Anti-carbamylated protein antibodies drive AEC II toward a profibrotic phenotype by interacting with carbamylated TLR5.

OBJECTIVES: This study was to explore the role of Anti-carbamylated protein (Anti-CarP) antibodies in contributing to lung fibrosis in connective tissue disease (CTD)-associated interstitial lung disease (ILD) in an autoantigen-dependent manner. METHODS: ELISA tested serum samples, including 89 of CTD-ILD group and 170 of non-ILD CTD, for the anti-CarP levels. Male C57BL/6 mice were used for pulmonary fibrosis model and anti-CarP treatment in vivo (n = 5), and patient serum-derived or commercialized anti-CarP for cell treatment. We identified the carbamylated membrane protein via immunofluorescence (IF) and coimmunoprecipitation followed by mass spectrometry (MS) analysis. RT-qPCR, IF and western blot were performed to explore the antigen-dependent role of anti-CarP. Native electrophoretic mobility shift assay and MS analysis were used to verify direct interaction and carbamylation sites. RESULTS: A significantly higher serum anti-CarP level was observed in CTD with ILD than without ILD. In vivo, intrapulmonary delivery of anti-CarP induces epithelial-mesenchymal transition (EMT) and micro fibrotic foci. Carbamylation was enriched in type II alveolar epithelial cells (AEC II). A novel carbamylated membrane receptor, specifically recognized by anti-CarP, was identified as toll-like receptor 5 (TLR5). We found anti-CarP induces the nuclear translocation of NF-κB and downstream events, including EMT and expression of inflammatory cytokines in AEC II, which were reversed by TLR5 blocking or TLR5 knockdown. Moreover, up to 12 lysine carbamylation sites were found in TLR5 ectodomain, allowing the interaction of anti-CarP with carbamylated TLR5. CONCLUSIONS: Overall, we found anti-CarP drives aberrant AEC II activation by interacting with carbamylated TLR5 to promote ILD progress.

Acoustofluidic manipulation for submicron to nanoparticles.

Particles, ranging from submicron to nanometer scale, can be broadly categorized into biological and non-biological types. Submicron-to-nanoscale bioparticles include various bacteria, viruses, liposomes, and exosomes. Non-biological particles cover various inorganic, metallic, and carbon-based particles. The effective manipulation of these submicron to nanoparticles, including their separation, sorting, enrichment, assembly, trapping, and transport, is a fundamental requirement for different applications. Acoustofluidics, owing to their distinct advantages, have emerged as a potent tool for nanoparticle manipulation over the past decade. Although recent literature reviews have encapsulated the evolution of acoustofluidic technology, there is a paucity of reports specifically addressing the acoustical manipulation of submicron to nanoparticles. This article endeavors to provide a comprehensive study of this topic, delving into the principles, apparatus, and merits of acoustofluidic manipulation of submicron to nanoparticles, and discussing the state-of-the-art developments in this technology. The discourse commences with an introduction to the fundamental theory of acoustofluidic control and the forces involved in nanoparticle manipulation. Subsequently, the working mechanism of acoustofluidic manipulation of submicron to nanoparticles is dissected into two parts, dominated by the acoustic wave field and the acoustic streaming field. A critical analysis of the advantages and limitations of different acoustofluidic platforms in nanoparticles control is presented. The article concludes with a summary of the challenges acoustofluidics face in the realm of nanoparticle manipulation and analysis, and a forecast of future development prospects.

Online identification of chemical constituents in Mongolian medicine Zhachong-13 pills by UHPLC-Q-exactive Orbitrap MS.

Zhachong-13 pills (ZC-13), as a traditional prescription of Mongolian medicine, are often used in the clinical practice of Mongolian hospitals for the treatment of stroke and rheumatic arthritis. In this experiment, UHPLC-Q-Exactive Orbitrap MS was used to explore the chemical composition of ZC-13. The results showed that 315 compounds were identified or inferred, including 56 alkaloids, 77 2-(2-phenylethyl)chromones, 61 flavonoids, 31 tannins, 8 coumarins, 16 lignans, 21 terpenoids, 5 amino acids, 19 organic acids, and 21 other components. In addition, the pharmacological activities related to anti-cerebral ischemia of these components were summarized. This result laid a foundation for further study on the pharmacodynamic material basis of ZC-13 and provided a scientific basis for the formulation of ZC-13 quality specifications.

Role of CXCL16 in BLM-induced epithelial-mesenchymal transition in human A549 cells.

Alveolar epithelial cells play an essential role in the initiation and progression of pulmonary fibrosis, and the occurrence of epithelial-mesenchymal transition (EMT) may be the early events of pulmonary fibrosis. Recent studies have shown chemokines are involved in the complex process of EMT, and CXC chemokine ligand 16 (CXCL16) is also associated with many fibrosis-related diseases. However, whether CXCL16 is dysregulated in alveolar epithelial cells and the role of CXCL16 in modulating EMT in pulmonary fibrosis has not been reported. In this study, we found that CXCL16 and its receptor C-X-C motif chemokine receptor 6 (CXCR6) were upregulated in bleomycin induced EMT in human alveolar type II-like epithelial A549 cells. Synergistic effect of CXCL16 and bleomycin in promoting EMT occurrence, extracellular matrix (ECM) excretion, as well as the pro-inflammatory and pro-fibrotic cytokines productions in A549 cells were observed, and those biological functions were impaired by CXCL16 siRNA. We further confirmed that CXCL16 regulated EMT in A549 cells via the TGF-ß1/Smad3 pathways. These results indicated that CXCL16 could promote pulmonary fibrosis by promoting the process of EMT via the TGF-ß1/Smad3 signaling pathway.

Expression of caveolin family proteins in serum of patients with systemic lupus erythematosus.

OBJECTIVES: Caveolin family proteins, including caveolin-1 (Cav-1), caveolin-2 (Cav-2), and caveolin-3 (Cav-3), are identified as the principal protein components of caveolae in mammalian cells. Circulating form of caveolin family proteins can be used as a good potential biomarker for predicting disease. METHODS: To investigate the clinical significance of the serological levels of caveolin family proteins in patients with systemic lupus erythematosus (SLE), we evaluated the soluble serum levels of caveolin family proteins in patients with SLE by enzyme-linked immunosorbent assay (ELISA) and assessed their associations with various known clinical variables. RESULTS: The major findings of our study are as follows: Cav-2 was not detected in serum of SLE patients and normal controls (NCs). Serum Cav-1 and Cav-3 levels were higher in SLE patients compared with NCs. There were no significant correlations between serum Cav-1 and Cav-3 levels and SLE disease activity. Further analysis showed that serum Cav-3 may be more valuable as a marker than serum Cav-1 in SLE patients. CONCLUSION: Serum levels of Cav-1 and Cav-3 might have a diagnostic role in patients with SLE. However, their predictive and prognostic value was not determined. Further studies are necessary to determine the potential clinical significance of these assays in SLE.

Concentration-induced wettability alteration of nanoscale NaCl solution droplets on the CSH surface.

Due to the hydrophilic nature of concrete, moisture and corrosive ions adsorbed on its surface pose a severe challenge to the durability of concrete structures; therefore, investigating the wettability of a concrete surface is an indispensable prerequisite for designing durable and sustainable concrete. This paper utilizes molecular dynamics to simulate the concentration-induced wettability alteration of nanoscale NaCl droplets on a CSH surface, and verifies the feasibility and rationality of predicting the contact angle of a droplet on the CSH surface based on the surface tension. Results suggest that the wetting ability of droplets on the CSH surface is weakened with the increase of the NaCl mass fraction. Microscopic analysis reveals that water molecules clustered around Na+ and Cl- ions to form an ion hydration shell (Na+-Ow and Cl--Hw pairs); the binding energy barrier of these ion pairs is much larger than the dissociation energy barrier, which enhances the associative ability of the NaCl droplets. The particles on the CSH surface attract Na+ and Cl- ions by forming Oh(Os)-Na+ and Ca(Ho)-Cl- connections with droplets, which further weakens the spreading ability of water molecules on the CSH surface.

Structure, dynamics and transport behavior of migrating corrosion inhibitors on the surface of calcium silicate hydrate: a molecular dynamics study.

The incorporation of a corrosion inhibitor into a cement-based material can enhance the durability of the reinforced concrete. In this study, molecular dynamics simulation is utilized to study the interfacial structure and dynamic behavior of a solution with three migrating corrosion inhibitors (MCI) functionalized by hydroxyl (-OH), carboxyl (-COO-), and phenyl (-PH) groups in calcium silicate hydrate (CSH) gel pores. The transport rate of inhibitors is greatly dependent on the polarity of the functional group: -PH > -OH > -COO-. The slow migration rate of the inhibitor with -OH and -COO- is attributed to the chemical bond formed between CSH and MCI. The silicate chains near the CSH surface can provide plenty of non-bridging oxygen sites to accept the H-bond from the hydroxyl group in the inhibitor molecule. The surface calcium atom can capture the -COO- by forming an ionic COO-Ca bond. Furthermore, the hydration structure of the inhibitor molecule also influences its transport properties. The inhibitor functionalized by the carboxyl group, associating with the neighboring water molecules, forms ion-water clusters, and the inhibitor molecule and its hydration shell with a long resident time retard the migration rate. Hopefully, this study is able to provide molecules for the development of a migration-type corrosion inhibitor to elongate the service life of cement-based materials.

The contribution of macrophages to systemic lupus erythematosus.

As a heterogeneous autoimmune disease associated with severe organ damage, the precise mechanisms of systemic lupus erythematosus (SLE) remain to be clarified. Recent research indicates that innate immunity plays vital roles in SLE. Defects in the phagocytosis of apoptotic cells, aberrant activation and imbalanced polarization of macrophages, have been shown to participate in the pathogenesis of SLE. Treatments targeting these processes may ameliorate the disease activity in lupus models as well as in patients with SLE. Macrophages participate in the initiation of autoimmunity and the development of SLE in multiple levels. Better understanding of this complex disease is the prerequisite for exploring more effective therapies of SLE.

Association of polymorphisms in TNF and GRN genes with ankylosing spondylitis in a Chinese Han population.

The aim of this study is to investigate the association of the polymorphisms in tumor necrosis factor (TNF) and granulin (GRN) with ankylosing spondylitis (AS) in a Chinese Han population. Five single nucleotide polymorphisms (SNPs) covering TNF and six SNPs covering GRN were investigated in 861 Chinese Han AS patients and 864 healthy controls. For rs1799964, the C allele was linked to reduced risk of AS (p < 0.0001, OR = 0.60, 95% CI = 0.50-0.71). The carriers of the C/C homozygote showed a significantly lower risk of AS compared with the TT homozygote and the C/T heterozygote under the recessive model (p < 0.0001, OR = 0.23, 95% CI = 0.12-0.45). For rs1800629, the A allele was also linked to reduced risk of AS (p < 0.0001, OR = 0.54, 95% CI = 0.39-0.74). For rs1800630, the A allele was also linked to reduced risk of AS (p < 0.0001, OR = 0.59, 95% CI = 0.48-0.72). The carriers of the A/A homozygote showed a significantly lower risk of AS compared with the C/C homozygote and the A/C heterozygote under the recessive model (p < 0.0001, OR = 0.18, 95% CI = 0.07-0.47). For rs769178, the T allele was linked to increased risk of AS (p < 0.0001, OR = 2.59, 95% CI = 2.18-3.09). The carriers of the T/T homozygote showed a significantly higher risk of AS compared with the GG homozygote and the G/T heterozygote under the recessive model (p < 0.0001, OR = 3.34, 95 %CI = 1.95-5.72). There was no significant difference between the AS patients and the controls in the genotype or allele frequencies of rs361525. For GRN, there was no significant difference between the AS patients and the controls in the genotype or allele frequencies of rs25646, rs3760365, rs3785817, rs4792939, rs5848, rs850713 (p > 0.05). This study indicates that polymorphisms in TNF are related to AS, but polymorphisms in GRN are not related to AS susceptibility in a Chinese Han population.

Novel Gas Sensor Arrays Based on High-Q SAM-Modified Piezotransduced Single-Crystal Silicon Bulk Acoustic Resonators.

This paper demonstrates a novel micro-size (120 µm × 200 µm) piezoelectric gas sensor based on a piezotransduced single-crystal silicon bulk acoustic resonator (PSBAR). The PSBARs operate at 102 MHz and possess high Q values (about 2000), ensuring the stability of the measurement. A corresponding gas sensor array is fabricated by integrating three different self-assembled monolayers (SAMs) modified PSBARs. The limit of detection (LOD) for ethanol vapor is demonstrated to be as low as 25 ppm with a sensitivity of about 1.5 Hz/ppm. Two sets of identification code bars based on the sensitivities and the adsorption energy constants are utilized to successfully discriminate isopropanol (IPA), ethanol, hexane and heptane vapors at low and high gas partial pressures, respectively. The proposed sensor array shows the potential to form a portable electronic nose system for volatile organic compound (VOC) differentiation.

Modelling the presence and identifying the determinant factors of dominant macroinvertebrate taxa in a karst river.

Modelling the macroinvertebrate community is important for evaluating the status of aquatic ecosystem health. Alternative to physical-based approaches, this study proposed two data-driven methods, support vector machine (SVM) and artificial neural network (ANN), to model the presence of macroinvertebrate species in rivers based on abiotic features. A famous karst river, Lijiang River, in Southwest China was selected as the study case. A total of 300 records containing data on 11 physicochemical parameters were collected from the upstream, midstream and downstream reaches of the river over a 2-year period (2009-2010) and were used for model construction and verification. Ten dominant macroinvertebrate taxa in the study area were modelled. In addition, the performance of the two methods was compared, and the relative importance of the independent variables was identified. The obtained results mapped abiotic factors to the species presence and could be used in combination with a two-dimensional hydro-environmental model to assess the impacts of flow regulation on macroinvertebrate dynamics. Furthermore, the SVM model performed slightly better than the ANN model in the studied case.

A standardized method for quantifying proliferation by Ki-67 and cyclin A immunohistochemistry in breast cancer.

Immunohistochemical analysis of proliferation markers such as Ki-67 and cyclin A is widely used in clinical evaluation as a prognostic factor in breast cancer. The proliferation status of tumors is guiding the decision of whether or not a patient should be treated with chemotherapy because low-proliferative tumors are less sensitive by such treatment. However, the lack of optimal cutoff points and selection of tumor areas hamper its use in clinical practice. This study was performed to compare the Ki-67 and cyclin A expression counted in hot-spot vs average counting based on 5 to 14 random tumor areas in 613 breast carcinomas. We correlated the findings with 10-year follow-up in order to standardize the evaluation of proliferation markers in clinical practice. A significant correlation was found between the percentage of positive cells estimated by Ki-67 and cyclin A both by hot-spot and by average counting. Both methods showed that high expression of Ki-67 and cyclin A is associated with more adverse tumor stage. The cutoff value for Ki-67 for distant metastases was set to 22% and to 15%, using hot-spot and average counting, respectively. For cyclin A, the values were set to 14% and 8% using the respective methods. Survival curves revealed that patients with a high hot-spot proliferation index had a significantly greater risk of shorter tumor-free survival. Our findings suggest that the determination of proliferation markers in breast cancer should be standardized to hot-spot counting and that specific cutoff values for proliferation could be useful as prognostic markers in clinical practice. Moreover, we suggest that expression levels of cyclin A could be used as a complementary marker to estimate the proliferation status in tumors, especially those with "borderline" expression levels of Ki-67, in order to more accurately estimate the proliferations status of the tumors.

Association of polymorphisms in SPARC and NLRP2 genes with rheumatoid arthritis in a Chinese Han population.

OBJECTIVES: To investigate the association of the polymorphisms in SPARC and NLRP2 with rheumatoid arthritis (RA) in a Chinese Han population. METHODS: Four single nucleotide polymorphisms (SNPs) covering SPARC and three SNPs covering NLRP2 were investigated in 624 Chinese Han RA patients and 1920 healthy controls. RESULTS: The A allele at SPARC rs3210714, SPARC rs11950384, NLRP2 rs2217659, and NLRP2 rs703468 were linked to reduced risk of RA (p = 0.0016, p = 0.0051, p < 0.0001, and p = 0.0033, respectively). Under the recessive model, the A/A genotype of rs3210714, rs11950384, rs2217659, and rs703468 were relevant with RA (p = 0.0071, p = 0.017, p < 0.0001 and p = 0.0066, respectively). Haplotype analysis identified the SPARC GGCG haplotype, AAAA haplotype were associated with the risk for RA (p < 0.0001 and p = 0.0015, respectively), while the risk of RA was lower for carriers of the GAAA haplotype (p < 0.0001), AACG haplotype (p < 0.0001), and the AGCG haplotype (p < 0.0001). The NLRP2 GG haplotype was a risk factor (p < 0.0001), while the GA haplotype and the AG haplotype were associated with lower risk of RA (p < 0.0001 and p = 0.0017, respectively). There was no significant difference between the RA patients and the controls in polymorphisms of rs7719521, rs1978707, and rs269913. CONCLUSION: This study indicates that polymorphisms in SPARC and NLRP2 are related to RA susceptibility in a Chinese Han population.

The aberrant expression of stimulatory and inhibitory killer immunoglobulin-like receptors in NK- and NKT-cells contributes to lupus.

BACKGROUND: Killer cell immunoglobulin-like receptors (KIR) contribute to the pathogenesis of multiple auto-immune diseases via the modulation of NK-, NKT- and T-cells. Thus, we want to know whether the expression pattern of KIR is associated with systemic lupus erythematosus (SLE) susceptibility. METHODS: Here, real-time quantitative PCR and fluorescence-activated cell sorting (FACS) were used to measure the stimulatory KIR (sKIR) and inhibitory KIR (iKIR) mRAN and protein levels on NK-, NKT- and T-cells in both SLE patients and healthy controls. RESULTS: In SLE patients, CD158a/h (KIR2DL1/S1) was highly expressed while CD158b/i/j (KIR2DL2/L3/S2, iKIR/iKIR/sKIR) was lowly expressed in NK- and NKT-cells in patients. The expression levels of KIR2DL1 and KIR2DL2 (iKIRs) were decreased while the expression levels of KIR2DS1 (sKIR) were increased in NK- and NKT-cells in the patients. CONCLUSIONS: We found that SLE patients represent aberrant expression of stimulatory and inhibitory KIRs in NK- and NKT-cells. Consequently, these different expression levels of KIRs may contribute to the abnormal function of these cells, which lead to the risk of SLE.

Long-term efficacy, safety, and cumulative retention rate of antitumor necrosis factor-alpha treatment for patients with Behcet's uveitis: A systematic review and meta-analysis.

AIM: This study aims to evaluate the long-term efficacy, safety, and cumulative retention rate of antitumor necrosis factor-alpha (anti-TNF-α) therapy for patients with Behcet's uveitis (BU) using meta-analysis. METHODS: We searched the Web of Science and PubMed databases for eligible studies up to December 1, 2022. The quality of each identified study was assessed using the Joanna Briggs Institute's case series literature quality assessment tool. Statistical analysis was conducted using Stata 16.0 software with a random-effects model. RESULTS: Twelve studies comprising 1156 patients with BU were included in our analysis. We found that 85.0% of patients achieved ocular inflammation remission after receiving anti-TNF-α treatment, with a 95% confidence interval (CI) ranging from 78.7% to 90.5%. Additionally, 77.4% (95% CI: 57.5%-92.5%) experienced an improvement in visual acuity (VA). Moreover, the pooled dose reduction of glucocorticoids (GCs) was 11.08 mg (95% CI: -13.34 mg to -8.83 mg). Throughout the follow-up period, the cumulative retention rate of the medication was 67.3% (95% CI: 53.7%-79.6%). Serious adverse events occurred in 5.8% (95% CI: 3.1%-8.9%) of cases, with the three most common types being severe infusion or injection reactions (2.7%; 95% CI: 0.8%-5.4%), tuberculosis (1.3%; 95% CI: 0.0%-3.9%), and bacterial pneumonia (1.3%; 95% CI: 0.1%-3.4%). Subgroup analysis revealed that ocular inflammation remission rates were 89.3% (95% CI: 81.2%-95.5%) for adalimumab treatment and 83.7% (95% CI: 75.3%-90.8%) for infliximab treatment. The drug retention rate after adalimumab therapy was 70.3% (95% CI: 62.0%-78.0%) compared to 66.4% (95% CI: 48.6%-82.2%) for infliximab treatment. Furthermore, the incidence of severe infusion or injection reactions was 2.2% (95% CI: 0.1%-5.8%) following adalimumab treatment and 3.5% (95% CI: 0.7%-7.7%) following infliximab treatment. CONCLUSIONS: Anti-TNF-α therapy represents an effective treatment for BU patients with favorable safety profile and high drug retention rate and a potential advantage of adalimumab over infliximab in terms of ocular inflammation remission, drug retention, and the incidence of severe infusion or injection reactions.

Concentration of Microparticles/Cells Based on an Ultra-Fast Centrifuge Virtual Tunnel Driven by a Novel Lamb Wave Resonator Array.

The µTAS/LOC, a highly integrated microsystem, consolidates multiple bioanalytical functions within a single chip, enhancing efficiency and precision in bioanalysis and biomedical operations. Microfluidic centrifugation, a key component of LOC devices, enables rapid capture and enrichment of tiny objects in samples, improving sensitivity and accuracy of detection and diagnosis. However, microfluidic systems face challenges due to viscosity dominance and difficulty in vortex formation. Acoustic-based centrifugation, particularly those using surface acoustic waves (SAWs), have shown promise in applications such as particle concentration, separation, and droplet mixing. However, challenges include accurate droplet placement, energy loss from off-axis positioning, and limited energy transfer from low-frequency SAW resonators, restricting centrifugal speed and sample volume. In this work, we introduce a novel ring array composed of eight Lamb wave resonators (LWRs), forming an Ultra-Fast Centrifuge Tunnel (UFCT) in a microfluidic system. The UFCT eliminates secondary vortices, concentrating energy in the main vortex and maximizing acoustic-to-streaming energy conversion. It enables ultra-fast centrifugation with a larger liquid capacity (50 µL), reduced power usage (50 mW) that is one order of magnitude smaller than existing devices, and greater linear speed (62 mm/s), surpassing the limitations of prior methods. We demonstrate successful high-fold enrichment of 2 µm and 10 µm particles and explore the UFCT's potential in tissue engineering by encapsulating cells in a hydrogel-based micro-organ with a ring structure, which is of great significance for building more complex manipulation platforms for particles and cells in a bio-compatible and contactless manner.

Low-Voltage High-Frequency Lamb-Wave-Driven Micromotors.

By leveraging the benefits of a high energy density, miniaturization and integration, acoustic-wave-driven micromotors have recently emerged as powerful tools for microfluidic actuation. In this study, a Lamb-wave-driven micromotor is proposed for the first time. This motor consists of a ring-shaped Lamb wave actuator array with a rotor and a fluid coupling layer in between. On a driving mechanism level, high-frequency Lamb waves of 380 MHz generate strong acoustic streaming effects over an extremely short distance; on a mechanical design level, each Lamb wave actuator incorporates a reflector on one side of the actuator, while an acoustic opening is incorporated on the other side to limit wave energy leakage; and on electrical design level, the electrodes placed on the two sides of the film enhance the capacitance in the vertical direction, which facilitates impedance matching within a smaller area. As a result, the Lamb-wave-driven solution features a much lower driving voltage and a smaller size compared with conventional surface acoustic-wave-driven solutions. For an improved motor performance, actuator array configurations, rotor sizes, and liquid coupling layer thicknesses are examined via simulations and experiments. The results show the micromotor with a rotor with a diameter of 5 mm can achieve a maximum angular velocity of 250 rpm with an input voltage of 6 V. The proposed micromotor is a new prototype for acoustic-wave-driven actuators and demonstrates potential for lab-on-a-chip applications.

Phenotypes of patients with systemic sclerosis in the Chinese Han population: a cluster analysis.

OBJECTIVE: Systemic sclerosis (SSc) is a heterogeneous connective tissue disease that is commonly subdivided into limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) based on the extent of skin involvement. This subclassification may not reflect the full range of clinical phenotypic variation. This study aimed to investigate clinical features and aggregation of patients with SSc in Chinese based on SSc manifestations and organ involvements, in order to achieve precise treatment of SSc early prevention of complications. METHODS: In total 287 SSc patients were included in this study. A cluster analysis was applied according to 13 clinical and serologic variables to determine subgroups of patients. Survival rates between obtained clusters and risk factors affecting prognosis were also compared. RESULT: In this study, six clusters were observed: cluster 1 (n = 66) represented the skin type, with all patients showing skin thickening. In cluster 2 (n = 56), most patients had vascular and articular involvement. Cluster 3 (n = 14) individuals mostly had cardiac and pulmonary involvement. In cluster 4 (n = 52), the gastrointestinal type, 50 patients presented with stomach symptoms and 28 patients presented with esophageal symptoms. In cluster 5 (n = 50), patients barely had any major organ involvement. Cluster 6 (n = 49) included 46% of all patients presenting with renal crisis. CONCLUSION: The results of our cluster analysis study implied that limiting SSc patient subgroups to those based only on skin involvement might not capture the full heterogeneity of the disease. Organ damage and antibody profiles should be considered when identifying homogeneous patient groups with a specific prognosis. Key Points • Provides a new method of categorizing SSc patients. • Can better explain disease progression and guide subsequent treatment.

Miniaturized Multi-Cantilever MEMS Resonators with Low Motional Impedance.

Microelectromechanical system (MEMS) cantilever resonators suffer from high motional impedance (Rm). This paper investigates the use of mechanically coupled multi-cantilever piezoelectric MEMS resonators in the resolution of this issue. A double-sided actuating design, which utilizes a resonator with a 2.5 µm thick AlN film as the passive layer, is employed to reduce Rm. The results of experimental and finite element analysis (FEA) show agreement regarding single- to sextuple-cantilever resonators. Compared with a standalone cantilever resonator, the multi-cantilever resonator significantly reduces Rm; meanwhile, the high quality factor (Q) and effective electromechanical coupling coefficient (Kteff2) are maintained. The 30 µm wide quadruple-cantilever resonator achieves a resonance frequency (fs) of 55.8 kHz, a Q value of 10,300, and a series impedance (Rs) as low as 28.6 kΩ at a pressure of 0.02 Pa; meanwhile, the smaller size of this resonator compared to the existing multi-cantilever resonators is preserved. This represents a significant advancement in MEMS resonators for miniaturized ultra-low-power oscillator applications.

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) activates p38 to affect pulmonary fibrosis.

Objective: We aimed to examine whether heparin-binding epidermal growth factor-like growth factor (HB-EGF) affects the lung fibrosis process through the activation of p38 protein in mitogen-activated protein kinases (MAPK) signaling pathway, as well as the expression of downstream inflammatory factors. Methods: The expression levels of HB-EGF, collagen type I (COL-I), and hexokinase 2 (HK2) in peripheral blood mononuclear cells (PBMCs) of patients with connective tissue disease-related interstitial lung disease (CTD-ILD) were examined by qPCR, Western blotting and ELISA. Results: In vitro experiments showed that HB-EGF was increased in almost all subtypes [rheumatoid arthritis (RA), systemic sclerosis (SSc) and idiopathic inflammatory myopathies (IIMs)] as well as in all groups (P < 0.05). For embryonic lung fibroblast (A549) cells, the expression levels of HK2 and α-smooth muscle actin (α-SMA) genes were elevated during 0-4 h and then plateaued. Transforming growth factor-ß1 (TGF-ß1) induced fibrosis in human embryonic lung fibroblasts (MRC-5) cells and A549 for a certain period of time, but the degree of induction varied, which may be related to the redifferentiability of cells at different spatial locations. Moreover, HB-EGF at concentrations above 1 ng/ml stimulation increased COL-I expression (P < 0.05), and for α-SMA gene, even 1 ng/ml concentration of HB-EGF had a stimulatory effect, and different concentrations of HB-EGF did activate the expression of p38 in a concentration-dependent manner within a certain concentration range, and by The qPCR results showed that for interleukin 6 (IL-6), an inflammatory factor regulated downstream of p38, the expression was significantly increased in A549 cells compared to control (P < 0.05), but tumor necrosis factor-α (TNF-α) expression was downregulated (P < 0.05), but for interleukin-1ß (IL-1ß) gene, there was no significant difference in A549 cells, and expression was downregulated in MRC-5 cells. Therefore, it is suggested that HB-EGF regulates the expression of inflammatory factors through p38 will be differential across cells. Conclusion: Our study shows that HB-EGF can suppress pulmonary fibrosis through downstream activation of p38/MAPK pathway activity, as well as the expression of various inflammatory factors downstream of it.