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Abstract Introduction Pyroptosis, inflammatory necrosis of cells, is a programmed cell death involved in the pathological process of diseases. Endoplasmic reticulum stress (ERS), as a protective stress response of cell, decreases the unfold protein concentration to inhibit the unfold protein agglutination. Whereas the relationship between endoplasmic reticulum stress and pyroptosis in pulmonary hypertension (PH) remain unknown. Previous evident indicated that circular RNA (circRNA) can participate in several biological process, including cell pyroptosis. However, the mechanism of circRNA regulate pyroptosis of pulmonary artery smooth muscle cells through endoplasmic reticulum stress still unclear. Here, we proved that circSSR1 was down-regulate expression during hypoxia in pulmonary artery smooth muscle cells, and over-expression of circSSR1 inhibit pyroptosis both in vitro and in vivo under hypoxic. Our experiments have indicated that circSSR1 could promote host gene SSR1 translation via m6A to activate ERS leading to pulmonary artery smooth muscle cell pyroptosis. In addition, our results showed that G3BP1 as upstream regulator mediate the expression of circSSR1 under hypoxia. These results highlight a new regulatory mechanism for pyroptosis and provide a potential therapy target for pulmonary hypertension. Methods RNA-FISH and qRT-PCR were showed the location of circSSR1 and expression change. RNA pull-down and RIP verify the circSSR1 combine with YTHDF1. Western blotting, PI staining and LDH release were used to explore the role of circSSR1 in PASMCs pyroptosis. Results CircSSR1 was markedly downregulated in hypoxic PASMCs. Knockdown CircSSR1 inhibited hypoxia induced PASMCs pyroptosis in vivo and in vitro. Mechanistically, circSSR1 combine with YTHDF1 to promote SSR1 protein translation rely on m6A, activating pyroptosis via endoplasmic reticulum stress. Furthermore, G3BP1 induce circSSR1 degradation under hypoxic. Conclusion Our findings clarify the role of circSSR1 up-regulated parental protein SSR1 expression mediate endoplasmic reticulum stress leading to pyroptosis in PASMCs, ultimately promoting the development of pulmonary hypertension.

Abstract Introduction ARDS (acute respiratory distress syndrome) is the most severe form of acute hypoxic respiratory failure. Most studies related to ARDS have excluded patients with hematologic diseases, let alone allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Numerous patients experiencing severe hypoxic respiratory failure do not meet the Berlin definition due to the limitations of diagnosis and treatment. A new definition of ARDS, remove some diagnosis restrictions, was proposed in 2023. Based on the 2023 new definition of ARDS, we investigated the clinical features of ARDS in allo-HSCT recipients and reported risk factors for in-hospital mortality in allo-HSCT recipients defined by the Berlin definition and the new definition of ARDS respectively. Methods From Jan 2016 to Dec 2020, 135 allo-HSCT recipients identified with the new definition and 87 identified with the Berlin definition at three teaching hospitals were retrospectively included in this study. Variables (demographic information, characteristics of hematologic disease and ARDS episode, laboratory tests and SOFA score) with P

BackgroundNeuropathic pain (NeP) presents considerable challenges in terms of effective management and significantly impacts the quality of life for affected patients. The current treatment options for NeP are limited, highlighting the need for alternative therapeutic approaches. Dahuang Fuzi Decoction (DF), a formula from traditional Chinese medicine, has shown potential in relieving pain symptoms associated with various types of NeP. However, the mechanisms through which DF exerts its effects remain largely unknown.MethodsIn this study, we employed ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry (UHPLC-HRMS) to analyze the chemical composition of DF. A chronic sciatic nerve compression injury (CCI) rat mode was used to assess the analgesic efficacy of DF for NeP. Network pharmacology analysis was performed to identify the potential signaling pathways affected by DF.ResultsDF treatment significantly increased the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) in CCI rats, indicating its analgesic effect. Network pharmacology analysis suggested that DF potentially modulated TNF-α and PI3K-AKT signaling pathways. Furthermore, DF treatment decreased the levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) in spinal cord tissues of CCI rats, suggesting an anti-inflammatory effect. Western blot analysis revealed that DF treatment reduced the expression of TNF-α, TNFR1, and phosphorylated forms of PI3K, AKT, IKKα/β, IKBα, and NF-κB in the spinal cord of CCI rats. Immunofluorescence analysis confirmed significant reductions in TNF-α and TNFR1 expression, as well as in AKT and NF-κB phosphorylation within astrocytes following DF administration.ConclusionOur findings characterize the chemical constituents of DF and elucidate its underlying mechanism for relieving NeP. The analgesic effect of DF involves the inhibition of TNF-α and PI3K-AKT signaling pathways, providing a potential therapeutic approach for NeP management.

Summary: The abnormal expression of circular RNAs (circRNAs) is emerging as a critical cause in regulation of pathological changes of hypoxic pulmonary hypertension (PH), in which ferroptosis is a new pathological change reported recently. However, how circRNAs regulate ferroptosis remains unclear. Here, we proved a significant decrease in circMyst4 expression in hypoxia. In vitro assays revealed that circMyst4 alleviated hypoxic pulmonary artery smooth muscle cell (PASMC) ferroptosis through directly combing with DDX5 in the nucleus to promote GPX4 mRNA processing and inhibiting the formation of the Eef1a1/ACSL4 complex in the cytoplasm. Additionally, superenhancer (SE) was verified to drive the generation of circMyst4. In vivo assays revealed that circMyst4 inhibited the progression of hypoxic PH. Overall, SE-driven circMyst4 may be a new potential therapeutic target for mediating PASMC ferroptosis through promoting DDX5-regulated GPX4 mRNA processing and inhibiting the binding between Eef1a1 and ACSL4.

Neuropathic pain (NeP) is a condition charactesized by nervous system injury or dysfunction that affects a significant portion of the population. Current treatments are ineffective, highlighting the need for novel therapeutic approaches. Mahuang Fuzi Xixin decoction (MFXD) has shown promise for treating pain conditions in clinical practice; however, its potential against NeP and the underlying mechanisms remain unclear. This study identified 35 compounds in MFXD using ultra-high performance liquid chromatography coupled with high-resolution mass spectrometry (UHPLC-HRMS). The analgesic effects of MFXD on chronic constriction injury (CCI) rats were evaluated through the detection of mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL). The analgesic effects of MFXD in rats with chronic constriction injury (CCI) were evaluated by measuring the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL). Low-dose MFXD (L-MFXD) group (4.8 g/kg) and high-dose MFXD (H-MFXD) group (9.6 g/kg) exhibited significantly higher MWT and TWL values than the CCI group on days 11 and 15 post-CCI surgery, substantiating the remarkable analgesic efficacy of MFXD. Network pharmacology analysis identified 58 key targets enriched in pathways such as long-term potentiation (LTP) and glutamatergic synapse. The MCODE algorithm further identified core targets with significant enrichment in LTP. Molecular docking revealed that mesaconitine, rosmarinic acid, and delgrandine from MFXD exhibited high binding affinity with NMDAR2B (−11 kcal/mol), CaMKIIα (−14.3 kcal/mol), and ERK (−10.8 kcal/mol). Western blot and immunofluorescence confirmed that H-MFXD significantly suppressed the phosphorylation levels of NMDAR2B, CaMKIIα, ERK, and CREB in the spinal cord tissue of CCI rats. In conclusion, this study demonstrates that MFXD possesses potent analgesic effects on NeP by suppressing the NMDAR2B/CaMKIIα/ERK/CREB signalling pathway. This study unlocks a path toward potentially revolutionising NeP treatment with MFXD, encouraging further research and clinical development.

Abstract Exercise is usually regarded to have short-term beneficial effects on immune health. Here we show that early-life regular exercise exerts long-term beneficial effects on inflammatory immunity. Swimming training for 3 months in male mice starting from 1-month-old curbs cytokine response and mitigates sepsis when exposed to lipopolysaccharide challenge, even after an 11-month interval of detraining. Metabolomics analysis of serum and liver identifies pipecolic acid, a non-encoded amino acid, as a pivotal metabolite responding to early-life regular exercise. Importantly, pipecolic acid reduces inflammatory cytokines in bone marrow-derived macrophages and alleviates sepsis via inhibiting mTOR complex 1 signaling. Moreover, early-life exercise increases histone 3 lysine 4 trimethylation at the promoter of Crym in the liver, an enzyme responsible for catalyzing pipecolic acid production. Liver-specific knockdown of Crym in adult mice abolishes this early exercise-induced protective effects. Our findings demonstrate that early-life regular exercise enhances anti-inflammatory immunity during middle-aged phase in male mice via epigenetic immunometabolic modulation, in which hepatic pipecolic acid production has a pivotal function.

Abstract Understanding the impact of long‐term opioid exposure on the embryonic brain is critical due to the surging number of pregnant mothers with opioid dependency. However, this has been limited by human brain inaccessibility and cross‐species differences in animal models. Here, a human midbrain model is established that uses hiPSC‐derived midbrain organoids to assess cell‐type‐specific responses to acute and chronic fentanyl treatment and fentanyl withdrawal. Single‐cell mRNA sequencing of 25,510 cells from organoids in different treatment groups reveals that chronic fentanyl treatment arrests neuronal subtype specification during early midbrain development and alters synaptic activity and neuron projection. In contrast, acute fentanyl treatment increases dopamine release but does not significantly alter gene expression related to cell lineage development. These results provide the first examination of the effects of opioid exposure on human midbrain development at the single‐cell level.

Abstract Quantum-dot light-emitting diodes promise a new generation of high-performance and solution-processed electroluminescent light sources. Understanding the operational degradation mechanisms of quantum-dot light-emitting diodes is crucial for their practical applications. Here, we show that quantum-dot light-emitting diodes may exhibit an anomalous degradation pattern characterized by a continuous increase in electroluminescent efficiency upon electrical stressing, which deviates from the typical decrease in electroluminescent efficiency observed in other light-emitting diodes. Various in-situ/operando characterizations were performed to investigate the evolutions of charge dynamics during the efficiency elevation, and the alterations in electric potential landscapes in the active devices. Furthermore, we carried out selective peel-off-and-rebuild experiments and depth-profiling analyses to pinpoint the critical degradation site and reveal the underlying microscopic mechanism. The results indicate that the operation-induced efficiency increase results from the degradation of electron-injection capability at the electron-transport layer/cathode interface, which in turn leads to gradually improved charge balance. Our work provides new insights into the degradation of red quantum-dot light-emitting diodes and has far-reaching implications for the design of charge-injection interfaces in solution-processed light-emitting diodes.

Herpes simplex virus type 2 (HSV-2) is a sexually transmitted virus, the cause of genital herpes, and its infection can increase the risk of HIV-1 infection. After initial infection, HSV-2 can establish lifelong latency within the nervous system, which is likely associated with the virus-mediated immune evasion. In this study, we found that HSV-2 UL24 significantly inhibited the activation of the IFN-β promoter and the production of IFN-β at both mRNA and protein levels. Of importance, the inhibitory effect of HSV-2 on IFN-β production was significantly impaired in the context of HSV-2 infection when UL24 was knocked down. Additional studies revealed that, although the full-length HSV-2 UL24 affected cell cycle and viability to some extent, its N-terminal 1–202AA domain showed no obvious cytotoxicity while its C-terminal 201–281 AA domain had a minimal impact on cell viability. Further studies showed that the N-terminal 1–202 AA domain of HSV-2 UL24 (HSV-2 UL24-N) was the main functional region responsible for the inhibition of IFN-β production mediated by HSV-2 UL24. This domain significantly suppressed the activity of RIG-IN, MAVS, TBK-1, IKK-ε, or the IRF-3/5D-activated IFN-β promoter. Mechanistically, HSV-2 UL24-N suppressed IRF-3 phosphorylation, resulting in the inhibition of IFN-β production. The findings of this study highlight the significance of HSV-2 UL24 in inhibiting IFN-β production, revealing two potential roles of UL24 during HSV-2 infection: facilitating immune evasion and inducing cell cycle arrest.

Dilated cardiomyopathy (DCM) is one of the major causes of heart failure. Although significant progress has been made in elucidating the underlying mechanisms, further investigation is required for clarifying molecular diagnostic and therapeutic targets. In this study, we found that the mRNA level of protein phosphatase 2 regulatory subunit B’ delta (Ppp2r5d) was altered in the peripheral blood plasma of DCM patients. Knockdown of Ppp2r5d in murine cardiomyocytes increased the intracellular levels of reactive oxygen species (ROS) and inhibited adenosine triphosphate (ATP) synthesis. In vivo knockdown of Ppp2r5d in an isoproterenol (ISO)-induced DCM mouse model aggravated the pathogenesis and ultimately led to heart failure. Mechanistically, Ppp2r5d-deficient cardiomyocytes showed an increase in phosphorylation of STAT3 at Y705 and a decrease in phosphorylation of STAT3 at S727. The elevated levels of phosphorylation at Y705 in STAT3 triggered the upregulation of interleukin 6 (IL6) expression. Moreover, the decreased phosphorylation at S727 in STAT3 disrupted mitochondrial electron transport chain function and dysregulated ATP synthesis and ROS levels. These results hereby reveal a novel role for Ppp2r5d in modulating STAT3 pathway in DCM, suggesting it as a potential target for the therapy of the disease.

The φ16 mm single crystal copper rod was prepared by heated-mold horizontal continuous casting, and the φ16 mm polycrystalline copper rod was prepared by up-casting technology. Both of them were drawn to φ0.2 mm, the conductivity, strength, elongation, and microstructure evolution of single-crystal copper wire and polycrystal copper wire were compared and analyzed. The results show that the plasticity of as-cast single-crystal copper rod is 13.94% higher than that of as-cast polycrystalline copper rod. When drawing to φ0.2 mm, a single crystal copper wire with high strength (506 MPa) and high conductivity (98.01% IACS). At the same deformation amount, the single crystal copper wire obviously deforms more slowly and has a higher plastic deformation capacity; the texture transformation of single crystal copper wire is from soft → hard orientation, selective orientation to discrete distribution, while the weave transformation of polycrystalline copper wire is from soft → hard orientation, then from hard → soft orientation, and finally stabilizes to selective orientation. The microstructural evolution of single-crystal copper wire and polycrystalline copper wire during continuous deformation was observed: dislocation entanglement into dislocation cells by slip → microstrip structure → lamellar organization → twinning organization, single-crystal copper wire appears twinning later, single-crystal copper deformation coordination ability is better than polycrystalline copper. It is found that the increase of dislocation density, the decrease of grain width and the increase of texture are the main factors for the strength improvement of micro-nano pure copper wires.

The vibrations in functionally graded porous Cu-Si microcantilever beams are investigated based on physical neutral plane theory, modified coupled stress theory, and scale distribution theory (MCST&SDT). Porous microcantilever beams define four pore distributions. Considering the physical neutral plane theory, the material properties of the beams are computed through four different power-law distributions. The material properties of microcantilever beams are corrected by scale effects based on modified coupled stress theory. Considering the fluid driving force, the amplitude-frequency response spectra and resonant frequencies of the porous microcantilever beam in three different fluids are obtained based on the Euler–Bernoulli beam theory. The quality factors of porous microcantilever beams in three different fluids are derived by estimating the equation. The computational analysis shows that the presence of pores in microcantilever beams leads to a decrease in Young’s modulus. Different pore distributions affect the material properties to different degrees. The gain effect of the scale effect is weakened, but the one-dimensional temperature field and amplitude-frequency response spectra show an increasing trend. The quality factor is decreased by porosity, and the degree of influence of porosity increases as the beam thickness increases. The gradient factor n has a greater effect on the resonant frequency. The effect of porosity on the resonant frequency is negatively correlated when the gradient factor is small (n<1) but positively correlated when the gradient factor is large (n>1).

Least squares support vector machine (LSSVM) and variational mode decomposition are common research methods for wind speed time series prediction. Addressing the challenge of selecting relevant parameters of LSSVM and VMD, a fractional-order Beetle swarm optimization algorithm is proposed to optimize the relevant parameters. To weaken the negative impact of wind speed volatility on the accuracy of the prediction model, a two-stage modal decomposition strategy based on extreme-point symmetric mode decomposition, FO-BSO algorithm, and VMD is proposed. ESMD is used to decompose the original wind speed time series. The diversity entropy is introduced as the criterion, and the FO-BSO-VMD secondary decomposition is applied for the high-entropy modal components to further weaken the volatility of wind speed. Simulation results show that compared with the original LSSVM model, the ESMD-FO-BSO-VMD-LSSVM model presented in this study exhibits an average 44.10% increase in the fitting degree of wind speed prediction over three steps, which verifies the superior performance of the model in short-term multistep wind speed prediction.

In this paper, the prepared Cu-0.25Cr alloy and Cu-0.25Cr-0.03Ti alloy strips were treated with aging at 490 °C for different holding time. The electrical conductivity and the yield strength of the alloy were tested. The morphology, size, spacing and phase structure of Cr-rich precipitates in the copper matrix were observed by TEM. The results show that the evolution rule of Cr-rich precipitates in Cu-0.25Cr alloy is as follows: supersaturated solid solution→G. P region (Cr atom-rich region)→ Cr-rich precipitates with fcc structure→Cr-rich precipitates with ordered bcc structure. The precipitates of peak aged Cu-0.25Cr alloy consist of fcc Cr-rich precipitates and ordered bcc Cr-rich precipitates. The electrical conductivity and the yield strength is 93.5%IACS and 178 MPa, respectively. The strengthening mechanism is mainly attributed to the synergistic effect of dislocation shear and dislocation bypass. Compared with Cu-0.25Cr alloy, the yield strength of Cu-0.25Cr-0.03Ti alloy at peak aging state increases by 31.5%, while the electrical conductivity remains at 82.4%IACS. The great increase in strength is mainly attributed to the refinement of bcc Cr-rich precipitates by adding trace Ti element. The addition of Ti promotes the nucleation of Cr-rich precipitates and refines the Cr-rich precipitates of bcc structure. The interaction mechanism is that there is a strong mutual attraction between Ti and Cr atoms, which promotes the formation of clusters between Ti and Cr. This research results can provide a theoretical basis for the development of copper alloy for high-performance electrical connectors in aerospace, new energy vehicles and other fields.

Abstract Patent foramen ovale (PFO) is a congenital defect in the partition between two atria, which may cause right‐to‐left shunt (RLS), leading to neurological chronic diseases with episodic manifestations (NCDEMs), such as migraine and epilepsy. However, whether PFO closure was effective in improving NCDEMs and the mechanism were unclear. Twenty‐eight patients with migraine or epilepsy who underwent PFO closure were recruited. Notably, approximately half of patients received 50% or more reduction in seizure or headache attacks. Meanwhile, the postoperative blood oxygen partial pressure and oxygen saturation were elevated after PFO closure. Multisite (peripheral, right, and left atrial) and multitimepoint (before and after surgery) plasma proteomics from patients showed that the levels of free hemoglobin and cell adhesion molecules (CAMs) were significantly increased after PFO closure, which may be related to the relief of the hypoxic state. Furtherly, the omics data from multiple brain regions of mice revealed that a large number of proteins were differentially expressed in the occipital region in response to PFO, including redox molecules and CAMs, suggesting PFO‐caused hypoxia may have great impacts on occipital region. Collectively, PFO may cause NCDEMs due to RLS‐induced hypoxia, and PFO closure could prevent RLS to improve migraine and epilepsy.

The double-hole rice vacuum seed meter is critical equipment for the planting precision of rice direct seeding. The effects of shaped holes and seed disturbance on the precision of rice bunch planting were investigated to improve the precision of bunch planting with the double-hole rice vacuum seed meter. A test bench with the rice vacuum seed meter was set up to analyze the trends in the quality of feed index, miss index, and multiple index of seed meters with different shaped holes at different speeds and vacuum pressures. Based on the optimal hole structure, different seed disturbance structures were designed to investigate the influence of the seed disturbance structure on the precision of bunch planting. A multiple linear regression model was established for the relationship between the disturbance structure, vacuum pressure, rotational speed, and the precision of bunch planting. Discrete element numerical simulation experiments were carried out to analyze the effect of disturbance structures on seeds. The planting precision of the seed meter with the shaped hole was significantly higher than that of the seed meter without the shaped hole while the shaped hole B was the optimum structure. Disturbance structure affects the quality of feed index, multiple index rate, and miss index. The planting precision of the seed disturbance structure II was better than the other structures. At a speed of 60 rpm and vacuum pressures of 2.0 kPa, 2.4 kPa, and 2.8 kPa, the qualities of feed index of seed disturbance structure II were 90%, 91.11%, and 89.17%, respectively, and the miss indexes were 2.96%, 1.94%, and 1.57%, respectively. At high rotational speeds, the precision of rice bunch planting with the seed disturbance structure is better than that without the seed disturbance structure. In the simulation test, the seed velocity and total force magnitude of the meter without disturbance structures were less than those with the disturbed structure. Simulation experiments showed that the seed disturbance structure breaks up the stacked state of seeds. Research has shown that the shaped hole holds the seed in a stable suction posture, which helps to increase the seed-filling rate. Seed disturbance improves seed mobility, thereby enhancing the precision of bunch planting.

Abstract Background Pyroptosis is a form of programmed cell death involved in the pathophysiological progression of hypoxic pulmonary hypertension (HPH). Emerging evidence suggests that N6-methyladenosine (m6A)-modified transcripts of long noncoding RNAs (lncRNAs) are important regulators that participate in many diseases. However, whether m6A modified transcripts of lncRNAs can regulate pyroptosis in HPH progression remains unexplored. Methods The expression levels of FENDRR in hypoxic pulmonary artery endothelial cells (HPAECs) were detected by using quantitative real-time polymerase chain reaction (qRT-PCR) and fluorescence in situ hybridization (FISH). Western blot, Lactate dehydrogenase (LDH) release assay, Annexin V-FITC/PI double staining, Hoechst 33342/PI fluorescence staining and Caspase-1 activity assay were used to detect the role of FENDRR in HPAEC pyroptosis. The relationship between FENDRR and dynamin-related protein 1 (DRP1) was explored using bioinformatics analysis, Chromatin Isolation by RNA Purification (CHIRP), Electrophoretic mobility shift assay (EMSA) and Methylation-Specific PCR (MSP) assays. RNA immunoprecipitation (RIP) and m6A dot blot were used to detect the m6A modification levels of FENDRR. A hypoxia-induced mouse model of pulmonary hypertension (PH) was used to test preventive effect of conserved fragment TFO2 of FENDRR. Results We found that FENDRR was significantly downregulated in the nucleus of hypoxic HPAECs. FENDRR overexpression inhibited hypoxia-induced HPAEC pyroptosis. Additionally, DRP1 is a downstream target gene of FENDRR, and FENDRR formed an RNA–DNA triplex with the promoter of DRP1, which led to an increase in DRP1 promoter methylation that decreased the transcriptional level of DRP1. Notably, we illustrated that the m6A reader YTHDC1 plays an important role in m6A-modified FENDRR degradation. Additionally, conserved fragment TFO2 of FENDEE overexpression prevented HPH in vivo. Conclusion In summary, our results demonstrated that m6A-induced decay of FENDRR promotes HPAEC pyroptosis by regulating DRP1 promoter methylation and thereby provides a novel potential target for HPH therapy.

Heavy metals (HMs) pollution in the environment is a persistent issue and draws public attention constantly. However, there is little research assessing the pollution level of HMs in the Henan section of the Yellow River although the river is one of the most important water supply rivers in Henan province. In this research, the fraction contents of six HMs in the Henan section of the Yellow River were investigated by adopting the European Community Bureau of Reference (BCR) sequential extraction procedure. Moreover, the potential health risk caused by HMs was evaluated by adopting both the geo-accumulation index (Igeo) and ecological hazard index method. The results indicate the presence of a light HM pollution level in the Yellow River generally. However, the health risk caused by Cd cannot be neglected. Fraction analysis indicates that the content of the B2 fraction is high, which needs more attention. Overall, branch afflux might be one of the important pathways through which anthropogenic activities influence the Yellow River. The results of both the Igeo and ecological hazard index indicate that the potential health risk caused by HMs is low in the Yellow River, and the Yellow River protection policies implemented by Henan province may be the underlying reason. HIGHLIGHTS In this study, the content of six heavy metals in the Yellow River of the Henan section was investigated by adopting the BCR method.; The concentration of Cd was significantly higher than the background value.; The B1 fraction of Mn and B2 fraction of Pb were high, and the potential health risk should receive more attention.;

Optimal body structure design is a central focus in the field of passive automotive safety. A well-designed body structure enhances the lower threshold for crash safety, serving as a basis for the deployment of other safety systems. Frontal crashes, particularly those with an overlap rate below 25%, are the most frequent types of vehicular accidents and pose elevated risks to occupants due to variable energy absorption and force transmission mechanisms. This study aims to identify an optimized, cost-effective, and lightweight solution that minimizes occupant injuries. Using a micro-vehicle as a case study and accounting for noise, vibration, and harshness (NVH) performance, this paper employs Elman neural networks to predict key variables such as the first-order modes of the body, the body’s mass, and the head injury values for the driver. Guided by these predictions and constrained by the first-order modes and body mass, a genetic algorithm was applied to explore optimal solutions within the solution space defined by the body panel thickness. The optimized design yielded a reduction of approximately 173.43 in the driver’s head injury value while also enhancing the noise, vibration, and harshness performance of the vehicle body. This approach offers a methodological framework for future research into the multidisciplinary optimization of automotive body structures.

Given that fermentation time has significant impact on quality and flavor of soy sauce, a global understanding of the metabolic mechanism as fermentation time prolonged is essential for producing satisfactory and consistent quality of traditional soy sauce. Herein, the metabolic compounds changes of soy sauce associated with fermentation time up to 10 years were comprehensively investigated by using Chinese traditional fermented soy sauce (CTFSS) as a demonstration. Results showed that formaldehyde nitrogen, total soluble nitrogen (TSN), non-salt soluble solids, amino acids, free 5’-nucleotides and volatile compounds in CTFSS changed obviously during fermentation. Specifically, glutamic acid and aspartic acid were prominent in CTFSS. Continuous decrease in content of hypoxanthine (Hx) was found from 1 M (1-month soy sauce) to 7 M (7-months soy sauce). Furthermore, a significant opposite tendency for changes between some volatile compounds and amino acids was indicated that there was a transformation between these two components. Therefore, a better understanding to the influence of fermentation time on soy sauce had been proposed. As the formation and conversion of amino acids and sugars might be mainly responsible for flavor formation in CTFSS, the ratio of these two reactions rate led the metabolism to be divided into three steps, degradation, conversion and balance.

Changes in structure of oral solid dosage forms (OSDF) elementally determine the drug release and its therapeutic effects. In this research, synchrotron radiation X-ray micro-computed tomography was utilized to visualize the 3D structure of enteric coated pellets recovered from the gastrointestinal tract of rats. The structures of pellets in solid state and in vitro compendium media were measured. Pellets in vivo underwent morphological and structural changes which differed significantly from those in vitro compendium media. Thus, optimizations of the dissolution media were performed to mimic the appropriate in vivo conditions by introducing pepsin and glass microspheres in media. The sphericity, pellet volume, pore volume and porosity of the in vivo esomeprazole magnesium pellets in stomach for 2 h were recorded 0.47, 1.55 × 108 μm3, 0.44 × 108 μm3 and 27.6%, respectively. After adding pepsin and glass microspheres, the above parameters in vitro reached to 0.44, 1.64 × 108 μm3, 0.38 × 108 μm3 and 23.0%, respectively. Omeprazole magnesium pellets behaved similarly. The structural features of pellets between in vitro media and in vivo condition were bridged successfully in terms of 3D structures to ensure better design, characterization and quality control of advanced OSDF.

Abstract Background Excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) is the main cause of hypoxic pulmonary hypertension (PH), and mitochondrial homeostasis plays a crucial role. However, the specific molecular regulatory mechanism of mitochondrial function in PASMCs remains unclear. Methods In this study, using the CCK8 assay, EdU incorporation, flow cytometry, Western blotting, co-IP, mass spectrometry, electron microscopy, immunofluorescence, Seahorse extracellular flux analysis and echocardiography, we investigated the specific involvement of apoptosis-inducing factor (AIF), a mitochondrial oxidoreductase in regulating mitochondrial energy metabolism and mitophagy in PASMCs. Results In vitro, AIF deficiency in hypoxia leads to impaired oxidative phosphorylation and increased glycolysis and ROS release because of the loss of mitochondrial complex I activity. AIF was also downregulated and ubiquitinated under hypoxia leading to the abnormal occurrence of mitophagy and autophagy through its interaction with ubiquitin protein UBA52. In vivo, treatment with the adeno-associated virus vector to overexpress AIF protected pulmonary vascular remodeling from dysfunctional and abnormal proliferation. Conclusions Taken together, our results identify AIF as a potential therapeutic target for PH and reveal a novel posttranscriptional regulatory mechanism in hypoxia-induced mitochondrial dysfunction.

Abstract Chemotherapy, although effective against primary tumors, may promote metastasis by causing the release of proinflammatory factors from damaged cells. Here, polymeric nanoparticles that deliver chemotherapeutics and scavenge proinflammatory factors simultaneously to inhibit chemotherapy‐induced breast cancer metastasis are developed. The cationic nanoparticles can adsorb cell‐free nucleic acids (cfNAs) based on charge–charge interaction, which downregulates the expression of Toll‐like receptors and then reduces the secretion of inflammatory cytokines. Through in vitro structural optimization, cationic polyamidoamine (PAMAM) dendrimers modified with drug‐binding dodecyl groups and diethylethanolamine surface groups (PAMAM‐G3‐C125‐DEEA20) exhibit the most desirable combination of nanoparticle size (≈140 nm), drug loading, cytotoxicity, cfNA binding, and anti‐inflammatory activity. In the mouse models of breast cancer metastasis, paclitaxel‐loaded nanoparticles reduce serum levels of cfNAs and inflammatory cytokines compared with paclitaxel treatment alone and inhibit both primary tumor growth and tumor metastasis. Additionally, no significant side effects are detected in the serum or major organs. These results provide a strategy to deliver chemotherapeutics to primary tumors while reducing the prometastatic effects of chemotherapy.

Metal-organic frameworks (MOFs), comprised of organic ligands and metal ions/metal clusters via coordinative bonds are highly porous, crystalline materials. Their tunable porosity, chemical composition, size and shape, and easy surface functionalization make this large family more and more popular for drug delivery. There is a growing interest over the last decades in the design of engineered MOFs with controlled sizes for a variety of biomedical applications. This article presents an overall review and perspectives of MOFs-based drug delivery systems (DDSs), starting with the MOFs classification adapted for DDSs based on the types of constituting metals and ligands. Then, the synthesis and characterization of MOFs for DDSs are developed, followed by the drug loading strategies, applications, biopharmaceutics and quality control. Importantly, a variety of representative applications of MOFs are detailed from a point of view of applications in pharmaceutics, diseases therapy and advanced DDSs. In particular, the biopharmaceutics and quality control of MOFs-based DDSs are summarized with critical issues to be addressed. Finally, challenges in MOFs development for DDSs are discussed, such as biostability, biosafety, biopharmaceutics and nomenclature.

Normal heart development is vital for maintaining its function, and the development process is involved in complex interactions between different cell lineages. How mammalian hearts develop differently is still not fully understood. In this study, we identified several major types of cardiac cells, including cardiomyocytes (CMs), fibroblasts (FBs), endothelial cells (ECs), ECs/FBs, epicardial cells (EPs), and immune cells (macrophage/monocyte cluster, MACs/MONOs), based on single-cell transcriptome data from embryonic hearts of both human and mouse. Then, species-shared and species-specific marker genes were determined in the same cell type between the two species, and the genes with consistent and different expression patterns were also selected by constructing the developmental trajectories. Through a comparison of the development stage similarity of CMs, FBs, and ECs/FBs between humans and mice, it is revealed that CMs at e9.5 and e10.5 of mice are most similar to those of humans at 7 W and 9 W, respectively. Mouse FBs at e10.5, e13.5, and e14.5 are correspondingly more like the same human cells at 6, 7, and 9 W. Moreover, the e9.5-ECs/FBs of mice are most similar to that of humans at 10W. These results provide a resource for understudying cardiac cell types and the crucial markers able to trace developmental trajectories among the species, which is beneficial for finding suitable mouse models to detect human cardiac physiology and related diseases.

Summary: Glycyrrhetinic acid (GA) is a natural product of licorice with mitochondria targeting properties and shows broad anticancer activities, but its targets and underlying mechanisms remain elusive. Here, we identified the mitochondrial enzyme serine hydroxymethyltransferase 2 (SHMT2) as a target of GA by using chemical proteomics. Binding to and inhibiting the activity of SHMT2 by GA were validated in vitro and in vivo. Knockout of SHMT2 or inhibiting SHMT2 with GA restricts mitochondrial energy supplies by downregulating mitochondrial oxidative phosphorylation (OXPHOS) and fatty acid β-oxidation, and consequently suppresses cancer cell proliferation and tumor growth. Crystal structures of GA derivatives indicate that GA occupies SHMT2 folate-binding pocket and regulates SHMT2 activity. Modifications at GA carboxylic group with diamines significantly improved its anticancer potency, demonstrating GA as a decent structural template for SHMT2 inhibitor development.

Classification of pain levels from evoked electroencephalography (eEEG) has been achieved for the purpose of objective assessment of pain. However, differentiation of acute and chronic pain resulting from the activation of nociceptive nerves, the Aδ and C fibers, respectively, has remained unsolved, mainly due to the lack of effective features. Granger causality (GC) was applied to show the role of specific brain areas in the differentiation between pain and tactile sensation but yet was used to differentiate nociceptive fiber activations. The purpose of this study is two-fold: first, to develop pain perception classification systems using GC as features, and second, to identify causal connectivity for effective differentiation of nociceptive fiber activations. The eEEG responding to three stimulation waveforms, 1 Hz square waves, 5 Hz sine waves, both targeting C fibers, and 250 Hz sine waves, targeting Aδ, were recorded. Three GC categories based on channel areas, frequency bands, and stimulation waveforms were computed from the eEEG and used as features to classify nociceptive fiber activations and pain levels. It was found that GCs in the alpha band produced the highest average classification accuracy of 99.71%, followed by the gamma band, with 98.66%. Meanwhile, the GC feature contributing most to differentiating Aδ and C was found in the alpha band. The GC flow computed from the results of 5 Hz and 250 Hz stimulation had an important role in the prediction of mild pain and maximum pain, respectively. These results demonstrated the high potential of GC as features of pain-related information.

Emerging evidence has suggested that circular RNAs (circRNAs) are involved in multiple physiological processes and participate in a variety of human diseases. However, the underlying biological function of circRNAs in pulmonary hypertension (PH) is still ambiguous. Herein, we investigated the implication and regulatory effect of a typical circRNA, CDR1as, in the pathological process of vascular calcification in PH. Human pulmonary artery smooth muscle cell (HPASMC) calcification was analyzed by western blotting, immunofluorescence, alizarin red S staining, alkaline phosphatase activity analysis, and calcium deposition quantification. CDR1as targets were identified by bioinformatics analysis and validated by dual-luciferase reporter and RNA antisense purification assays. We identified that CDR1as was upregulated in hypoxic conditions and promoted a phenotypic switch of HPASMCs from a contractile to an osteogenic phenotype. Moreover, microRNA (miR)-7-5p was shown to be a target of CDR1as, and calcium/calmodulin-dependent kinase II-delta (CAMK2D) and calponin 3 (CNN3) were suggested to be the putative target genes and regulated by CDR1as/miR-7-5p. The results showed that the CDR1as/miR-7-5p/CNN3 and CAMK2D regulatory axis mediates HPASMC osteoblastic differentiation and calcification induced by hypoxia. This evidence reveals an approach to the treatment of PH.

Background. Acute respiratory distress syndrome (ARDS) is associated with high in-hospital mortality and most ARDS patients require ventilatory support. Applying appropriate ventilation strategies based on patients’ individual situations has a direct impact upon patients’ outcome. The neutrophil-to-lymphocyte ratio (NLR) has been shown to predict the early requirement of invasive mechanical ventilation (IMV) in patients with coronavirus disease 2019 (COVID-19). Our study aimed to investigate the relationship between baseline NLR and IMV in ARDS. Methods. A retrospective study was performed on patients who were diagnosed with ARDS using the Berlin definition and admitted to the First Affiliated Hospital of Soochow University from 2017 to 2022. Clinical data within 24 h after the ARDS diagnosis were collected from the medical record system. Based on the ventilation strategies during hospitalization, patients were divided into three groups and their clinical characteristics were compared. Furthermore, logistic regression analysis was used to screen the independent risk factors for IMV. STROBE checklist was used for this manuscript. Results. 520 ARDS patients were included and the median NLR value in IMV group was significantly higher than that of other groups (P

Measuring the sum of the three active neutrino masses, M _ν , is one of the most important challenges in modern cosmology. Massive neutrinos imprint characteristic signatures on several cosmological observables, in particular, on the large-scale structure of the universe. In order to maximize the information that can be retrieved from galaxy surveys, accurate theoretical predictions in the nonlinear regime are needed. Currently, one way to achieve those predictions is by running cosmological numerical simulations. Unfortunately, producing those simulations requires high computational resources—several hundred to thousand core hours for each neutrino mass case. In this work, we propose a new method, based on a deep-learning network (D ^3 M), to quickly generate simulations with massive neutrinos from standard ΛCDM simulations without neutrinos. We computed multiple relevant statistical measures of deep-learning generated simulations and conclude that our approach is an accurate alternative to the traditional N -body techniques. In particular the power spectrum is within ≃6% down to nonlinear scales k = 0.7 h Mpc ^−1 . Finally, our method allows us to generate massive neutrino simulations 10,000 times faster than the traditional methods.

Excessive UV-B exposure is well known to be a risk factor for corneal phototoxicity including direct DNA damage and disturbances in the antioxidant balance. Here, we showed a successful synthesis of a water-soluble and biocompatible small molecule DHPM 1 with dihydropyrimidinthione skeleton, which could effectively protect human corneal epithelial (HCE-2) cells from UV-B damage. In separate experiments, DHPM 1 absorbed UV-B rays and exhibited scavenging activity against intracellular ROS induced by UV-B radiation, thereby reducing the levels of DNA fragmentation. Additionally, UV-B exposure increased the expression of cleaved caspase-3, as well as the ratio of Bax/Bcl-2 at protein levels, while pretreatment with DHPM 1 significantly reversed these changes. To the best of our knowledge, this is the first report of a study based on dihydropyrimidinthione derivatives to develop a promising eye drops, which may well find extensive applications in UV-B caused corneal damage.

It has been reported that stimulating nociceptive unmyelinated C nerves (C) near the sarcolemma could induce the secretion of endogenous opioids that relieve chronic pain. However, a substantial concern remains: concomitant stimulation might cause acute pain to nociceptive myelinated Aδ nerves (Aδ), which generally have a lower activation threshold than the C. However, few studies have reported on C selectivity over Aδ (C-selectivity). In this study, the C and Aδ nerves were modeled using the Hodgkin-Huxley (HH) and McIntyre-Richardson-Grill (MRG) models, respectively. Two potential stimulation schemes, including bipolar square waves and burst modulated alternating current, together with a new stimulation scheme named inhibit-Aδ (i-Aδ) that inhibits the excitability of theAδ, were systematically investigated. Their stimuli were given to the C and Aδ nerves through point electrodes located near the nerve fibers. Simulation results revealed that i-Aδ presented the highest C-selectivity, which provides a basis for non-invasive effective chronic-pain relief.

Pulmonary arterial hypertension (PAH) is defined as elevation of mean pulmonary arterial pressure to ≥25 mmHg within the low pressure pulmonary circulatory system. PAH is characterized by obstructive vascular remodeling, partially due to excessive pulmonary arterial smooth muscle cell (PASMC) proliferation. Puerarin is a natural flavonoid isolated from the herb Radix puerariae, which has been widely used for the treatment of cardiovascular and cerebrovascular disorders and diabetes. However, how puerarin mediates autophagy in the progression of pulmonary vascular remodeling is unclear. In this study, we explored the effects of puerarin in a hypoxic pulmonary hypertension (PH) rat model using immunohistochemistry, and morphometric analyses of right ventricle. In addition, cell counting kit 8 assay, western blotting and flow cytometry were employed to test cell proliferation in PASMCs, and then autophagy was tested with mRFP-GFP-LC3 fluorescence microscopy and Western blot. We found that puerarin could alleviate hypoxia-induced PH in rats and improved pulmonary histopathology, and also reduced the expression of autophagy markers in vivo and in vitro. Moreover, puerarin also ameliorated hypoxia-induced PASMC proliferation in an autophagy-dependent manner. Overall, these findings demonstrated that puerarin could prevent hypoxia-induced PH in rats, possibly via reducing autophagy and suppressing cell proliferation. Keywords: Puerarin, Hypoxia, Pulmonary artery hypertension, Autophagy, Proliferation

In order to improve the single-grain seeding rate of the pneumatic single seed metering device, an airflow seed cleaning device was designed in combination with positive pressure airflow. The influence of the position of the seed cleaning mechanism on the seed cleaning effect is theoretically analyzed and a flow field simulation test analysis of different nozzle structures was carried out by using Fluent software (ANSYS, Inc., Canonsburg, PA, USA). The results of this test show that a nozzle with a Witoszynski curve has good airflow concentration and uniform air pressure distribution. In order to verify the performance of the seed cleaning mechanism, a 0.7 times coated seed (hybrid rice Wuyou 1179) was used as the test material and a quadratic regression test with three levels was carried out with the rotation speed of the seed plate, the negative pressure of the suction chamber, and the positive pressure of the seed cleaning as the test factors. The results showed that when the speed of sucking plate was 30 r/min, the negative pressure of the suction chamber was 1.8 kPa and the positive pressure of the seed cleaning was 0.2 kPa; the seeding effect was at its best and the qualified rate of the seed metering device was the highest at 86.43%, the minimum leakage rate was 3.81%, and the multiple rate was 9.76%. The proposed seed cleaning mechanism effectively improves the accuracy of seeding and provides a certain theoretical basis for the single-grain sowing of hybrid rice.

As a core component of the X-ray absorption fine structure spectroscopy (XAFS) system, the multi-channel double-crystal monochromator (DCM) can improve the time resolution of the system significantly. In contrast to the conventional single-channel DCM, the multi-channel DCM includes more pairs of crystals that are located separately in the master and slave motor axis with the same driving direction. However, a mismatched parallelism in the pitch direction, which can result from the manual mounting operation between the two separated crystals, directly affects the performance of the flux and the angular stability of the monochromatic beam. This poses a significant challenge to the precision position tracking of this system. In this paper, the mounting errors were translated into repetitive errors in the slave motor when the master motor was rotated at a constant velocity. Therefore, the iterative learning control (ILC) was considered in order to improve the tracking accuracy of the slave motor motion. The zero-magnitude error controller (ZMETC) was used to calculate the learning function to accelerate the convergence of the control inputs, and the convergence conditions of the control signal and error were also given. To validate the effectiveness of the proposed method, comparative experiments were performed on the motor motion platform. Experimental results indicated that the ILC effectively decreased the parallelism errors of the multi-channel DCM under various trajectories by comparing them with feedback controllers and the ZMETC, respectively.

The life cycle of intracellular RNA mainly involves transcriptional production, splicing maturation and degradation processes. Their dynamic changes are termed as RNA life cycle dynamics (RLCD). It is still challenging for the accurate and robust identification of RLCD under unknow the functional form of RLCD. By using the pulse model, we developed an R package named pulseTD to identify RLCD by integrating 4sU-seq and RNA-seq data, and it provides flexible functions to capture continuous changes in RCLD rates. More importantly, it also can predict the trend of RNA transcription and expression changes in future time points. The pulseTD shows better accuracy and robustness than some other methods, and it is available on the GitHub repository (https://github.com/bioWzz/pulseTD_0.2.0).

Fungal keratitis (FK) remains a severe eye disease, and effective therapies are limited by drug shortages and critical ocular barriers. Despite the high antifungal potency and broad spectrum of econazole, its strong irritant and insolubility in water hinder its ocular application. We designed and fabricated a new drug delivery system based on a polymeric vector for the ocular antifungal application of econazole. This novel system integrates the advantages of its constituent units and exhibits superior comprehensive performance. Using the new system, drug content was significantly increased more than 600 folds. The results of in vivo and in vitro experiments demonstrated that the econazole-loaded formulation exhibited significantly enhanced corneal penetration after a single topical ocular administration, excellent antifungal activity, and good tolerance in rabbits. Drug concentrations and ocular relative bioavailability in the cornea were 59- and 29-time greater than those in the control group, respectively. Following the topical administration of one eye drop (50 μL of 0.3% w/v econazole) in fungus-infected rabbits, a high concentration of antimycotic drugs in the cornea and aqueous humor was sustained and effective for 4 h. The mechanism of corneal penetration was also explored using dual fluorescent labeling. This novel drug delivery system is a promising therapeutic approach for oculomycosis and could serve as a candidate strategy for use with various hydrophobic drugs to overcome barriers in the treatment of many other ocular diseases.

Abstract Background Schistosomiasis is one of the most common parasitic diseases affecting millions of humans and animals worldwide. Understanding the signal transduction pathways and the molecular basis of reproductive regulation in schistosomes is critically important for developing new strategies for preventing and treating these infections. Syk kinases regulate the proliferation, differentiation, morphogenesis, and survival of various types of cells and have been identified in invertebrates. Tyrosine kinase 4 (TK4), a member of the Syk kinase family, plays a pivotal role in gametogenesis in S. mansoni, affecting the development of the testis and ovaries in this parasite. The role of TK4, however, in the reproduction of S. japonicum is poorly understood. Methods Here, the complete coding sequence of TK4 gene in S. japonicum (SjTK4) was cloned and characterized. The expression of SjTK4 was analyzed at different life-cycle stages and in various tissues of S. japonicum by qPCR. Piceatannol, a Syk kinase inhibitor, was applied to S. japonicum in vitro. The piceatannol-induced morphological changes of the parasites were observed using confocal laser scanning microscopy and the alterations in important egg-shell synthesis-related genes were examined using qPCR analyses. Results SjTK4 mRNA was differentially expressed throughout the life-cycle of S. japonicum. SjTK4 mRNA was highly expressed in the ovary and testis of S. japonicum, with the level of gene expression significantly higher in males than in females. The expression levels of some important egg-shell synthesis related genes were higher in the piceatannol-treated groups than in the vehicle-treated control group and the number of eggs and germ cells also decreased in a concentration-dependent manner. Importantly, large pore-like structures can be found in the testis and ovaries of males and females after treating with piceatannol. Conclusion The results suggest that SjTK4 may play an important role in regulating gametogenesis of S. japonicum. The findings may help better understand the fundamental biology of S. japonicum. Moreover, the effect of S. japonicum treatment by piceatannol provides us with a new idea that inhibition of SjTK4 signaling pathway can effectively retard the development of the testis and ovaries.

Abstract For patients carrying BRCA1 mutations, at least one‐third develop triple negative breast cancer (TNBC). Not only is TNBC difficult to treat due to the lack of molecular target receptors, but BRCA1 mutations (BRCA1m) also result in chemotherapeutic resistance, making disease recurrence more likely. Although BRCA1m are highly heterogeneous and therefore difficult to target, BRCA1 gene's synthetic lethal pair, PARP1, is conserved in BRCA1m cancer cells. Therefore, we hypothesize that targeting PARP1 might be a fruitful direction to sensitize BRCA1m cancer cells to chemotherapy. We used CRISPR/Cas9 technology to generate PARP1 deficiency in two TNBC cell lines, MDA‐MB‐231 (BRCA1 wild‐type) and MDA‐MB‐436 (BRCA1m). We explored whether this PARP1 disruption (PARP1m) could significantly lower the chemotherapeutic dose necessary to achieve therapeutic efficacy in both a 2D and 3D tumor‐on‐a‐chip model. With both BRCA1m and PARP1m, the TNBC cells were more sensitive to three representative chemotherapeutic breast cancer drugs, doxorubicin, gemcitabine and docetaxel, compared with the PARP1 wild‐type counterpart in the 2D culture environment. However, PARP1m did not result in this synergy in the 3D tumor‐on‐a‐chip model, suggesting that drug dosing in the tumor microenvironment may influence the synergy. Taken together, our results highlight a discrepancy in the efficacy of the combination of PARP1 inhibition and chemotherapy for TNBC treatment, which should be clarified to justify further clinical testing.