Endothelial phosphodiesterase 4B inactivation ameliorates endothelial-to-mesenchymal transition and pulmonary hypertension.

Pulmonary hypertension (PH) is a fatal disorder characterized by pulmonary vascular remodeling and obstruction. The phosphodiesterase 4 (PDE4) family hydrolyzes cyclic AMP (cAMP) and is comprised of four subtypes (PDE4A-D). Previous studies have shown the beneficial effects of pan-PDE4 inhibitors in rodent PH; however, this class of drugs is associated with side effects owing to the broad inhibition of all four PDE4 isozymes. Here, we demonstrate that PDE4B is the predominant PDE isozyme in lungs and that it was upregulated in rodent and human PH lung tissues. We also confirmed that PDE4B is mainly expressed in the lung endothelial cells (ECs). Evaluation of PH in Pde4b wild type and knockout mice confirmed that Pde4b is important for the vascular remodeling associated with PH. In vivo EC lineage tracing demonstrated that Pde4b induces PH development by driving endothelial-to-mesenchymal transition (EndMT), and mechanistic studies showed that Pde4b regulates EndMT by antagonizing the cAMP-dependent PKA-CREB-BMPRII axis. Finally, treating PH rats with a PDE4B-specific inhibitor validated that PDE4B inhibition has a significant pharmacological effect in the alleviation of PH. Collectively, our findings indicate a critical role for PDE4B in EndMT and PH, prompting further studies of PDE4B-specific inhibitors as a therapeutic strategy for PH.

Effects of deep brain stimulation on dopamine D2 receptor binding in patients with treatment-refractory depression.

BACKGROUND: Depression is a chronic psychiatric disorder related to diminished dopaminergic neurotransmission. Deep brain stimulation (DBS) has shown effectiveness in treating patients with treatment-refractory depression (TRD). This study aimed to evaluate the effect of DBS on dopamine D2 receptor binding in patients with TRD. METHODS: Six patients with TRD were treated with bed nucleus of the stria terminalis (BNST)-nucleus accumbens (NAc) DBS were recruited. Ultra-high sensitivity [11C]raclopride dynamic total-body positron emission tomography (PET) imaging was used to assess the brain D2 receptor binding. Each patient underwent a [11C]raclopride PET scan for 60-min under DBS OFF and DBS ON, respectively. A simplified reference tissue model was used to generate parametric images of binding potential (BPND) with the cerebellum as reference tissue. RESULTS: Depression and anxiety symptoms improved after 3-6 months of DBS treatment. Compared with two-day-nonstimulated conditions, one-day BNST-NAc DBS decreased [11C]raclopride BPND in the amygdala (15.9 %, p < 0.01), caudate nucleus (15.4 %, p < 0.0001) and substantia nigra (10.8 %, p < 0.01). LIMITATIONS: This study was limited to the small sample size and lack of a healthy control group. CONCLUSIONS: Chronic BNST-NAc DBS improved depression and anxiety symptoms, and short-term stimulation decreased D2 receptor binding in the amygdala, caudate nucleus, and substantia nigra. The findings suggest that DBS relieves depression and anxiety symptoms possibly by regulating the dopaminergic system.

Inactivation of Malic Enzyme 1 in Endothelial Cells Alleviates Pulmonary Hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a progressive cardiopulmonary disease with a high mortality rate. Although growing evidence has revealed the importance of dysregulated energetic metabolism in the pathogenesis of PH, the underlying cellular and molecular mechanisms are not fully understood. In this study, we focused on ME1 (malic enzyme 1), a key enzyme linking glycolysis to the tricarboxylic acid cycle. We aimed to determine the role and mechanistic action of ME1 in PH. METHODS: Global and endothelial-specific ME1 knockout mice were used to investigate the role of ME1 in hypoxia- and SU5416/hypoxia (SuHx)-induced PH. Small hairpin RNA and ME1 enzymatic inhibitor (ME1*) were used to study the mechanism of ME1 in pulmonary artery endothelial cells. Downstream key metabolic pathways and mediators of ME1 were identified by metabolomics analysis in vivo and ME1-mediated energetic alterations were examined by Seahorse metabolic analysis in vitro. The pharmacological effect of ME1* on PH treatment was evaluated in PH animal models induced by SuHx. RESULTS: We found that ME1 protein level and enzymatic activity were highly elevated in lung tissues of patients and mice with PH, primarily in vascular endothelial cells. Global knockout of ME1 protected mice from developing hypoxia- or SuHx-induced PH. Endothelial-specific ME1 deletion similarly attenuated pulmonary vascular remodeling and PH development in mice, suggesting a critical role of endothelial ME1 in PH. Mechanistic studies revealed that ME1 inhibition promoted downstream adenosine production and activated A2AR-mediated adenosine signaling, which leads to an increase in nitric oxide generation and a decrease in proinflammatory molecule expression in endothelial cells. ME1 inhibition activated adenosine production in an ATP-dependent manner through regulating malate-aspartate NADH (nicotinamide adenine dinucleotide plus hydrogen) shuttle and thereby balancing oxidative phosphorylation and glycolysis. Pharmacological inactivation of ME1 attenuated the progression of PH in both preventive and therapeutic settings by promoting adenosine production in vivo. CONCLUSIONS: Our findings indicate that ME1 upregulation in endothelial cells plays a causative role in PH development by negatively regulating adenosine production and subsequently dysregulating endothelial functions. Our findings also suggest that ME1 may represent as a novel pharmacological target for upregulating protective adenosine signaling in PH therapy.

Kinetic analysis of cardiac dynamic 18F-Florbetapir PET in healthy volunteers and amyloidosis patients: A pilot study.

Objectives: This study aimed to explore the potential of full dynamic PET kinetic analysis in assessing amyloid binding and perfusion in the cardiac region using 18F-Florbetapir PET, establishing a quantitative approach in the clinical assessment of cardiac amyloidosis disease. Materials & methods: The distribution volume ratios (DVRs) and the relative transport rate constant (R1), were estimated by a pseudo-simplified reference tissue model (pSRTM2) and pseudo-Logan plot (pLogan plot) with kidney reference for the region of interest-based and voxel-wise-based analyses. The parametric images generated using the pSRTM2 and linear regression with spatially constrained (LRSC) algorithm were then evaluated. Semi-quantitative analyses include standardized uptake value ratios at the early phase (SUVREP, 0.5-5 min) and late phase (SUVRLP, 50-60 min) were also calculated. Results: Ten participants [7 healthy controls (HC) and 3 cardiac amyloidosis (CA) subjects] underwent a 60-min dynamic 18F-Florbetapir PET scan. The DVRs estimated from pSRTM2 and Logan plot were significantly increased (HC vs CA; DVRpSRTM2: 0.95 ± 0.11 vs 2.77 ± 0.42, t'(2.13) = 7.39, P = 0.015; DVRLogan: 0.80 ± 0.12 vs 2.90 ± 0.55, t'(2.08) = 6.56, P = 0.020), and R1 were remarkably decreased in CA groups, as compared to HCs (HC vs CA; 1.08 ± 0.37 vs 0.56 ± 0.10, t'(7.63) = 3.38, P = 0.010). The SUVREP and SUVRLP were highly correlated to R1 (r = 0.97, P < 0.001) and DVR(r = 0.99, P < 0.001), respectively. The DVRs in the total myocardium region increased slightly as the size of FWHM increased and became stable at a Gaussian filter ≥6 mm. The secular equilibrium of SUVR was reached at around 50-min p.i. time. Conclusion: The DVR and R1 estimated from cardiac dynamic 18F-Florbetapir PET using pSRTM with kidney pseudo-reference tissue are suggested to quantify cardiac amyloid deposition and relative perfusion, respectively, in amyloidosis patients and healthy controls. We recommend a dual-phase scan: 0.5-5 min and 50-60 min p.i. as the appropriate time window for clinically assessing cardiac amyloidosis and perfusion measurements using 18F-Florbetapir PET.

SIRT1 activation promotes bone repair by enhancing the coupling of type H vessel formation and osteogenesis.

Bone repair is intricately correlated with vascular regeneration, especially of type H vessels. Sirtuin 1 (SIRT1) expression is closely associated with endothelial function and vascular regeneration; however, the role of SIRT1 in enhancing the coupling of type H vessel formation with osteogenesis to promote bone repair needs to be investigated. A co-culture system combining human umbilical vein endothelial cells and osteoblasts was constructed, and a SIRT1 agonist was used to evaluate the effects of SIRT1 activity. The angiogenic and osteogenic capacities of the co-culture system were examined using short interfering RNA. Mouse models with bone defects in the femur or mandible were established to explore changes in type H vessel formation and bone repair following modulated SIRT1 activity. SIRT1 activation augmented the angiogenic and osteogenic capacities of the co-culture system by activating the PI3K/AKT/FOXO1 signalling pathway and did not significantly regulate osteoblast differentiation. Inhibition of the PI3K/AKT/FOXO1 pathway attenuated SIRT1-mediated effects. The SIRT1 activity in bone defects was positively correlated with the formation of type H vessels and bone repair in vivo, whereas SIRT1 inhibition substantially weakened vascular and bone formation. Thus, SIRT1 is crucial to the coupling of type H vessels with osteogenesis during bone repair.

The role of zinc finger proteins in the fate determination of mesenchymal stem cells during osteogenic and adipogenic differentiation.

Zinc finger proteins (ZFPs) constitute a crucial group of transcription factors widely present in various organisms. They act as transcription factors, nucleases, and RNA-binding proteins, playing significant roles in cell differentiation, growth, and development. With extensive research on ZFPs, their roles in the determination of mesenchymal stem cells (MSCs) fate during osteogenic and adipogenic differentiation processes have become increasingly clear. ZFP521, for instance, is identified as an inhibitor of the Wnt signaling pathway and RUNX2's transcriptional activity, effectively suppressing osteogenic differentiation. Moreover, ZFP217 contributes to the inhibition of adipogenic differentiation by reducing the M6A level of the cell cycle regulator cyclin D1 (CCND1). In addition, other ZFPs can also influence the fate of mesenchymal stem cells (MSCs) during osteogenic and adipogenic differentiation through various signaling pathways, transcription factors, and epigenetic controls, participating in the subsequent differentiation and maturation of precursor cells. Given the prevalent occurrence of osteoporosis, obesity, and related metabolic disorders, a comprehensive understanding of the regulatory mechanisms balancing bone and fat metabolism is essential, with a particular focus on the fate determination of MSCs in osteogenic and adipogenic differentiation. In this review, we provide a detailed summary of how zinc finger proteins influence the osteogenic and adipogenic differentiation of MSCs through different signaling pathways, transcription factors, and epigenetic mechanisms. Additionally, we outline the regulatory mechanisms of ZFPs in controlling osteogenic and adipogenic differentiation based on various stages of MSC differentiation.

Dark respiration explains nocturnal stomatal conductance in rice regardless of drought and nutrient stress.

The ecological mechanism underlying nocturnal stomatal conductance (gsn ) in C3 and C4 plants remains elusive. In this study, we proposed a 'coordinated leaf trait' hypothesis to explain gsn in rice plants. We conducted an open-field experiment by applying drought, nutrient stress and the combined drought-nutrient stress. We found that gsn was neither strongly reduced by drought nor consistently increased by nutrient stress. With the aforementioned multiple abiotic stressors considered as random effects, gsn exhibited a strong positive correlation with dark respiration (Rn ). Notably, gsn primed early morning (5:00-7:00) photosynthesis through faster stomatal response time. This photosynthesis priming effect diminished after mid-morning (9:00). Leaves were cooled by gsn -derived transpiration. However, our results clearly suggest that evaporative cooling did not reduce dark respiration cost. Our results indicate that gsn is more closely related to carbon respiration and assimilation than water and nutrient availability, and that dark respiration can explain considerable variation of gsn .

New-generation geostationary satellite reveals widespread midday depression in dryland photosynthesis during 2020 western U.S. heatwave.

Emerging new-generation geostationary satellites have broadened the scope for studying the diurnal cycle of ecosystem functions. We exploit observations from the Geostationary Operational Environmental Satellite-R series to examine the effect of a severe U.S. heatwave in 2020 on the diurnal variations of ecosystem photosynthesis. We find divergent responses of photosynthesis to the heatwave across vegetation types and aridity gradients, with drylands exhibiting widespread midday and afternoon depression in photosynthesis. The diurnal centroid and peak time of dryland gross primary production (GPP) substantially shift toward earlier morning times, reflecting notable water and heat stress. Our geostationary satellite-based method outperforms traditional radiation-based upscaling methods from polar-orbiting satellite snapshots in estimating daily GPP and GPP loss during heatwaves. These findings underscore the potential of geostationary satellites for diurnal photosynthesis monitoring and highlight the necessity to consider the increased diurnal asymmetry in GPP under stress when evaluating carbon-climate interactions.

Vegetation photosynthetic phenology dataset in northern terrestrial ecosystems.

Vegetation phenology can profoundly modulate the climate-biosphere interactions and thus plays a crucial role in regulating the terrestrial carbon cycle and the climate. However, most previous phenology studies rely on traditional vegetation indices, which are inadequate to characterize the seasonal activity of photosynthesis. Here, we generated an annual vegetation photosynthetic phenology dataset with a spatial resolution of 0.05 degrees from 2001 to 2020, using the latest gross primary productivity product based on solar-induced chlorophyll fluorescence (GOSIF-GPP). We combined smoothing splines with multiple change-point detection to retrieve the phenology metrics: start of the growing season (SOS), end of the growing season (EOS), and length of growing season (LOS) for terrestrial ecosystems above 30° N latitude (Northern Biomes). Our phenology product can be used to validate and develop phenology or carbon cycle models and monitor the climate change impacts on terrestrial ecosystems.

N-Heterocyclic Olefin Type Ionic Liquid with Innate Soft Lewis-Base Character as an Effective Additive for Hybrid Quasi-2D and 3D Perovskite Solar Cells.

In optimizing perovskites with ionic liquid (IL), the comparative study on Lewis acid-base (LAB) and hydrogen-bonding (HB) interactions between IL and perovskite is lacking. Herein, methyl is substituted for hydrogen on 2-position of imidazolium ring of N-heterocyclic carbene (NHC) type IL IdH to weaken HB interactions, and the resulting N-heterocyclic olefin (NHO) type IL IdMe with softer Lewis base character is studied in both hybrid quasi-2D (Q-2D) and 3D perovskites. It is revealed that IdMe participates in constructing high-quality Q-2D perovskite (n = 4) and provides stronger passivation for 3D perovskite compared with IdH. Power conversion efficiency (PCE) of Q-2D PEA2 MA3 Pb4 I13 perovskite solar cells (PVSCs) is boosted to 17.68% from 14.03%. PCE and device stability of 3D PVSCs enhances simultaneously. Both theoretical simulations and experimental results show that LAB interactions between NHO and Pb2+ take the primary optimization effects on perovskite. The success of engineering LAB interactions also offers inspiration to develop novel ILs for high-performance PVSCs.

A novel Bayesian framework for harmonizing information across tissues and studies to increase cell type deconvolution accuracy.

Computational cell type deconvolution on bulk transcriptomics data can reveal cell type proportion heterogeneity across samples. One critical factor for accurate deconvolution is the reference signature matrix for different cell types. Compared with inferring reference signature matrices from cell lines, rapidly accumulating single-cell RNA-sequencing (scRNA-seq) data provide a richer and less biased resource. However, deriving cell type signature from scRNA-seq data is challenging due to high biological and technical noises. In this article, we introduce a novel Bayesian framework, tranSig, to improve signature matrix inference from scRNA-seq by leveraging shared cell type-specific expression patterns across different tissues and studies. Our simulations show that tranSig is robust to the number of signature genes and tissues specified in the model. Applications of tranSig to bulk RNA sequencing data from peripheral blood, bronchoalveolar lavage and aorta demonstrate its accuracy and power to characterize biological heterogeneity across groups. In summary, tranSig offers an accurate and robust approach to defining gene expression signatures of different cell types, facilitating improved in silico cell type deconvolutions.

Adenovirus-mediated Overexpression of FcγRIIB Attenuates Pulmonary Inflammation and Fibrosis.

Progressive fibrosing interstitial lung diseases (PF-ILDs) result in high mortality and lack effective therapies. The pathogenesis of PF-ILDs involves macrophages driving inflammation and irreversible fibrosis. Fc-γ receptors (FcγRs) regulate macrophages and inflammation, but their roles in PF-ILDs remain unclear. We characterized the expression of FcγRs and found upregulated FcγRIIB in human and mouse lungs after exposure to silica. FcγRIIB deficiency aggravated lung dysfunction, inflammation, and fibrosis in silica-exposed mice. Using single-cell transcriptomics and in vitro experiments, FcγRIIB was found in alveolar macrophages, where it regulated the expression of fibrosis-related genes Spp1 and Ctss. In mice with macrophage-specific overexpression of FcγRIIB and in mice treated with adenovirus by intratracheal instillation to upregulate FcγRIIB, silica-induced functional and histological changes were ameliorated. Our data from three genetic models and a therapeutic model suggest that FcγRIIB plays a protective role that can be enhanced by adenoviral overexpression, representing a potential therapeutic strategy for PF-ILDs.

Development of a 16-Channel Broadband Piezoelectric Micro Ultrasonic Transducer Array Probe for Pipeline Butt-Welded Defect Detection.

Butt welding is extensively applied in long-distance oil and gas pipelines, and it is of great significance to conduct non-destructive ultrasonic testing of girth welds in order to avoid leakage and safety accidents during pipeline production and operation. In view of the limitations of large transducer size, single fixed beam angle, low detection resolution and high cost of conventional ultrasonic inspection technologies, a 16-channel piezoelectric micro ultrasonic transducer (PMUT) array probe was developed through theoretical analysis and structural optimization design. After the probe impedance characterization, the experimental results show that the theoretical model can effectively guide the design of the ultrasonic transducer array, offering the maximum operating frequency deviation of less than 5%. The ultrasonic echo performance tests indicate that the average -6 dB bandwidth of the PMUT array probe can be up to 77.9%. In addition, the fabricated PMUT array probe has been used to successfully detect five common internal defects in pipeline girth welds. Due to the multiple micro array elements, flexible handling of each element, large bandwidth and high resolution of defect detection, the designed PMUT array probe can provide a good application potential in structural health monitoring and medical ultrasound imaging fields.

Phosphodiesterase 4D contributes to angiotensin II-induced abdominal aortic aneurysm through smooth muscle cell apoptosis.

Abdominal aortic aneurysm (AAA) is a permanent expansion of the abdominal aorta that has a high mortality but limited treatment options. Phosphodiesterase (PDE) 4 family members are cAMP-specific hydrolyzing enzymes and have four isoforms (PDE4A-PDE4D). Several pan-PDE4 inhibitors are used clinically. However, the regulation and function of PDE4 in AAA remain largely unknown. Herein, we showed that PDE4D expression is upregulated in human and angiotensin II-induced mouse AAA tissues using RT-PCR, western blotting, and immunohistochemical staining. Furthermore, smooth muscle cell (SMC)-specific Pde4d knockout mice showed significantly reduced vascular destabilization and AAA development in an experimental AAA model. The PDE4 inhibitor rolipram also suppressed vascular pathogenesis and AAA formation in mice. In addition, PDE4D deficiency inhibited caspase 3 cleavage and SMC apoptosis in vivo and in vitro, as shown by bulk RNA-seq, western blotting, flow cytometry and TUNEL staining. Mechanistic studies revealed that PDE4D promotes apoptosis by suppressing the activation of cAMP-activated protein kinase A (PKA) instead of the exchange protein directly activated by cAMP (Epac). Additionally, the phosphorylation of BCL2-antagonist of cell death (Bad) was reversed by PDE4D siRNA in vitro, which indicates that PDE4D regulates SMC apoptosis via the cAMP-PKA-pBad axis. Overall, these findings indicate that PDE4D upregulation in SMCs plays a causative role in AAA development and suggest that pharmacological inhibition of PDE4 may represent a potential therapeutic strategy.

Physiological responses to heat stress in the liver of rainbow trout (Oncorhynchus mykiss) revealed by UPLC-QTOF-MS metabolomics and biochemical assays.

Rainbow trout (Oncorhynchus mykiss) is one of the world's most widely farmed cold-water fish. However, the rise in water temperature caused by global warming has seriously restricted the development of rainbow trout aquaculture. In this study, we investigated the physiological responses in the liver of rainbow trout exposed to 20 â„ƒ and 24 â„ƒ and returning to the initial temperature (14 â„ƒ) by combining biochemical analyses and UPLC-QTOF-MS metabolomics. The results of the biochemical analysis showed that serum aminotransferase, lysozyme, total bilirubin, alkaline phosphatase and liver superoxide dismutase, glutathione peroxidase, and malondialdehyde in rainbow trout under heat stress changed significantly. Even after the temperature recovery, some of the above indicators were still affected. Compared to the control group, 115, 130, and 121 differentially expressed metabolites were identified in the 20 â„ƒ, 24 â„ƒ, and recovery groups, respectively. Further pathway enrichment of these metabolites revealed that heat stress mainly affected the linoleic acid metabolism, α-linolenic acid metabolism, glycerophospholipid metabolism, and sphingolipid metabolism in the liver of rainbow trout, and continuously affected these metabolic pathways during the recovery period. Notably, the enrichment of glutathione metabolic pathways was consistent with the changes in glutathione peroxidase in the biochemical results. The results above suggest that heat stress can induce immune responses and oxidative stress inside the rainbow trout. After temperature recovery, some of the hepatic functions of fish return to normal gradually. The biochemical analysis and UPLC-QTOF-MS metabolomics tools provide insight into the physiological regulation of rainbow trout in response to heat stress.

Rethinking Liver Fibrosis Staging in Patients with Hepatocellular Carcinoma: New Insights from a Large Two-Center Cohort Study.

Background: Hepatocellular carcinoma (HCC) is a prevalent and aggressive malignancy closely related to background chronic liver disease. This study aimed to explore predictive factors associated with background liver fibrosis burden in patients with HCC and sought to construct a practical predictive model for clinical use. Methods: This large two-center retrospective cohort study evaluated data from Chinese medical centers. Uni- and multivariate ordinal logistic regression analyses were performed to identify variables associated with liver fibrosis stages. Predictive models based on variables identified by multivariate analysis were established in the Derivation Cohort and subjected to internal and external validation. Model performance was evaluated for discriminative and calibration abilities. Results: Multivariate ordinal logistic regression analysis identified liver fibrosis severity score (LFSS), portal hypertension (PH) severity, plateletcrit (PCT) and model for end-stage liver disease-sodium (MELD-Na) as independent predictors of liver fibrosis stage in HCC patients. Nomograms that integrated these factors disclosed that the area under receiver operating characteristic curves (AUROCs) to predict S1 in the Derivation and External Validation cohorts were 0.850 and 0.919, respectively. Internal validation disclosed C-indexes of 0.823 and 0.833 in the Derivation and External Validation cohorts, respectively, indicating that the nomogram had good and excellent performance for distinguishing between S1 and non-S1 patients. Nomogram performance in the Derivation and External Validation cohorts, respectively, was fair and good to predict stage S2 (AUROCs 0.726, 0.806; C-indexes 0.713, 0.791); poor for S3 (AUROCs 0.648, 0.698; C-indexes 0.616, 0.666); good for S4 (AUROCs 0.812, 0.824; C-indexes 0.804, 0.792); and good for S3+S4 (AUROCs 0.806, 0.840; C-indexes 0.795, 0.811). Conclusion: We propose new predictive models for the staging of background liver fibrosis in patients with HCC that can be implemented into clinical practice as important complements to hepatic imaging to inform HCC management strategy.

Gefitinib and fostamatinib target EGFR and SYK to attenuate silicosis: a multi-omics study with drug exploration.

Silicosis is the most prevalent and fatal occupational disease with no effective therapeutics, and currently used drugs cannot reverse the disease progress. Worse still, there are still challenges to be addressed to fully decipher the intricated pathogenesis. Thus, specifying the essential mechanisms and targets in silicosis progression then exploring anti-silicosis pharmacuticals are desperately needed. In this work, multi-omics atlas was constructed to depict the pivotal abnormalities of silicosis and develop targeted agents. By utilizing an unbiased and time-resolved analysis of the transcriptome, proteome and phosphoproteome of a silicosis mouse model, we have verified the significant differences in transcript, protein, kinase activity and signaling pathway level during silicosis progression, in which the importance of essential biological processes such as macrophage activation, chemotaxis, immune cell recruitment and chronic inflammation were emphasized. Notably, the phosphorylation of EGFR (p-EGFR) and SYK (p-SYK) were identified as potential therapeutic targets in the progression of silicosis. To inhibit and validate these targets, we tested fostamatinib (targeting SYK) and Gefitinib (targeting EGFR), and both drugs effectively ameliorated pulmonary dysfunction and inhibited the progression of inflammation and fibrosis. Overall, our drug discovery with multi-omics approach provides novel and viable therapeutic strategies for the treatment of silicosis.

A phosphorus-containing imidazole derivative towards the liquid oxygen compatibility and toughness of epoxy resin.

In order to develop a liquid oxygen-compatible (LOX-compatible) matrix resins for polymer-based fiber-reinforced composites, a novel phosphorus-containing imidazole derivative called VAD containing multifunctional groups was synthesized and used as a co-curing agent for epoxy resin (EP) with simultaneous LOX-compatibility and mechanical improvement. A phosphorus group was introduced into the EP to capture the free radicals generated during the pyrolysis of the polymer to improve LOX compatibility, and the trimethylene group was introduced as a flexible spacer to enhance the toughness of the cured material. In comparison to pure EP, the modified EP with only 2.5 wt% VAD showed excellent mechanical properties with 23.0% and 75.6% increase in tensile and impact strength, respectively. Furthermore, as the content of VAD increased, a thermoset compatible with LOX (according to the liquid oxygen impact test) was obtained, and the flame retardancy was improved (according to the limiting oxygen index test). However, there was no significant sacrifice of transparency or thermal stability. In addition, the LOX compatibility mechanism was analyzed using X-ray photoelectron spectroscopy. As an efficient multi-functional modifier, VAD has a bright future in the modification realm of EP materials.

Single-Cell Transcriptome Profiles Reveal Fibrocytes as Potential Targets of Cell Therapies for Abdominal Aortic Aneurysm.

Abdominal aortic aneurysm (AAA) is potentially life-threatening in aging population due to the risk of aortic rupture and a lack of optimal treatment. The roles of different vascular and immune cells in AAA formation and pathogenesis remain to be future characterized. Single-cell RNA sequencing was performed on an angiotensin (Ang) II-induced mouse model of AAA. Macrophages, B cells, T cells, fibroblasts, smooth muscle cells and endothelial cells were identified through bioinformatic analyses. The discovery of multiple subtypes of macrophages, such as the re-polarization of Trem2 + Acp5 + osteoclast-like and M2-like macrophages toward the M1 type macrophages, indicates the heterogenous nature of macrophages during AAA development. More interestingly, we defined CD45+COL1+ fibrocytes, which was further validated by flow cytometry and immunostaining in mouse and human AAA tissues. We then reconstituted these fibrocytes into mice with Ang II-induced AAA and found the recruitment of these fibrocytes in mouse AAA. More importantly, the fibrocyte treatment exhibited a protective effect against AAA development, perhaps through modulating extracellular matrix production and thus enhancing aortic stability. Our study reveals the heterogeneity of macrophages and the involvement of a novel cell type, fibrocyte, in AAA. Fibrocyte may represent a potential cell therapy target for AAA.

Modeling and Optimization of a Novel ScAlN-Based MEMS Scanning Mirror with Large Static and Dynamic Two-Axis Tilting Angles.

The piezoelectric MEMS (micro-electro-mechanical systems) scanning mirrors are in a great demand for numerous optoelectronic applications. However, the existing actuation strategies are severely limited for poor compatibility with CMOS process, non-linear control, insufficient mirror size and small angular travel. In this paper, a novel, particularly efficient ScAlN-based piezoelectric MEMS mirror with a pupil size of 10 mm is presented. The MEMS mirror consists of a reflection mirror plate, four meandering springs with mechanical rotation transformation, and eight right-angle trapezoidal actuators designed in Union Jack-shaped form. Theoretical modeling, simulations and comparative analysis have been investigated for optimizing two different device designs. For Device A with a 1 mm-length square mirror, the orthogonal and diagonal static tilting angles are ±36.2°@200 VDC and ±36.2°@180 VDC, respectively, and the dynamic tilting angles increases linearly with the driving voltage. Device B with a 10 mm-length square mirror provides the accessible tilting angles of ±36.0°@200 VDC and ±35.9°@180 VDC for horizontal and diagonal actuations, respectively. In the dynamic actuation regime, the orthogonal and diagonal tilting angles at 10 Hz are ±8.1°/Vpp and ±8.9°/Vpp, respectively. This work confirmed that the Union Jack-shaped arrangement of trapezoidal actuators is a promising option for designing powerful optical devices.