected to expand the possibility of micro-fabrication technology. [ABSTRACT FROM AUTHOR]

This note reports on an experimental demonstration of non-impact deposition for electrostatic micromanipulation of a conductive particle by a single probe. The experimental system consists of a probe, a 30-micrometers-in-diameter particle, and a substrate plate. The particle, initially adhering to the probe tip, is detached and deposited onto the substrate by rapid change of the probe-substrate voltage designed on the basis of calculation by a boundary element method. The feasibility is experimentally shown; furthermore, the method of modifying the voltage sequence to improve the rate of success by considering the finite slew rate of the power source is discussed. [ABSTRACT FROM AUTHOR]