Mitochondrial dynamics in pulmonary disease: Implications for the potential therapeutics.

Mitochondria are dynamic organelles that continuously undergo fusion/fission to maintain normal cell physiological activities and energy metabolism. When mitochondrial dynamics is unbalanced, mitochondrial homeostasis is broken, thus damaging mitochondrial function. Accumulating evidence demonstrates that impairment in mitochondrial dynamics leads to lung tissue injury and pulmonary disease progression in a variety of disease models, including inflammatory responses, apoptosis, and barrier breakdown, and that the role of mitochondrial dynamics varies among pulmonary diseases. These findings suggest that modulation of mitochondrial dynamics may be considered as a valid therapeutic strategy in pulmonary diseases. In this review, we discuss the current evidence on the role of mitochondrial dynamics in pulmonary diseases, with a particular focus on its underlying mechanisms in the development of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), asthma, pulmonary fibrosis (PF), pulmonary arterial hypertension (PAH), lung cancer and bronchopulmonary dysplasia (BPD), and outline effective drugs targeting mitochondrial dynamics-related proteins, highlighting the great potential of targeting mitochondrial dynamics in the treatment of pulmonary disease.

Comprehensive investigation in oncogenic functions and immunological roles of NCBP2 and its validation in prostate cancer.

BACKGROUND: Nuclear cap-binding protein 2 (NCBP2), as the component of the cap-binding complex, participates in a number of biological processes, including pre-mRNA splicing, transcript export, translation regulation and other gene expression steps. However, the role of NCBP2 on the tumor cells and immune microenvironment remains unclear. To systematically analyze and validate functions of NCBP2, we performed a pan-cancer analysis using multiple approaches. METHODS: The data in this study were derived from sequencing, mutation, and methylation data in the TCGA cohort, normal sample sequencing data in the GTEx project, and cell line expression profile data in the CCLE database. RESULTS: Survival analyses including the Cox proportional-hazards model and log-rank test revealed the poor prognostic role of NCBP2 in multiple tumors. We further validated the oncogenic ability of NCBP2 in prostate cancer cell lines, organoids and tumor-bearing mice. A negative correlation was observed between NCBP2 expression and immune score by the ESTIMATE algorithm. Simultaneously, the NCBP2-induced immunosuppressive microenvironment might be related to the decline in CD8+T cells and the increase in regulatory T cells and neutrophils, examined by flow cytometry experiments for NCBP2 overexpressed tumor-bearing mice. CONCLUSION: This research offered strong proof supporting NCBP2 as the prognostic marker and the therapeutic target in the future.

Ultrasensitive triethylamine gas sensors with ZnSe nanospheres/nest-like Cr-doped MoO3.

Developing high-sensitivity TEA sensors has extremely important significance for human health. Design of three-dimensional (3D) nanostructures assembled from one-dimensional nanomaterials can effectively improve sensing performance. In this work, a nest-like structure assembled by Cr-doped MoO3 (Cr-MoO3) nanorods with relatively higher specific surface area was prepared. In order to improve the sensing performance, Cr-MoO3 skeleton was combined with ZnSe nanospheres of different mass ratios as sensing materials (ZnSe/Cr-MoO3), and the successful construction of the heterojunction structure was supported by various spectroscopies and charge density calculation. The prepared composite with an optimal moiety ratio showed very high response values of 371 and 1301 for 10 ppm and 50 ppm for TEA at 200 °C, respectively. Simultaneously, the composite sensor also exhibited a low detection limit (1.7 ppb). The improvement of the sensing performance of ZnSe/Cr-MoO3 was attributed to the formation of oxygen vacancies induced by Cr doping, the 3D nest-like structure provided an efficient network for charge transport/collection and the n-n heterojunctions between Cr-MoO3 nanorods and ZnSe nanospheres. The simulation analysis based on density functional theory (DFT) calculations indicated that the heterojunctions could effectively enhance the adsorption energy of TEA and the more charges transferring from TEA to the Cr-MoO3 nanorods.

Hydrodynamic analysis of fin-fin interactions in two-manta-ray schooling in the vertical plane.

This study investigates the interaction of a two-manta-ray school using computational fluid dynamics simulations. The baseline case consists of two in-phase undulating three-dimensional manta models arranged in a stacked configuration. Various vertical stacked and streamwise staggered configurations are studied by altering the locations of the top manta in the upstream and downstream directions. Additionally, phase differences between the two mantas are considered. Simulations are conducted using an in-house developed incompressible flow solver with an immersed boundary method. The results reveal that the follower will significantly benefit from the upstroke vortices (UVs) and downstroke vortices depending on its streamwise separation. We find that placing the top manta 0.5 body length (BL) downstream of the bottom manta optimizes its utilization of UVs from the bottom manta, facilitating the formation of leading-edge vortices (LEVs) on the top manta's pectoral fins during the downstroke. This LEV strengthening mechanism, in turn, generates a forward suction force on the follower that results in a 72% higher cycle-averaged thrust than a solitary swimmer. This benefit harvested from UVs can be further improved by adjusting the phase of the top follower. By applying a phase difference ofπ/3to the top manta, the follower not only benefits from the UVs of the bottom manta but also leverages the auxiliary vortices during the upstroke, leading to stronger tip vortices and a more pronounced forward suction force. The newfound interaction observed in schooling studies offers significant insights that can aid in the development of robot formations inspired by manta rays.

Characterization and expression analysis of seven lipid metabolism-related genes in yellow catfish Pelteobagrus fulvidraco fed high fat and bile acid diet.

SREBPs, such as SREBP1 and SREBP2, were the key transcriptional factors regulating lipid metabolism. The processing of SREBPs involved many genes, such as scap, s1p, s2p, cideb. Here, we deciphered the full-length cDNA sequences of scap, srebp1, srebp2, s1p, s2p, cideb and cidec from yellow catfish Pelteobagrus fulvidraco. Their full-length cDNA sequences ranged from 1587 to 3884 bp, and their ORF length from 1191 to 2979 bp, encoding 396-992 amino acids. Some conservative domains were predicted, including the multiple transmembrane domains in SCAP, the bHLH-ZIP domain in SREBP1 and SREBP2, the ApoB binding region, ER targeting region and LD targeting region in CIDEb, the LD targeting region in the CIDEc, the conserved catalytic site and processing site in S1P, and the transmembrane helix domain in S2P. Their mRNA expression could be observed in the heart, spleen, liver, kidney, brain, muscle, intestine and adipose, but varied with tissues. The changes of their mRNA expression in responses to high-fat (HFD) and bile acid (BA) diets were also investigated in the brain, heart, intestine, kidney and spleen tissues. In the brain, HFD significantly increased the mRNA expression of seven genes (scap, srebp1, srebp2, s1p, s2p, cideb and cidec), and the BA attenuated the increase of scap, srebp1, srebp2, s1p, s2p, cideb and cidec mRNA expression induced by HFD. In the heart, HFD significantly increased the mRNA abundances of six genes (srebp1, srebp2, scap, s2p, cideb and cidec), and BA attenuated the increase of their mRNA abundances induced by HFD. In the intestine, HFD increased the cideb, s1p and s2p mRNA abundances, and BA attenuated the HFD-induced increment of their mRNA abundances. In the kidney, HFD significantly increased the scap, cidec and s1p mRNA expression, and BA diet attenuated the increment of their mRNA expression. In the spleen, HFD treatment increased the scap, srebp2, s1p and s2p mRNA expression, and BA diet attenuated HFD-induced increment of their mRNA expression. Taken together, our study elucidated the characterization, expression profiles and transcriptional response of seven lipid metabolic genes, which would serve as the good basis for the further exploration into their function and regulatory mechanism in fish.

ALDOB/KAT2A interactions epigenetically modulate TGF-ß expression and T cell functions in hepatocellular carcinogenesis.

BACKGROUND AND AIMS: Cross talk between tumor cells and immune cells enables tumor cells to escape immune surveillance and dictate responses to immunotherapy. Previous studies have identified that downregulation of the glycolytic enzyme fructose-1,6-bisphosphate aldolase B (ALDOB) in tumor cells orchestrated metabolic programming to favor HCC. However, it remains elusive whether and how ALDOB expression in tumor cells affects the tumor microenvironment in HCC. APPROACH AND RESULTS: We found that ALDOB downregulation was negatively correlated with CD8 + T cell infiltration in human HCC tumor tissues but in a state of exhaustion. Similar observations were made in mice with liver-specific ALDOB knockout or in subcutaneous tumor models with ALDOB knockdown. Moreover, ALDOB deficiency in tumor cells upregulates TGF-ß expression, thereby increasing the number of Treg cells and impairing the activity of CD8 + T cells. Consistently, a combination of low ALDOB and high TGF-ß expression exhibited the worst overall survival for patients with HCC. More importantly, the simultaneous blocking of TGF-ß and programmed cell death (PD) 1 with antibodies additively inhibited tumorigenesis induced by ALDOB deficiency in mice. Further mechanistic experiments demonstrated that ALDOB enters the nucleus and interacts with lysine acetyltransferase 2A, leading to inhibition of H3K9 acetylation and thereby suppressing TGFB1 transcription. Consistently, inhibition of lysine acetyltransferase 2A activity by small molecule inhibitors suppressed TGF-ß and HCC. CONCLUSIONS: Our study has revealed a novel mechanism by which a metabolic enzyme in tumor cells epigenetically modulates TGF-ß signaling, thereby enabling cancer cells to evade immune surveillance and affect their response to immunotherapy.

The role of mitochondrial dynamics in disease.

Mitochondria are multifaceted and dynamic organelles regulating various important cellular processes from signal transduction to determining cell fate. As dynamic properties of mitochondria, fusion and fission accompanied with mitophagy, undergo constant changes in number and morphology to sustain mitochondrial homeostasis in response to cell context changes. Thus, the dysregulation of mitochondrial dynamics and mitophagy is unsurprisingly related with various diseases, but the unclear underlying mechanism hinders their clinical application. In this review, we summarize the recent developments in the molecular mechanism of mitochondrial dynamics and mitophagy, particularly the different roles of key components in mitochondrial dynamics in different context. We also summarize the roles of mitochondrial dynamics and target treatment in diseases related to the cardiovascular system, nervous system, respiratory system, and tumor cell metabolism demanding high-energy. In these diseases, it is common that excessive mitochondrial fission is dominant and accompanied by impaired fusion and mitophagy. But there have been many conflicting findings about them recently, which are specifically highlighted in this view. We look forward that these findings will help broaden our understanding of the roles of the mitochondrial dynamics in diseases and will be beneficial to the discovery of novel selective therapeutic targets.

Effects of Different Dietary Zinc (Zn) Sources on Growth Performance, Zn Metabolism, and Intestinal Health of Grass Carp.

This research was conducted to investigate the effects of four dietary zinc (Zn) sources on growth performance, Zn metabolism, antioxidant capacity, endoplasmic reticulum (ER) stress, and tight junctions in the intestine of grass carp Ctenopharyngodon idella. Four Zn sources consisted of Zn dioxide nanoparticles (ZnO NPs), Zn sulfate heptahydrate (ZnSO4·7H2O), Zn lactate (Zn-Lac), and Zn glycine chelate (Zn-Gly), respectively. Grass carp with an initial body weight of 3.54 g/fish were fed one of four experimental diets for 8 weeks. Compared to inorganic Zn (ZnSO4·7H2O), grass carp fed the ZnO NPs and Zn-Gly diets exhibited better growth performance. Furthermore, grass carp fed the organic Zn (Zn-Lac and Zn-Gly) diets displayed enhanced Zn transport activity, improved intestinal histology, and increased intestinal tight junction-related genes expression compared to other groups. In comparison to other Zn sources, dietary ZnO NPs caused increased Zn deposition and damaged antioxidation capacity by suppressing antioxidant enzymatic activities and related gene expression in the intestine. Grass cap fed the ZnO NPs diet also exhibited lower mRNA abundance of endoplasmic reticulum (ER) stress- and tight junction-associated genes. According to the above findings, it can be concluded that dietary organic Zn addition (Zn-Lac and Zn-Gly) is more beneficial for intestinal health in grass carp compared to inorganic and nanoform Zn sources. These findings provide valuable insights into the application of organic Zn sources, specifically Zn-Lac and Zn-Gly, in the diets for grass carp and potentially for other fish species.

Thrust generation and propulsive efficiency in dolphin-like swimming propulsion.

Given growing interest in emulating dolphin morphology and kinematics to design high-performance underwater vehicles, the current research effort is dedicated to studying the hydrodynamics of dolphin-like oscillatory kinematics in forward propulsion. A computational fluid dynamics method is used. A realistic three-dimentional surface model of a dolphin is made with swimming kinematics reconstructed from video recording. The oscillation of the dolphin is found to enhance the attachment of the boundary layer to the posterior body, which then leads to body drag reduction. The flapping motion of the flukes is found to generate high thrust forces in both the downstroke and the upstroke, during which vortex rings are shed to produce strong thrust jets. The downstroke jets are found to be on average stronger than the upstroke jet, which then leads to net positive lift production. The flexion of the peduncle and flukes is found to be a crucial feature of dolphin-like swimming kinematics. Dolphin-inspired swimming kinematics were created by varying the flexion angle of the peduncle and flukes, which then resulted in significant performance variation. The thrust benefits and propulsive efficiency benefits are associated with a slight decrease and slight increase of the flexion of the peduncle and flukes, respectively.

Antiandrogen treatment induces stromal cell reprogramming to promote castration resistance in prostate cancer.

Lineage plasticity causes therapeutic resistance; however, it remains unclear how the fate conversion and phenotype switching of cancer-associated fibroblasts (CAFs) are implicated in disease relapse. Here, we show that androgen deprivation therapy (ADT)-induced SPP1+ myofibroblastic CAFs (myCAFs) are critical stromal constituents that drive the development of castration-resistant prostate cancer (CRPC). Our results reveal that SPP1+ myCAFs arise from the inflammatory CAFs in hormone-sensitive PCa; therefore, they represent two functional states of an otherwise ontogenically identical cell type. Antiandrogen treatment unleashes TGF-ß signaling, resulting in SOX4-SWI/SNF-dependent CAF phenotype switching. SPP1+ myCAFs in turn render PCa refractory to ADT via an SPP1-ERK paracrine mechanism. Importantly, these sub-myCAFs are associated with inferior therapeutic outcomes, providing the rationale for inhibiting polarization or paracrine mechanisms to circumvent castration resistance. Collectively, our results highlight that therapy-induced phenotypic switching of CAFs is coupled with disease progression and that targeting this stromal component may restrain CRPC.

Atherosclerosis: The Involvement of Immunity, Cytokines and Cells in Pathogenesis, and Potential Novel Therapeutics.

As a leading contributor to coronary artery disease (CAD) and stroke, atherosclerosis has become one of the major cardiovascular diseases (CVD) negatively impacting patients worldwide. The endothelial injury is considered to be the initial step of the development of atherosclerosis, resulting in immune cell migration and activation as well as inflammatory factor secretion, which further leads to acute and chronic inflammation. In addition, the inflammation and lipid accumulation at the lesions stimulate specific responses from different types of cells, contributing to the pathological progression of atherosclerosis. As a result, recent studies have focused on using molecular biological approaches such as gene editing and nanotechnology to mediate cellular response during atherosclerotic development for therapeutic purposes. In this review, we systematically discuss inflammatory pathogenesis during the development of atherosclerosis from a cellular level with a focus on the blood cells, including all types of immune cells, together with crucial cells within the blood vessel, such as smooth muscle cells and endothelial cells. In addition, the latest progression of molecular-cellular based therapy for atherosclerosis is also discussed. We hope this review article could be beneficial for the clinical management of atherosclerosis.

Remediation of soil contaminated with PAHs and γ-HCH using Fenton oxidation activated by carboxymethyl cellulose-modified iron oxide-biochar.

The remediation of soil contaminated with hydrophobic organic pollutants has attracted great public concern. In the present study, a novel catalyst using biochar supported ferro ferric oxide modified by carboxymethyl cellulose (CMC-Fe3O4/BC) was developed to activate the Fenton reaction for hazardous hydrophobic organic pollutants, and the degradation mechanisms were analyzed in terms of free radicals, electron transfer pathways and degradation intermediates. The results showed that the CMC-Fe3O4/BC-activated H2O2 system degraded nearly 100% of pyrene in the aqueous system after a 1440-min reaction. The catalyst was also applied to remediate industrial field soil contaminated with PAHs and γ-HCH. The removal rate of the total pollutants reached 61.1% after a 10-day reaction, which was higher than that of Fe3O4/BC without modification. CMC enabled the Fe3O4 particles to more equably distribute on the BC surface, further effectively activating H2O2 to generate more ⋅OH and forming different degradation products compared to the Fe3O4/BC. Additionally, the CMC-Fe3O4/BC-activated H2O2 system obviously enhanced electron transfer on the BC surface. Thus, the PAHs and γ-HCH could be degraded via electron transfer pathways.

Efficient remediation of the field soil contaminated with PAHs by amorphous porous iron material activated peroxymonosulfate.

An amorphous porous iron material (FH) was firstly self-synthesized using a simple coprecipitation approach and then utilized to activate peroxymonosulfate (PMS) for the catalytic degradation of pyrene and remediation of PAHs contaminated soil on site. FH exhibited more excellent catalytic activity than traditional hydroxy ferric oxide and possessed stability at a pH range of 3.0-11.0. According to quenching studies and electron paramagnetic resonance (EPR) analyses, non-radicals (Fe(IV) = O and 1O2) were the major reactive oxygen species (ROS) in the FH/PMS system's degradation of pyrene. X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared spectroscopy (FT-IR) of FH before and after the catalytic reaction, as well as active site substitution experiments and electrochemical analysis all verified that PMS adsorbed on FH could produce more abundant bonded hydroxyl groups (Fe-OH) which dominated the radical and non-radical oxidation reactions. Then, a possible pathway for pyrene degradation was presented according to gas chromatography-mass spectrometry (GC-MS). Furthermore, the FH/PMS system exhibited excellent catalytic degradation in the remediation of PAH-contaminated soil at real sites. This work provides a remarkable potential remediation technology of persistent organic pollutants (POPs) in environmental and will contribute to understanding the mechanism of Fe-based hydroxides in advanced oxidation processes.

Three Experimental Common High-Risk Procedures: Emission Characteristics Identification and Source Intensity Estimation in Biosafety Laboratory.

Biosafety laboratory is an important place to study high-risk microbes. In biosafety laboratories, with the outbreak of infectious diseases such as COVID-19, experimental activities have become increasingly frequent, and the risk of exposure to bioaerosols has increased. To explore the exposure risk of biosafety laboratories, the intensity and emission characteristics of laboratory risk factors were investigated. In this study, high-risk microbe samples were substituted with Serratia marcescens as the model bacteria. The resulting concentration and particle size segregation of the bioaerosol produced by three experimental procedures (spill, injection, and sample drop) were monitored, and the emission sources' intensity were quantitatively analyzed. The results showed that the aerosol concentration produced by injection and sample drop was 103 CFU/m3, and that by sample spill was 102 CFU/m3. The particle size of bioaerosol is mainly segregated in the range of 3.3-4.7 µm. There are significant differences in the influence of risk factors on source intensity. The intensity of sample spill, injection, and sample drop source is 3.6 CFU/s, 78.2 CFU/s, and 664 CFU/s. This study could provide suggestions for risk assessment of experimental operation procedures and experimental personnel protection.

Idebenone attenuates ferroptosis by inhibiting excessive autophagy via the ROS-AMPK-mTOR pathway to preserve cardiac function after myocardial infarction.

Cardiovascular diseases (CVDs) are the leading causes of mortality worldwide. As a type of CVDs, myocardial infarction (MI) induces ischemia hypoxia, which leads to excessive reactive oxygen species (ROS), resulting in multiple cell deaths and contributing to the subsequent development of heart failure or premature death. Recent evidence indicates that ROS-induced lipid peroxidation promotes autophagy and ferroptosis, leading to the loss of healthy myocardium and resulting in the dysfunction of cardiac tissue. Theoretically, cardiac function would be preserved after MI by inhibiting autophagy and ferroptosis. As an analog of coenzyme Q10 (CoQ10) and a clinically approved drug, idebenone would be used to inhibit ferroptosis and preserve cardiac function due to its capacity to improve mitochondrial physiology with antioxidant and anti-inflammatory properties. Here, we confirmed that the addition of idebenone inhibited H2O2-induced and RSL3-induced ferroptosis. Furthermore, the ROS-AMPK-mTOR pathway axis was identified as the signaling pathway that idebenone stimulated to prevent excessive autophagy and consequent ferroptosis. In the MI animal model, idebenone demonstrated a cardioprotective role by regulating ROS-dependent autophagy and inhibiting ferroptosis, which paves the way for the future clinical translation of idebenone in MI management.

Systemic immune-inflammation index as a prognostic marker for advanced chronic heart failure with renal dysfunction.

AIMS: We aim to investigate the correlation between high levels of the systemic immune-inflammation index (SII) and long-term mortality and major cardiovascular adverse events in advanced chronic heart failure patients with renal dysfunction. METHODS AND RESULTS: Seven hundred seventeen advanced chronic heart failure patients with renal dysfunction, who visited the First affiliated hospital of Zhengzhou University from September 2019 to December 2020, were included. All-cause mortalities (ACM) were selected as primary endpoints and major cardiovascular adverse events (MACEs) as the secondary endpoints. Based on the receiver operating characteristic (ROC) curve and the Youden index, the optimal cut-off values of SII for ACM and MACEs were 1228 and 1406. In the group where ACM were the primary endpoint, patients were categorized into the low-SII group (n = 479) and the high-SII group (n = 238). Patients in the group using MACEs as the secondary endpoint were also categorized into the low-SII groups (n = 514) and the high-SII groups (n = 203). Univariate and multivariate COX regression were used to screen the independent predictors for ACM and MACEs, revealing the relationship between SII levels and endpoints. According to the univariate COX analysis, SII was the risk factor (hazard ratio [HR] = 2.144, 95% confidence interval [CI]: 1.565-2.938, P < 0.001) for the ACM subgroup. It was also the risk factor (HR = 1.625, CI: 1.261-2.905, P < 0.001) for the MACEs subgroup. Multivariate COX regression analysis indicated that the occurrence of ACM and MACEs in high-level SII and low-level SII patients had statistical differences. The incidence of ACM increased by 70.3% (HR = 1.703; 95% CI: 1.200-2.337; P = 0.002) in patients of the high SII level group, the incidence of MACEs increased by 58.3% (HR = 1.583, 95% CI: 1.213-2.065, P = 0.001). Kaplan-Meier (K-M) survival analysis further suggested that patients with a high SII level had an increased risk of having ACM (log-rank P < 0.001) and MACEs (log-rank P < 0.001) within 30 months. SII could be considered as a novel predictor of the occurrence of ACM and MACEs for patients with advanced chronic heart failure and renal dysfunction. CONCLUSIONS: This study suggested that SII is a novel independent predictor of mortality in advanced chronic heart failure patients with renal dysfunction, and it should be considered in current clinical management.

Anti-vibriosis bioactive molecules from Arctic Penicillium sp. Z2230.

Vibrio species (Vibrio sp.) is a class of Gram-negative aquatic bacteria that causes vibriosis in aquaculture, which have resulted in big economic losses. Utilization of antibiotics against vibriosis has brought concerns on antibiotic resistance, and it is essential to explore potential antibiotic alternatives. In this study, seven compounds (compounds 1-7) were isolated from the Arctic endophytic fungus Penicillium sp. Z2230, among which compounds 3, 4, and 5 showed anti-Vibrio activity. The structures of the seven compounds were comprehensively elucidated, and the antibacterial mechanism of compounds 3, 4, and 5 was explored by molecular docking. The results suggested that the anti-Vibrio activity could come from inhibition of the bacterial peptide deformylase (PDF). This study discovered three Penicillium-derived compounds to be potential lead molecules for developing novel anti-Vibrio agents, and identified PDF as a promising antibacterial target. It also expanded the bioactive diversity of polar endophytic fungi by showing an example in which the secondary metabolites of a polar microbe were a good source of natural medicine.

Smooth muscle cell fate decisions decipher a high-resolution heterogeneity within atherosclerosis molecular subtypes.

BACKGROUND: Mounting evidence has revealed the dynamic variations in the cellular status and phenotype of the smooth muscle cell (SMC) are vital for shaping the atherosclerotic plaque microenvironment and ultimately mapping onto heterogeneous clinical outcomes in coronary artery disease. Currently, the underlying clinical significance of SMC evolutions remains unexplored in atherosclerosis. METHODS: The dissociated cells from diseased segments within the right coronary artery of four cardiac transplant recipients and 1070 bulk samples with atherosclerosis from six bulk cohorts were retrieved. Following the SMC fate trajectory reconstruction, the MOVICS algorithm integrating the nearest template prediction was used to develop a stable and robust molecular classification. Subsequently, multi-dimensional potential biological implications, molecular features, and cell landscape heterogeneity among distinct clusters were decoded. RESULTS: We proposed an SMC cell fate decision signature (SCFDS)-based atherosclerosis stratification system and identified three SCFDS subtypes (C1-C3) with distinguishing features: (i) C1 (DNA-damage repair type), elevated base excision repair (BER), DNA replication, as well as oxidative phosphorylation status. (ii) C2 (immune-activated type), stronger immune activation, hyper-inflammatory state, the complex as well as varied lesion microenvironment, advanced stage, the most severe degree of coronary stenosis severity. (iii) C3 (stromal-rich type), abundant fibrous content, stronger ECM metabolism, immune-suppressed microenvironment. CONCLUSIONS: This study uncovered atherosclerosis complex cellular heterogeneity and a differentiated hierarchy of cell populations underlying SMC. The novel high-resolution stratification system could improve clinical outcomes and facilitate individualized management.

ARID1A loss induces polymorphonuclear myeloid-derived suppressor cell chemotaxis and promotes prostate cancer progression.

Chronic inflammation and an immunosuppressive microenvironment promote prostate cancer (PCa) progression and diminish the response to immune checkpoint blockade (ICB) therapies. However, it remains unclear how and to what extent these two events are coordinated. Here, we show that ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, functions downstream of inflammation-induced IKKß activation to shape the immunosuppressive tumor microenvironment (TME). Prostate-specific deletion of Arid1a cooperates with Pten loss to accelerate prostate tumorigenesis. We identify polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) as the major infiltrating immune cell type that causes immune evasion and reveal that neutralization of PMN-MDSCs restricts the progression of Arid1a-deficient tumors. Mechanistically, inflammatory cues activate IKKß to phosphorylate ARID1A, leading to its degradation via ß-TRCP. ARID1A downregulation in turn silences the enhancer of A20 deubiquitinase, a critical negative regulator of NF-κB signaling, and thereby unleashes CXCR2 ligand-mediated MDSC chemotaxis. Importantly, our results support the therapeutic strategy of anti-NF-κB antibody or targeting CXCR2 combined with ICB for advanced PCa. Together, our findings highlight that the IKKß/ARID1A/NF-κB feedback axis integrates inflammation and immunosuppression to promote PCa progression.

Wing Kinematics and Unsteady Aerodynamics of a Hummingbird Pure Yawing Maneuver.

As one of few animals with the capability to execute agile yawing maneuvers, it is quite desirable to take inspiration from hummingbird flight aerodynamics. To understand the wing and body kinematics and associated aerodynamics of a hummingbird performing a free yawing maneuver, a crucial step in mimicking the biological motion in robotic systems, we paired accurate digital reconstruction techniques with high-fidelity computational fluid dynamics (CFD) simulations. Results of the body and wing kinematics reveal that to achieve the pure yaw maneuver, the hummingbird utilizes very little body pitching, rolling, vertical, or horizontal motion. Wing angle of incidence, stroke, and twist angles are found to be higher for the inner wing (IW) than the outer wing (OW). Unsteady aerodynamic calculations reveal that drag-based asymmetric force generation during the downstroke (DS) and upstroke (US) serves to control the speed of the turn, a characteristic that allows for great maneuvering precision. A dual-loop vortex formation during each half-stroke is found to contribute to asymmetric drag production. Wake analysis revealed that asymmetric wing kinematics led to leading-edge vortex strength differences of around 59% between the IW and OW. Finally, analysis of the role of wing flexibility revealed that flexibility is essential for generating the large torque necessary for completing the turn as well as producing sufficient lift for weight support.