Bioinformatics-based dynamics of cuproptosis -related indicators in experimental silicosis.

Pneumoconiosis is one of the most serious occupational diseases worldwide. Silicosis due to prolonged inhalation of free silica dust during occupational activities is one of the main types. Cuproptosis is a newly discovered mode of programmed cell death characterized by the accumulation of free copper in the cell, which ultimately leads to cell death. Increased copper in the serum of silicosis patients, suggests that the development of silicosis is accompanied by changes in copper metabolism, but whether cuproptosis is involved in the progression of silicosis is actually to be determined. To test this hypothesis, we screened the genetic changes in patients with idiopathic fibrosis by bioinformatics methods and predicted and functionally annotated the cuproptosis-related genes among them. Subsequently, we established a mouse silicosis model and detected the concentration of copper ions and the activity of ceruloplasmin (CP) in serum, as well as changes of the concentration of copper and cuproptosis related genes in mouse lung tissues. We identified 9 cuproptosis-related genes among the differential genes in patients with IPF at different times and the tissue-specific expression levels of ferredoxin 1 (FDX1) and Lipoyl synthase (LIAS) proteins. Furthermore, serum CP activity and copper ion levels in silicosis mice were elevated on days 7th and 56th after silica exposure. The expression of CP in mouse lung tissue elevated at all stages after silica exposure. The mRNA level of FDX1 decreased on days 7th and 56th, and the protein level remained in accordance with the mRNA level on day 56th. LIAS and Dihydrolipoamide dehydrogenase (DLD) levels were downregulated at all times after silica exposure. In addition, Heatshockprotein70 (HSP70) expression was increased on day 56. In brief, our results demonstrate that there may be cellular cuproptosis during the development of experimental silicosis in mice and show synchronization with enhanced copper loading in mice.

Expression levels of key immune indicators and immune checkpoints in manganese-exposed rats.

Manganese is essential trace elements, to participate in the body a variety of biochemical reactions, has important physiological functions, such as stimulate the immune cell proliferation, strengthen the cellular immunity, etc. However, excessive manganese exposure can cause damage to multiple systems of the body.The immune system is extremely vulnerable to external toxicants, however manganese research on the immune system are inadequate and biomarkers are lacking. Therefore, here we applied a manganese-exposed rat model to make preliminary observations on the immunotoxic effects of manganese. We found that manganese exposure inhibited humoral immune function in rats by decreasing peripheral blood IgG (ImmunoglobulinG, IgG), IgM (ImmunoglobulinM, IgM) and complement C3 levels; It also regulates rat cellular immune activity by influencing peripheral blood, spleen, and thymus T cell numbers and immune organ ICs (Immune Checkpoints, ICs) and cytokine expression. Furthermore, it was revealed that the impact of manganese exposure on the immune function of rats exhibited a correlation with both the dosage and duration of exposure. Notably, prolonged exposure to high doses of manganese had the most pronounced influence on rat immune function, primarily manifesting as immunosuppression.The above findings suggest that manganese exposure leads to impaired immune function and related changes in immune indicators, or may provide clues for the discovery of its biomarkers.

Prenatal ultrasound findings and prenatal diagnosis of fetal skeletal dysplasia.

OBJECTIVE: To analyze the value of prenatal ultrasound and molecular testing in diagnosing fetal skeletal dysplasia (SD). METHODS: Clinical data, prenatal ultrasound data, and molecular results of pregnant women with fetal SD were collected in the ultrasound department of our clinic from May 2019 to December 2021. RESULTS: A total of 40 pregnant women with fetal SD were included, with 82.5% exhibiting short limb deformity, followed by 25.0% with central nervous system malformations, 17.50% with facial malformations, 15% with cardiac malformations, and 12.5% with urinary system malformations. The genetic testing positive rate was 70.0% (28/40), with 92.8% (26/28) being single-gene disorders due to mutations in FGFR3, COL1A1, COL1A2, EVC2, FLNB, LBR, and TRPV4 genes. The most common SD subtypes were osteogenesis imperfecta (OI), thanatophoric dysplasia (TD), and achondroplasia (ACH). The gestational age (GA) at initial diagnosis for TD, OI, and ACH was 16.6, 20.9, and 28.3 weeks, respectively (p < 0.05), with no significant difference in femoral shortening between the three groups (p > 0.05). Of the OI cases, 5 out of 12 had a family history. CONCLUSION: Short limb deformity is the most prevalent phenotype of SD. When fetal SD is suspected, detailed ultrasound screening should be conducted, combined with GA at initial diagnosis, family history, and molecular evidence, to facilitate more accurate diagnosis and enhance prenatal counseling and perinatal management.

1,8-Cineole Alleviates OGD/R-Induced Oxidative Damage and Restores Mitochondrial Function by Promoting the Nrf2 Pathway.

This study examined the effects of 1,8-cineole on reducing oxidative stress injury and restoring mitochondrial function in oxygen-glucose deprivation and reoxygenation (OGD/R) HT22 cells via the nuclear factor erythrocyte 2 related factor 2 (Nrf2) pathway. The optimal concentration of 1,8-cineole to reduce OGD/R injury was screened via cell morphology, cell survival rate, and lactate dehydrogenase (LDH) leakage rate. Oxidative damage was observed by measuring superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), catalase (CAT) activities, and reactive oxygen species (ROS), glutathione (GSH), protein carbonyl, malondialdehyde (MDA), lipid peroxidation (LPO) content, and 8-hydroxy-2 deoxyguanosine (8-OHDG) expression. Mitochondrial function was observed by mitochondrial membrane potential (MMP) and ATPase activity. Nrf2 pathways were observed by the expression levels of total Nrf2, nucleus Nrf2, reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H): quinone oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1), the mRNA levels of HO-1 and NQO1. Among different concentrations of 1,8-cineole for promoting HT22 cell proliferation and attenuated OGD/R injury, 10 µmol/L 1,8-cineole was the best. After 1,8-cineole treatment, SOD, GSH-PX, and CAT activities and GSH content increased, while ROS, MDA, LPO, protein carbonyl, and 8-OHDG levels decreased. 1,8-Cineole could restore MMP and increase mitochondrial enzyme activity. It could also increase the total Nrf2, nucleus Nrf2, NQO1, and HO-1, and Nrf2 inhibitor brusatol reduced the effect of 1,8-cineole. Immunofluorescence assay showed that 1,8-cineole could facilitate the transfer of Nrf2 into the nucleus. 1,8-cineole increased the mRNA levels of NQO1 and HO-1. The above results showed that 1,8-cineole could alleviate OGD/R-induced oxidative damage and restores mitochondrial function by activating the Nrf2 signal pathway.

Temperature control and intermittent time-set protocol optimization for minimizing tissue carbonization in microwave ablation.

PURPOSE: The charring tissue formation in the ablated lesion during the microwave ablation (MWA) of tumors would induce various unwanted inflammatory responses. This paper aimed to deliver appropriate thermal dose for effective ablations while preventing tissue carbonization by optimizing the treatment protocol during MWA with the set combinations of temperature control and pulsed microwave energy delivery. MATERIAL AND METHODS: The thermal phase transition of ex vivo porcine liver tissues were recorded by differential scanning calorimetry (DSC) to determine the temperature threshold during microwave output control. MWA was performed by an in-house built system with the ease of microwave output parameter adjustment and real-time temperature monitoring. The effects of continuous and pulsed microwave deliveries as well as various intermittent time-set of MWA were evaluated by measuring the dimensions of the coagulation zone and the carbonization zone. RESULTS: The DSC scans demonstrated that the ex vivo porcine liver tissues have been in a state of endothermic heat during the heating process, where the maximum absorbed heat occurred at the temperature of 105 °C ± 5 °C. The temperature control during MWA resulted in effective coagulative necrosis while preventing tissue carbonization, after setting 100 °C as the upper threshold temperature and 60 °C as the lower threshold. Both the numerical simulation and ex vivo experiments have shown that, upon the optimization of the time-set parameters in the periodic intermittent pulsed microwave output, the tissue carbonization was significantly diminished. CONCLUSION: This study developed a straight-forward anti-carbonization strategy in MWA by modulating the pulsing mode and intermittent time. The programmed protocols of intermittent pulsing MWA have demonstrated its potentials toward future expansion of MWA technology in clinical application.

Study on the relationship between reduced scattering coefficient and Young's modulus of tumors in microwave ablation.

BACKGROUND AND OBJECTIVE: In the clinical treatment of tumors using microwave ablation (MWA), although temperature can be used as an important reference index for evaluating the curative effect of ablation, it cannot fully reflect the biological activity status of tumor tissue during thermal ablation. Finding multi-parameter comprehensive evaluation factors to achieve real-time evaluation of therapeutic effects has become the key for precise ablation. More and more scholars use the reduced scattering coefficient (µs') and Young's modulus (E) to evaluate the treatment outcomes of MWA. However, the intrinsic relationship between these parameters is unclear. This paper aims to investigate the specific relationship between µs' and E during MWA. MATERIAL AND METHODS: The MWA experiment was conducted on porcine liver in vitro, the two-parameter simultaneous acquisition system was designed to obtain the reduced scattering coefficient and Young's modulus of the liver tissue during MWA. The relationship between reduced scattering coefficient and Young's modulus was investigated. RESULTS: It is found that the trend of change of µs' is very similar to E in the process of MWA, i.e. first increasing and then reaching a steady state, and in some experiments there are synchronous changes. Based on this, the quantitative relationship between E-µs'  is established, enabling the quantitative estimation of Young's modulus of liver tissue based on reduced scattering coefficient. The maximum absolute error is 29.37 kPa and the minimum absolute error is 0.88 kPa. CONCLUSION: This study contributes to the further establishment of a multi-parameter MWA effectiveness evaluation model. It is also valuable for clinically evaluating the ablation outcomes of tumor in real time.

Study of cervical precancerous lesions detection by spectroscopy and support vector machine.

BACKGROUND AND OBJECTIVE: Diffuse reflectance spectroscopy (DRS) offers a fast, non-invasive, and low-cost alternative for cervical cancer diagnosis. We aim to develop a method for screening precancerous lesions based on DRS. MATERIAL AND METHODS: Characteristic parameters of cervical tissue were extracted from spectra, including optical characteristic parameters such as absorption and scattering coefficients, and some slope and area parameters of the spectrum. Data were randomly divided into training (60%) and test (40%) sets. Of the 210 included patients, 166 were healthy, 22 had erosion of the cervix, and 31 had cervical intraepithelial neoplasia (CIN). The support vector machine (SVM) algorithm was used to classify normal and abnormal cervical tissue based on 11 characteristic parameters. RESULTS: The SVM with linear kernel function, applied on the training data, could distinguish tissue with lesions from healthy tissue with an accuracy of 1.00. When the classifiers were applied to the test set, erosion of cervix and CIN could be discriminated from healthy tissue with an accuracy of 0.95 (±0.03). CONCLUSIONS: This research shows that the diagnostic algorithm can be valuable for non-invasive diagnosis of cervical cancer. This is a significant step toward the development of a tool for tissue assessment of cervical cancer.

Transcriptional reprogramming strategies and miRNA-mediated regulation networks of Taxus media induced into callus cells from tissues.

BACKGROUND: Taxus cells are a potential sustainable and environment-friendly source of taxol, but they have low survival ratios and slow grow rates. Despite these limitations, Taxus callus cells induced through 6 months of culture contain more taxol than their parent tissues. In this work, we utilized 6-month-old Taxus media calli to investigate their regulatory mechanisms of taxol biosynthesis by applying multiomics technologies. Our results provide insights into the adaptation strategies of T. media by transcriptional reprogramming when induced into calli from parent tissues. RESULTS: Seven out of 12 known taxol, most of flavonoid and phenylpropanoid biosynthesis genes were significantly upregulated in callus cells relative to that in the parent tissue, thus indicating that secondary metabolism is significantly strengthened. The expression of genes involved in pathways metabolizing biological materials, such as amino acids and sugars, also dramatically increased because all nutrients are supplied from the medium. The expression level of 94.1% genes involved in photosynthesis significantly decreased. These results reveal that callus cells undergo transcriptional reprogramming and transition into heterotrophs. Interestingly, common defense and immune activities, such as "plant-pathogen interaction" and salicylic acid- and jasmonic acid-signaling transduction, were repressed in calli. Thus, it's an intelligent adaption strategy to use secondary metabolites as a cost-effective defense system. MiRNA- and degradome-sequencing results showed the involvement of a precise regulatory network in the miRNA-mediated transcriptional reprogramming of calli. MiRNAs act as direct regulators to enhance the metabolism of biological substances and repress defense activities. Given that only 17 genes of secondary metabolite biosynthesis were effectively regulated, miRNAs are likely to play intermediate roles in the biosynthesis of secondary metabolites by regulating transcriptional factors (TFs), such as ERF, WRKY, and SPL. CONCLUSION: Our results suggest that increasing the biosynthesis of taxol and other secondary metabolites is an active regulatory measure of calli to adapt to heterotrophic culture, and this alteration mainly involved direct and indirect miRNA-induced transcriptional reprogramming. These results expand our understanding of the relationships among the metabolism of biological substances, the biosynthesis of secondary metabolites, and defense systems. They also provide a series of candidate miRNAs and transcription factors for taxol biosynthesis.

New different origins and evolutionary processes of AP2/EREBP transcription factors in Taxus chinensis.

BACKGROUND: Taxus spp. produces the anticancer drug, taxol, and hence is planted as an industrial crop in China. APETALA2/ethylene response element binding proteins (AP2/EREBPs) are the key regulators of plant development, growth, and stress responses. Several homologues control taxol biosynthesis. Identifying the AP2/EREBP proteins from Taxus is important to increase breeding and production and clarify their evolutionary processes. RESULTS: Among the 90 genes from multi Taxus chinensis transcriptome datasets, 81 encoded full-length AP2-containing proteins. A domain structure highly similar to that of angiosperm AP2/EREBPs was found in 2 AP2, 2 ANT, 1 RAV, 28 dehydration-responsive element-binding proteins, and 47 ethylene-responsive factors contained, indicating that they have extremely conservative evolution processes. A new subgroup protein, TcA3Bz1, contains three conserved AP2 domains and, a new domain structure of AP2/EREBPs that is different from that of known proteins. The new subtype AP2 proteins were also present in several gymnosperms (Gingko biloba) and bryophytes (Marchantia polymorpha). However, no homologue was found in Selaginella moellendorffii, indicating unknown evolutionary processes accompanying this plant's evolution. Moreover, the structures of the new subgroup AP2/EREBPs have different conserved domains, such as B3, zf-C3Hc3H, and agent domains, indicating their divergent evolution in bryophytes and gymnosperms. Interestingly, three repeats of AP2 domains have separately evolved from mosses to gymnosperms for most of the new proteins, but the AP2 domain of Gb_11937 has been replicated. CONCLUSION: The new subtype AP2/EREBPs have different origins and would enrich our knowledge of the molecular structure, origin, and evolutionary processes of AP2/EREBP transcription factors in plants.

The Role of Astragaloside IV against Cerebral Ischemia/Reperfusion Injury: Suppression of Apoptosis via Promotion of P62-LC3-Autophagy.

Background: Ischemia/reperfusion (I/R) caused by ischemic stroke treatments leads to brain injury, and autophagy plays a role in the pathology. Astragaloside IV is a potential neuroprotectant, but its underlying mechanism on cerebral I/R injury needs to be explored. The objective of this study is to investigate the neuroprotective mechanism of Astragaloside IV against cerebral I/R injury. Methods: Middle cerebral artery occlusion method (MCAO) and oxygen and glucose deprivation/reoxygenation (OGD/R) method were used to simulate cerebral I/R injury in Sprague-Dawley (SD) rats and HT22 cells, respectively. The neurological score, 2,3,5-Triphe-nyltetrazolium chloride (TTC) staining, and transmission electron microscope were used to detect cerebral damage in SD rats. Cell viability and cytotoxicity assay were tested in vitro. Fluorescent staining and flow cytometry were applied to detect the level of apoptosis. Western blotting was conducted to examine the expression of proteins associated with autophagy. Results: This study found that Astragaloside IV could decrease the neurological score, reduce the infarct volume in the brain, and alleviate cerebral I/R injury in MCAO rats. Astragaloside IV promoted cell viability and balanced Bcl-2 and Bax expression in vitro, reduced the rate of apoptosis, decreased the expression of P62, and increased the expression of LC3II/LC3I in HT22 cells after OGD/R. Conclusions: These data suggested that Astragaloside IV plays a neuroprotective role by down-regulating apoptosis by promoting the degree of autophagy.

[Design and Research of Thermal Ablation System Based on Dual-frequency Microwave Solid State Source].

Microwave thermal ablation technology is widely used in the treatment of liver tumors because of its minimal invasiveness and small side effects. The precise control of the thermal dose largely determines the therapeutic effect of microwave thermal ablation. However, the current magnetron-based microwave thermal ablation device has the disadvantages of poor power output stability and high operating voltage. In view of the above problems, this paper selected the microwave solid-state source as the core device of microwave output, and designed a dual-frequency microwave thermal ablation system based on 2 450 MHz and 433 MHz. The system used the power detection circuit to perform PID feedback control on the actual output power of the system. The experimental results show that the maximum output power of the system is less than 1 W. The PID algorithm further enhances the accuracy and stability of the system output power while improving the system security. The dual-frequency microwave thermal ablation system designed in this paper can provide a safe and reliable experimental platform for subsequent research.

[Clinical characteristics and molecular epidemiology of carbapenem- resistant Acinetobacter baumannii infections at Shenzhen People's Hospital during an 8-year period].

OBJECTIVE: To investigate the clinical features, mechanism of resistance and molecular epidemiology of carbapenem-resistant Acinetobacter baumannii (CRAB) infections at Shenzhen People's Hospital during an 8-year period. METHODS: A. baumannii isolates were recovered from nosocomial infections patients at this hospital from 2002 to 2009. The minimum inhibitory concentrations (MICs) of antimicrobial agents against A. baumannii isolates were detected by agar dilution method. Polymerase chain reaction (PCR) and DNA sequencing were used to examine the carbapenemase genotype among CRAB. All isolates were typed by pulse field gel electrophoresis (PFGE). Clinical cases of CRAB infections were retrospectively analyzed according to Chinese experts' consensus on diagnosis, treatments, preventions and controls of Acinetobacter baumannii infections in China. RESULTS: A total of 87 cases of CRAB nosocomial infections were diagnosed in this study. The most prominent infections caused by CRAB was lung infections, followed by bloodstream infections, wound infections and abdominal infections, accounting for 69.0%, 8.0%, 8.0% and 6.9% of 87 cases, respectively. Approximately 80.5% (70/87) of CRAB isolated from intensive care unit (ICU). A sharp increase of CRAB infections (42/87) occurred in 2009, with the majority of pulmonary infections (34/42). Genotyping by PFGE found eight distinct PFGE patterns among 87 isolates of CRAB. The prominent CRAB clone A, carrying a blaOXA-58-like carbapenemase gene, had been prevalent from 2002 to 2006 at this hospital. The CRAB clone C, harboring a blaOXA-23-like carbapenemase gene, as well as clone A became the prominent clones during 2007 to 2008. The CRAB clone D, carrying a blaOXA-23-like carbapenemase gene, replaced clone A and C, and became the dominant clone in 2009. CONCLUSION: The spread of the CRAB clone D harboring a blaOXA-23-like gene causes a rapid increase of CRAB infections at this hospital during 2009.

Mechanism of astragaloside IV regulating NLRP3 through LOC102555978 to attenuate cerebral ischemia reperfusion induced microglia pyroptosis.

Astragaloside IV(ASⅣ), the main component of Radix Astragali, has been used to treat cerebral ischemia reperfusion injury (CIRI). However, the molecular mechanism of ASIV in CIRI needs to be further elucidated. Long non-coding RNA (lncRNA) is considered to be an important kind of regulatory molecule in CIRI. In this work, the biological effect and molecular mechanism of ASIV in CIRI through lncRNA were analyzed by using rat middle cerebral artery occlusion and reperfusion (MCAO/R) model and primary rat microglia (RM) cells oxygen and glucose deprivation/reoxygenation (OGD/R) model. The neurological deficit score was evaluated, the volume of cerebral infarction was calculated, and pyroptosis related molecules were detected by qPCR and western blot. Then, high-throughput sequencing was performed in sham and MCAO/R groups. The competitive endogenous RNA (ceRNA) networks associated with pyroptosis were constructed by functional enrichment analysis. CCK-8 detection of cell survival rate, qPCR and western blot were used to determine the specific molecular mechanism of ASⅣ through ceRNA in vitro. Results showed thatASⅣ could decrease the neurological deficit score, reduce the volume of cerebral infarction, inhibit inflammatory reaction and pyroptosis in MCAO/R model rats. Next, the ceRNA network was established, including the LOC102555978/miR-3584-5p/NLRP3 regulatory network. In vitro experiments showed that LOC102555978 promotes NLRP3 mediated pyroptosis of RM cells through sponge adsorption of miR-3584-5p, which may provide a potential therapeutic target for post-CIRI inflammation regulation. ASⅣ could inhibit pyroptosis of RM cells by down-regulating LOC102555978. LOC102555978/miR-3584-5p/NLRP3 may be the molecular mechanism of ASⅣ's CIRI protective effect.

Multi-channel Small Animal Drug Metabolism Real-Time Monitoring Fluorescence System.

PURPOSE: The data acquisition of drug metabolism analysis requires a lot of time and animal resources. However, there are often many deviations in the results of pharmacokinetic analysis. Conventional methods cannot measure the blood drug concentration data in multiple tissues at the same time, and the data is obtained by in vitro measurement, which produces time errors, in vitro data errors, and individual differences between animals. In the analysis of pharmacokinetic parameters, it will seriously affect the pass rate of clinical trials of R&D drugs and the accuracy of the dosing schedule. To the best of our knowledge, we have not found the study of in vivo blood drug concentration using multi-channel equipment. Therefore, the purpose of this paper is to build a set of multi-organ monitoring and analysis instruments for synchronously monitoring the metabolism of drugs in various tissues of small animals, so as to obtain real in vivo data of blood drug concentration in real time. PROCEDURES: Using the fluorescence properties and laser-induced fluorescence principle of drugs, we designed six channels to monitor the changes of fluorescence-labeled drugs in their main metabolic organs, a multi-channel calibration method was proposed to improve the accuracy of the time-division multiplexing, the real-time collection of drug concentration in vivo is realized, and the drug metabolism curve in vivo can be observed. RESULTS: The instrument satisfies the collection of small doses of drugs such as microgram; the detection sensitivity can reach 10 ng/ml, and can monitor and collect the drug metabolism of multiple small animal tissues at the same time, which greatly reduces the use of animals, reduces the differences between individuals, and reduces consumption cost and improve the detection efficiency of parameters, and obtain data information that is closer to the real biology. CONCLUSION: The real-time continuous monitoring and data collection of the drug metabolism in the plasma of living small animals and the important organs such as kidney, liver, and spleen were realized. The research and development of new drugs and clinical research have higher practical value.

Fiber optic-based integrated system for in vivo multiscale pharmacokinetic monitoring.

This paper presents the development of a fiber-optic-based fluorescence detection system for multi-scale monitoring of drug distribution in living animals. The integrated system utilized dual laser sources at the wavelengths of 488 nm and 650 nm and three photomultiplier channels for multi-color fluorescence detection. The emission spectra of fluorescent substances were tracked using the time-resolved fluorescence spectroscopy module to continuously monitor their blood kinetics. The fiber bundle, consisting of 30,000 optic filaments, was designed for wide-field mesoscopic imaging of the drug's interactions within organs. The inclusion of a gradient refractive index (GRIN) lens within the setup enabled fluorescence confocal laser scanning microscopy to visualize the drug distribution at the cellular level. The system performance was verified by imaging hepatic and renal tissues in mice using cadmium telluride quantum dots (CdTe QDs) and R3. By acquiring multi-level images and real-time data, our integrated system underscores its potential as a potent tool for drug assessment, specifically within the realms of pharmacokinetic and pharmacodynamic investigations.

FOXF1 reverses lung fibroblasts transdifferentiation via inhibiting TGF-ß/SMAD2/3 pathway in silica-induced pulmonary fibrosis.

Silicosis is one of the most common and severe types of pneumoconiosis and is characterized by lung dysfunction, persistent lung inflammation, pulmonary nodule formation, and irreversible pulmonary fibrosis. The transdifferentiation of fibroblasts into myofibroblasts is one of the main reasons for the exacerbation of silicosis. However, the underlying mechanism of transcription factors regulating silicosis fibrosis has not been clarified. The aim of this study was to investigate the potential mechanism of transcription factor FOXF1 in fibroblast transdifferentiation in silica-induced pulmonary fibrosis. Therefore, a silicosis mouse model was established, and we found that FOXF1 expression level was significantly down-regulated in the silicosis group, and after overexpression of FOXF1 by adeno-associated virus (AAV), FOXF1 expression level was up-regulated, and silicosis fibrosis was alleviated. In order to further explore the specific regulatory mechanism of FOXF1 in silicosis, we established a fibroblasts transdifferentiation model induced by TGF-ß in vitro. In the model, the expression levels of SMAD2/3 and P-SMAD2/3 were up-regulated, but the expression levels of SMAD2/3 and P-SMAD2/3 were down-regulated, inhibiting transdifferentiation and accumulation of extracellular matrix after the overexpressed FOXF1 plasmid was constructed. However, after silencing FOXF1, the expression levels of SMAD2/3 and P-SMAD2/3 were further up-regulated, aggravating transdifferentiation and accumulation of extracellular matrix. These results indicate that the activation of FOXF1 in fibroblasts can slow down the progression of silicosis fibrosis by inhibiting TGF-ß/SMAD2/3 classical pathway, which provides a new idea for further exploration of silicosis treatment.

Rosmarinic acid liposomes suppress ferroptosis in ischemic brain via inhibition of TfR1 in BMECs.

BACKGROUND: Iron deposition and ferroptosis are involved in ischemic stroke injury, but the choice of drugs for treatment is limited. PURPOSE: To investigate the potential neuroprotective effects of Rosmarinic acid (RosA) encapsulated within nanoliposomes (RosA-LIP) on ischemic stroke. METHODS: Wild-type (WT) and TfR1EC cKO (specific knockout of the TfR1 gene in BMECs) mice used to establish a dMCAO model, with simultaneous administration of RosA-LIP (20 mg/kg/d, i.p.) or RosA (20 mg/kg/d, i.p.). RESULTS: The successful synthesis of RosA-LIP resulted in enhanced stability and precise delivery in both the serum and brain. The administration of RosA-LIP effectively mitigated ischemia-induced behavioral abnormalities and pathological damage. RosA-LIP inhibited ferroptosis by ameliorating mitochondrial abnormalities, increasing GPX4 levels, and decreasing ACSL4/LPCAT3/Lox-dependent lipid peroxidation. RosA-LIP effectively improved blood‒brain barrier (BBB) permeability, increased tight junctions (TJs) protein expression and reduced iron levels in ischemic tissue and brain microvascular endothelial cells (BMECs) by modulating FPN1 and TfR1 levels. Furthermore, RosA-LIP suppressed TfR1 to attenuate ACSL4/LPCAT3/Lox-mediated ferroptosis in TfR1EC cKO mice subjected to dMCAO. CONCLUSION: RosA-LIP effectively increased the brain level of RosA and protected against ferroptosis through the regulation of TfR1 in BMECs.

Darwin3: a large-scale neuromorphic chip with a novel ISA and on-chip learning.

Spiking neural networks (SNNs) are gaining increasing attention for their biological plausibility and potential for improved computational efficiency. To match the high spatial-temporal dynamics in SNNs, neuromorphic chips are highly desired to execute SNNs in hardware-based neuron and synapse circuits directly. This paper presents a large-scale neuromorphic chip named Darwin3 with a novel instruction set architecture, which comprises 10 primary instructions and a few extended instructions. It supports flexible neuron model programming and local learning rule designs. The Darwin3 chip architecture is designed in a mesh of computing nodes with an innovative routing algorithm. We used a compression mechanism to represent synaptic connections, significantly reducing memory usage. The Darwin3 chip supports up to 2.35 million neurons, making it the largest of its kind on the neuron scale. The experimental results showed that the code density was improved by up to 28.3× in Darwin3, and that the neuron core fan-in and fan-out were improved by up to 4096× and 3072× by connection compression compared to the physical memory depth. Our Darwin3 chip also provided memory saving between 6.8× and 200.8× when mapping convolutional spiking neural networks onto the chip, demonstrating state-of-the-art performance in accuracy and latency compared to other neuromorphic chips.

Manganese accumulation in red blood cells as a biomarker of manganese exposure and neurotoxicity.

Although overexposure to manganese (Mn) is known to cause neurotoxic damage, effective exposure markers for assessing Mn loading in Mn-exposed workers are lacking. Here, we construct a Mn-exposed rat model to perform correlation analysis between Mn-induced neurological damage and Mn levels in various biological samples. We combine this analysis with epidemiological investigation to assess whether Mn concentrations in red blood cells (MnRBCs) and urine (MnU) can be used as valid exposure markers. The results show that Mn exposure resulted in neurotoxic damage in rats and that MnRBCs correlated well with neurological damage, showing potential as a novel Mn exposure biomarker. These findings provide a basis for health monitoring of Mn-exposed workers and the development of more appropriate biological exposure limits.

Origin, development and advantageous disease spectrum of the "Zhibian (BL 54) through Shuidao (ST 28)" needling technique. / "秩边透水道"é’ˆæ³•æºæµæŽ¢æžåŠä¼˜åŠ¿ç— è°±.

This paper systematically reviews the historical evolution of the "Zhibian (BL 54) through Shuidao (ST 28)" needling technique by examining the history of the Mang needle, controversies and positioning of the Zhibian (BL 54), and the formation and essentials of the needling technique. Furthermore, the advantageous disease spectrum of this needling technique is summarized, and speculates on potential advantageous disease spectrum from the neural mechanisms of obtaining qi and achieving efficacy. Lastly, this paper discusses the inadequacies in the research on " Zhibian (BL 54) through Shuidao (ST 28)" needling technique, aiming to provide a comprehensive understanding and reference for further research on this technique.