Responsive regularity of neurons in the hindlimb region of primary somatosensory cortex to different temperature thermal needle stimulation of "Zusanli"(ST36) in mice. / å°é¼ åˆçº§ä½“æ„Ÿçš®å±‚åŽè‚¢åŒºç¥žç»å ƒå¯¹"足三里"不同温度热刺激的响应规律.

OBJECTIVES: To study the regularity of central response to thermal needle stimulation of "Zusanli" (ST36) at different temperature, and to analyze the temperature difference of central responses. METHODS: Six male C57BL/6j adult mice were used in the present study. For observing activities of neurons in the hindlimb region of left primary somatosensory cortex (S1HL, A/P=0.46 mm, M/L=1.32 mm, D/V=-0.14 mm) by using a fast high-resolution miniature two-photon microscopy (FHIRM-TPM), the mice were anesthetized with 3% isoflurane (inhalation), with its head fixed in a stereotaxic apparatus, then, adeno-associated virus (AAV-hSyn-GCaMP6f-WPRE-hGHpA, for showing intracellular calcium transients in neurons transfected) was injected into the left S1HL region using a micro-syringe after scalp surgical operation. The mice's right ST36 were stimulated using internal thermal needles with the temperature being 43 ℃, or 45 ℃, or 47 ℃, separately. Image J software and MATLAB 2020b software were used to process the image data of neuronal calcium activity (Ca2+ signaling) in the left S1HL region, including the instant maximum calcium peak value (ΔF/F) in 2 s, instant calcium spike frequency in 2 s, short-term calcium peak value (ΔF/F) in 3.5 min, short-term calcium spike frequency in 3.5 min, calcium peak duration in 3.5 min, maximum calcium peak value (ΔF/F) at the 1st , 2nd and 3rd min, and calcium spike frequency at the 1st, 2nd and 3rd min after thermal needle stimulation. RESULTS: In comparison with the normal temperature needle stimulation, the instant intracellular maximum calcium peak value, instant calcium spike frequency, short-term maximum calcium peak value, short-term calcium spike frequency, and calcium peak duration of S1HL neurons in response to 43 ℃, 45 ℃ and 47 ℃ internal thermal needle stimulation of ST36 were significantly increased (P<0.001, P<0.01). Comparison among the 43 ℃, 45 ℃ and 47 ℃ thermal needle stimulation showed that the 45 ℃ thermal needle stimulation was obviously superior to 43 ℃ and 47 ℃ thermal needle stimulation in increasing instant calcium spike frequency, short-term calcium spike frequency and calcium peak duration of S1HL neurons (P<0.001, P<0.01). The 47 ℃ thermal needle stimulation was stronger than 43 ℃ and 45 ℃ thermal needle stimulation in increasing the instant maximum calcium peak value (P<0.001). The maximum calcium peak value was apparently higher (P<0.001) at the 2nd min than that at the 1st and 3rd min after 43 ℃, 45 ℃ and 47 ℃ thermal needle stimulation. No significant differences were found in the short-term maximum calcium peak value among the 3 thermal needle stimulation and in the calcium spike frequency among the 3 time points after 43 ℃, 45 ℃ and 47 ℃ thermal needle stimulation. CONCLUSIONS: S1HL neurons respond to all 43 ℃, 45 ℃ and 47 ℃ thermal needle stimulation of ST36 in mice, while more actively to 45 ℃ thermal needle stimulation.

Circulation immune cell landscape in canonical pathogenesis of colorectal adenocarcinoma by CyTOF analysis.

Current studies on the immune microenvironment of colorectal cancer (CRC) were mostly limited to the tissue level, lacking relevant studies in the peripheral blood, and failed to describe its alterations in the whole process of adenocarcinoma formation, especially of adenoma carcinogenesis. Here, we constructed a large-scale population cohort and used the CyTOF to explore the changes of various immune cell subsets in peripheral blood of CRC. We found monocytes and basophils cells were significantly higher in adenocarcinoma patients. Compared with early-stage CRC, effector CD4+T cells and naive B cells were higher in patients with lymph node metastasis, whereas the basophils were lower. We also performed random forest algorithm and found monocytes play the key role in carcinogenesis. Our study draws a peripheral blood immune cell landscape of the occurrence and development of CRC at the single-cell level and provides a reference for other researchers.

Identifying Hmga2 preserving visual function by promoting a shift of Müller glia cell fate in mice with acute retinal injury.

BACKGROUND: Unlike in lower vertebrates, Müller glia (MG) in adult mammalian retinas lack the ability to reprogram into neurons after retinal injury or degeneration and exhibit reactive gliosis instead. Whether a transition in MG cell fate from gliosis to reprogramming would help preserve photoreceptors is still under exploration. METHODS: A mouse model of retinitis pigmentosa (RP) was established using MG cell lineage tracing mice by intraperitoneal injection of sodium iodate (SI). The critical time point for the fate determination of MG gliosis was determined through immunohistochemical staining methods. Then, bulk-RNA and single-cell RNA seq techniques were used to elucidate the changes in RNA transcription of the retina and MG at that time point, and new genes that may determine the fate transition of MG were screened. Finally, the selected gene was specifically overexpressed in MG cells through adeno-associated viruses (AAV) in the mouse RP model. Bulk-RNA seq technique, immunohistochemical staining methods, and visual function testing were used to elucidate and validate the mechanism of new genes function on MG cell fate transition and retinal function. RESULTS: Here, we found the critical time point for MG gliosis fate determination was 3 days post SI injection. Hmga2 was screened out as a candidate regulator for the cell fate transition of MG. After retinal injury caused by SI, the Hmga2 protein is temporarily and lowly expressed in MG cells. Overexpression of Hmga2 in MG down-regulated glial cell related genes and up-regulated photoreceptor related genes. Besides, overexpressing Hmga2 exclusively to MG reduced MG gliosis, made MG obtain cone's marker, and retained visual function in mice with acute retinal injury. CONCLUSION: Our results suggested the unique reprogramming properties of Hmga2 in regulating the fate transition of MG and neuroprotective effects on the retina with acute injury. This work uncovers the reprogramming ability of epigenetic factors in MG.

Fate of glyphosate in lakes with varying trophic levels and its modification by root exudates of submerged macrophytes.

Accelerated eutrophication in lakes reduces the number of submerged macrophytes and alters the residues of glyphosate and its degradation products. However, the effects of submerged macrophytes on the fate of glyphosate remain unclear. We investigated eight lakes with varying trophic levels along the middle and lower reaches of the Yangtze River in China, of which five lakes contained either glyphosate or aminomethylphosphate (AMPA). Glyphosate and AMPA residues were significantly positively correlated with the trophic levels of lakes (P < 0.01). In lakes, glyphosate is degraded through the AMPA and sarcosine pathways. Eight shared glyphosate-degrading enzymes and genes were observed in different lake sediments, corresponding to 44 degrading microorganisms. Glyphosate concentrations in sediments were significantly higher in lakes with lower abundances of soxA (sarcosine oxidase) and soxB (sarcosine oxidase) (P < 0.05). In the presence of submerged macrophytes, oxalic and malonic acids secreted by the roots of submerged macrophytes increased the abundance of glyphosate-degrading microorganisms containing soxA or soxB (P < 0.05). These results revealed that a decrease in the number of submerged macrophytes in eutrophic lakes may inhibit glyphosate degradation via the sarcosine pathway, leading to a decrease in glyphosate degradation and an increase in glyphosate residues.

Optimization of cabin seating arrangement strategies based on the Wells-Riley risk theory.

Civil aviation transport is an important source of global respiratory disease spread due to the closely-spaced environment. In order to reduce the probability of infection of passengers, an improved Wells-Riley model for cabin passenger risk assessment have been given in this work, the cabin ventilation and passenger nose and mouth orientation were considered. The model's effectiveness has been verified with published data. Finally, how the load factor and use of an empty seat scheme are associated with the number of infected people was assessed. The results demonstrated that the number of infected people positively correlates with the passenger load factor, and the most suitable load factor can be determined by controlling the final number of infected people with the condition of the epidemic situation in the departure city. Additionally, infection risk was found to be lower among passengers in window seats than in those in aisle seats and middle seats, and keeping empty seats in the middle or aisle could reduce the cabin average probability of infection by up to 37.47%. Using the model developed here, airlines can determine the optimal load factor threshold and seating arrangement strategy to improve economic benefits and reduce the probability of passenger infection.

Spatial distributions and environmentally-mediated factors of dimethylsulfoxide off the northern Antarctic Peninsula in summer.

Spatial distributions of dissolved and particulate dimethylsulfoxide (DMSOd and DMSOp) were investigated off the northern Antarctic Peninsula during the austral summer of 2018, an ecologically and climatically important region of the world. In the upper waters, DMSOd was concentrated in the ice-melt zone because DMSO functions physiologically as an intracellular osmolyte and cryoprotectant. DMSOd concentrations had a weak positive correlation with temperature but a negative correlation with nutrients. This highlighted the importance of temperature-dependent biological activities and photolysis in DMSOd production and the important role of the intracellular antioxidation system in phytoplankton cells. The decrease of average DMSOp:Chl-a ratios in upper waters from west to east, along with decreasing temperatures and increasing diatoms proportions in the phytoplankton, illustrates how seawater DMSO production capacities depend on ambient temperatures and the composition of phytoplankton assemblages. DMSOp were accumulated in deep waters through bio-debris accumulation and microbial activity.

[Effect of mild moxibustion at 45 ℃ with different durations at "Zusanli" （ST36） on the inflammatory factors in the abdominal aorta of hyperlipidemia rats].

OBJECTIVE: To investigate the effects of mild moxibustion at 45°C on the chronic inflammatory response of the abdominal aorta in rats with hyperlipidemia and the effects of different moxibustion durations. METHODS: Thirty-six SD rats were randomly divided into the following groups： blank control group (2 weeks), model group (2 weeks), moxibustion group (2 weeks), blank group (4 weeks), model group (4 weeks), and moxibustion group (4 weeks). A model of hyperlipidemia with chronic inflammation was established through high-fat diet feeding for 8 weeks. Rats in the moxibustion groups received mild moxibustion treatment at bilateral "Zusanli"(ST36) at 45 °C, 10 min every time, once a day, for consecutive 2 or 4 weeks. The morphology of the abdominal aorta in each group was observed by using HE staining. Contents of serum total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), oxidized low-density lipoprotein (ox-LDL), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), endothelin-1 (ET-1) and the contents of nitric oxide (NO), ox-LDL, and ET-1 in the abdominal aorta were measured by using ELISA. Protein and mRNA expressions of IL-6 and TNF-α in the abdominal aorta of rats in each group were detected by using Western blot and real-time fluorescence quantitative PCR respectively. The positive expression of IL-6 in the abdominal aorta of rats was detected by Immunofluorescence. RESULTS: Compared to the blank control group, rats in the model group had increased contents of LDL, TC, TG, ox-LDL, VCAM-1, ICAM-1, IL-6, TNF-α, and ET-1 in the serum, increased contents of ox-LDL and ET-1 in the abdominal aorta, increased protein and mRNA expressions of IL-6 and TNF-α in the abdominal aorta(P<0.01, P<0.05, P<0.001), with decreased HDL content in the serum, decreased NO content in the abdominal aorta (P<0.01, P<0.05), as well as dark pink abdominal aorta, rough textures in the adventitia, media, and intima, and rough endothelial layer. Compared to the model group(2 weeks), LDL, ICAM-1, ET-1 contents in the serum, ox-LDL content in the abdominal aorta were decreased(P<0.05), while serum IL-6 and TNF-α contents, and NO content in the abdominal aorta were significantly increased(P<0.01, P<0.05), with smoother vascular walls, and relatively clear nucleus and surrounding tissue structures of abdominal aorta in the moxibustion group(2 weeks). Compared to the model group(4 weeks), contents of LDL, TC, TG, VCAM-1, ICAM-1, IL-6, TNF-α, ox-LDL, and ET-1 in the serum, ox-LDL and ET-1 contents in abdominal aorta, protein and mRNA expressions of IL-6 and TNF-α in the abdominal aorta were significantly decreased(P<0.05, P<0.01), while HDL content in the serum and NO content in the abdominal aorta were significantly increased(P<0.05, P<0.01), with smoother vascular walls, and relatively clear nucleus and surrounding tissue structures of abdominal aorta in the moxibustion group(4 weeks). In addition, content of HDL in the serum were significantly increased(P<0.05), while TNF-α content in the serum, protein expression of IL-6 in the abdominal aorta were significantly decreased (P<0.001, P<0.05), with smoother vascular walls, and clearer nucleus and surrounding tissue structures of abdominal aorta in the moxibustion group(4 weeks), in comparison with the moxibustion group(2 weeks). CONCLUSION: Mild moxibustion of 45 °C at ST36 can improve vascular endothelial damage and inflammatory response induced by high-fat diet by regulating serum lipids, vascular tone, adhesion molecules, and inflammatory factors, of which the effect of moxibustion intervention for 4 weeks is more significant.

Synchronization analysis of coupled fractional-order neural networks with time-varying delays.

In this paper, the complete synchronization and Mittag-Leffler synchronization problems of a kind of coupled fractional-order neural networks with time-varying delays are introduced and studied. First, the sufficient conditions for a controlled system to reach complete synchronization are established by using the Kronecker product technique and Lyapunov direct method under pinning control. Here the pinning controller only needs to control part of the nodes, which can save more resources. To make the system achieve complete synchronization, only the error system is stable. Next, a new adaptive feedback controller is designed, which combines the Razumikhin-type method and Mittag-Leffler stability theory to make the controlled system realize Mittag-Leffler synchronization. The controller has time delays, and the calculation can be simplified by constructing an appropriate auxiliary function. Finally, two numerical examples are given. The simulation process shows that the conditions of the main theorems are not difficult to obtain, and the simulation results confirm the feasibility of the theorems.

Impact of blood-brain barrier disruption on clinical features and treatment response in patients with newly diagnosed autoimmune encephalitis.

AIMS: Blood-brain barrier (BBB) breakdown is an essential mechanism in inflammatory diseases of the central nervous system. However, the association between BBB integrity and autoimmune encephalitis (AE) has not been investigated. Our study aimed to analyze this relationship in patients with AE between BBB integrity with clinical manifestations and therapeutic responses. METHODS: Our study enrolled 147 patients with AE who were newly diagnosed at the First Affiliated Hospital of Zhengzhou University between August 2015 and December 2021. Patients were classified into normal or damaged BBB groups based on cerebrospinal fluid (CSF) albumin/serum albumin (QAlb). To evaluate the severity of the illness, we used the modified Rankin Scale (mRS) and the Clinical Assessment Scale for Autoimmune Encephalitis (CASE). RESULTS: We found a higher proportion of males, higher CSF protein, immunoglobulin IgG, and 24-h intrathecal IgG synthesis rate in the damaged BBB group. The improvement rate was lower in the damaged BBB group, but we found that double- or triple-combination immunotherapy had better clinical outcomes than single immunotherapy. In addition, there was a positive correlation between the CASE score and mRS score, and a positive correlation between the CASE score or mRS score and QAlb on admission. CONCLUSIONS: BBB integrity is closely related to the clinical features and treatment responses of newly diagnosed AE. Patients with AE and a damaged BBB may benefit from combination immunotherapy.

Influence of Surface Ligand Density and Particle Size on the Penetration of the Blood-Brain Barrier by Porous Silicon Nanoparticles.

Overcoming the blood-brain barrier (BBB) remains a significant challenge with regard to drug delivery to the brain. By incorporating targeting ligands, and by carefully adjusting particle sizes, nanocarriers can be customized to improve drug delivery. Among these targeting ligands, transferrin stands out due to the high expression level of its receptor (i.e., transferrin receptor) on the BBB. Porous silicon nanoparticles (pSiNPs) are a promising drug nanocarrier to the brain due to their biodegradability, biocompatibility, and exceptional drug-loading capacity. However, an in-depth understanding of the optimal nanoparticle size and transferrin surface density, in order to maximize BBB penetration, is still lacking. To address this gap, a diverse library of pSiNPs was synthesized using bifunctional poly(ethylene glycol) linkers with methoxy or/and carboxyl terminal groups. These variations allowed us to explore different transferrin surface densities in addition to particle sizes. The effects of these parameters on the cellular association, uptake, and transcytosis in immortalized human brain microvascular endothelial cells (hCMEC/D3) were investigated using multiple in vitro systems of increasing degrees of complexity. These systems included the following: a 2D cell culture, a static Transwell model, and a dynamic BBB-on-a-chip model. Our results revealed the significant impact of both the ligand surface density and size of pSiNPs on their ability to penetrate the BBB, wherein intermediate-level transferrin densities and smaller pSiNPs exhibited the highest BBB transportation efficiency in vitro. Moreover, notable discrepancies emerged between the tested in vitro assays, further emphasizing the necessity of using more physiologically relevant assays, such as a microfluidic BBB-on-a-chip model, for nanocarrier testing and evaluation.

Self-adaption and texture generation: A hybrid loss function for low-dose CT denoising.

BACKGROUND: Deep learning has been successfully applied to low-dose CT (LDCT) denoising. But the training of the model is very dependent on an appropriate loss function. Existing denoising models often use per-pixel loss, including mean abs error (MAE) and mean square error (MSE). This ignores the difference in denoising difficulty between different regions of the CT images and leads to the loss of large texture information in the generated image. PURPOSE: In this paper, we propose a new hybrid loss function that adapts to the noise in different regions of CT images to balance the denoising difficulty and preserve texture details, thus acquiring CT images with high-quality diagnostic value using LDCT images, providing strong support for condition diagnosis. METHODS: We propose a hybrid loss function consisting of weighted patch loss (WPLoss) and high-frequency information loss (HFLoss). To enhance the model's denoising ability of the local areas which are difficult to denoise, we improve the MAE to obtain WPLoss. After the generated image and the target image are divided into several patches, the loss weight of each patch is adaptively and dynamically adjusted according to its loss ratio. In addition, considering that texture details are contained in the high-frequency information of the image, we use HFLoss to calculate the difference between CT images in the high-frequency information part. RESULTS: Our hybrid loss function improves the denoising performance of several models in the experiment, and obtains a higher peak signal-to-noise ratio (PSNR) and structural similarity index (SSIM). Moreover, through visual inspection of the generated results of the comparison experiment, the proposed hybrid function can effectively suppress noise and retain image details. CONCLUSIONS: We propose a hybrid loss function for LDCT image denoising, which has good interpretation properties and can improve the denoising performance of existing models. And the validation results of multiple models using different datasets show that it has good generalization ability. By using this loss function, high-quality CT images with low radiation are achieved, which can avoid the hazards caused by radiation and ensure the disease diagnosis for patients.

Comparative analysis of proteomes and transcriptomes revealed the molecular mechanism of development and nutrition of Pleurotus giganteus at different fruiting body development stages.

Pleurotus giganteus is a commercially cultivated high-temperature mushroom. Investigating the molecular mechanism of fruiting body development will help us to better understand the regulation of substrates and energy in this process. However, little information has been reported on the development and nutrients of the P. giganteus fruiting body. In the present study, P. giganteus is cultivated in a climate chamber, and comparative transcriptome, proteome, and nutritional analysis of P. giganteus fruiting bodies were performed. Our results revealed that Cytochrome P450 monooxygenases and hydrophobin proteins play important roles during the differentiation in the elongation stage. Later, carbon metabolism dominate the fruiting body metabolism and genes related to the carbohydrate metabolic process, glycolytic process, and gluconeogenesis were up-regulated in the mature fruiting bodies. The up-regulation of carbohydrate substrates utilization CAZymes genes and inconsistent protein expression in pileus indicated a reverse transportation of mRNA from the fruiting body to vegetative mycelia. In addition, protein concentration in the pileus is higher than that in the stem, while the stem is the major nitrogen metabolic and amino acid synthetic location. The integrated transcriptomic, proteomic, and nutritional analysis indicated a two-way transportation of substrates and mRNAs in P. giganteus. Stem synthesizes amino acids and transported them to pileus with reducing sugars, while pileus induces the expression of substrate degradation mRNA according to the needs of growth and development and transports them in the other direction.

Serum levels of IL-6/IL-10/GLDH may be early recognition markers of anti-tuberculosis drugs (ATB) -induced liver injury.

To explore the potential value of serum glutamate dehydrogenase (GLDH) combined with inflammatory cytokines as diagnostic biomarkers for anti-tuberculosis drug -induced liver injury (ATB-DILI). We collected the residual serum from the patients who met the criteria after liver function tests. We have examined these parameters including GLDH which were determined by enzyme-linked immunosorbent assay and cytokines which were determined by cytokine combination detection kit. Multivariate logistics stepwise forward regression was applied to establish regression models. A total of 138 tuberculosis patients were included in the diagnostic markers study of ATB-DILI, including normal liver function group (n = 108) and ATB-DILI group(n = 30). Serum GLDH, IL-6 and IL-10 levels were significantly increased in the ATB-DILI group. Receiver operating characteristic curve (ROC) curve showed that the area under curve (AUC) of serum GLDH, IL-6 and IL-10 for the diagnosis of ATB-DILI were 0.870, 0.714 and 0.811, respectively. In logistic regression modeling, the AUC of GLDH combined with IL-10 as an ATB-DILI marker is 0.912. Serum IL-6、IL-10 and GLDH levels began to rise preceded the increase in ALT by 7 days, with significant differences in IL-6 compared with 7 days. Serum GLDH, IL-6 and IL-10 levels were correlated with the severity of liver injury. In conclusion, we found that GLDH, IL-6 and IL-10 alone as diagnostic markers of ATB-DILI had good diagnostic efficacy. Logistic regression model established by GLDH and IL-10 had better diagnostic efficacy and IL-6 may be an early predictor of liver injury in the setting of ATB poisoning.

Glutamate dehydrogenase combined with ferrochelatase as a biomarker of liver injury induced by antituberculosis drugs.

AIMS: To explore the potential value of serum glutamate dehydrogenase (GLDH), ferrochelatase (FECH), heme oxygenase-1 (HO-1) and glutathione-S-transferase-α (GST-α) as diagnostic biomarkers for liver injury caused by antituberculosis drugs. METHODS: We established a rat model of isoniazide-induced liver injury and recruited 122 hospitalized tuberculosis patients taking antituberculosis drugs. We detected the concentration of GLDH, FECH, HO-1 and GST-α by enzyme-linked immunosorbent assay. GraphPad Prism8 and SPSS 26.0 were used for statistical analysis. RESULTS: In the rat model, serum GLDH concentration gradually increased during isoniazid (INH) administration, while serum FECH, HO-1 and GST-α concentrations significantly increased after INH administration was stopped. The receiver operating characteristic curve showed that the areas under the curve (AUCs) of serum GLDH and FECH for the diagnosis of anti-tuberculosis (TB) drug-induced liver injury (anti-TB-DILI) were 0.7692 (95% confidence interval [CI] 0.5442-0.9943) and 0.7284 (95% CI 0.4863-0.9705) and the diagnostic accuracies were 81.25% and 78.79%, respectively. In clinical research, the AUCs of GLDH and FECH were 0.9124 (95% CI 0.8380-0.9867) and 0.6634 (95% CI 0.5391-0.7877), and the optimal thresholds were 10.40 mIU/mL and 1.304 ng/mL, respectively. The diagnostic accuracy, specificity and positive predictive value (PPV) of GLDH were 82.61%, 79.38% and 47.22%. We performed a joint diagnostic test for GLDH and FECH. The diagnostic accuracy (90.43%), specificity (91.75%) and PPV (65.21%) of serial tests were better than for GLDH and FECH alone. CONCLUSIONS: GLDH in the diagnosis of liver injury induced by anti-TB drugs has high sensitivity, but low specificity and low PPV. The combination of GLDH and FECH could significantly improve the specificity, PPV and diagnostic accuracy, and reduce the false-positive rate of anti-TB-DILI.

α-Lipoic acid alleviates myocardial injury and induces M2b macrophage polarization after myocardial infarction via HMGB1/NF-kB signaling pathway.

BACKGROUND: Myocardial infarction (MI) is a serious cardiovascular disease with a poor prognosis. Macrophages are the predominant immune cells in patients with MI and macrophage regulation during the different phases of MI has important consequences for cardiac recovery. Alpha-lipoic acid (ALA) plays a critical role in MI by modulating the number of cardiomyocytes and macrophages. METHODS: MI mice were generated by ligating the left anterior descending coronary artery. Macrophages were exposed to hypoxia to establish a hypoxia model and M1 polarization was induced by LPS and IFN-γ. Different groups of macrophages and MI mice were treated with ALA. The cardiomyocytes were treated with various macrophage supernatants and the cardiac function, cytokine levels, and pathology were also analyzed. Factors related to apoptosis, autophagy, reactive oxygen species (ROS), and the mitochondrial membrane potential (MMP) were assessed. Finally, the HMGB1/NF-κB pathway was identified. RESULTS: ALA promoted M2b polarization in normal cells and suppressed inflammatory cytokines during hypoxia. ALA inhibited ROS and MMP production in vitro. Supernatants containing ALA inhibited apoptosis and autophagy in hypoxic cardiomyocytes. Moreover, ALA suppressed the HMGB1/NF-κB pathway in macrophages, which may be a potential mechanism for attenuating MI. CONCLUSION: ALA alleviates MI and induces M2b polarization via the HMGB1/NF-κB pathway, impeding inflammation, oxidation, apoptosis, and autophagy, and might be a potential strategy for MI treatment.

Resilience Mediates the Relationship Between Parental Attachment and Posttraumatic Growth in Adolescents: A Longitudinal Study.

OBJECTIVE: Previous studies have shown that parental attachment was associated with higher levels of posttraumatic growth (PTG) in individuals who have experienced traumatic events. The aim of the current longitudinal study is to investigate resilience as one pathway through which parental attachment is related to PTG among Chinese adolescents following the Yancheng tornado. METHODS: A total of 351 adolescent survivors participated in this longitudinal study. Participants completed the revised version of Inventory of Parent and Peer Attachment (IPPA-R) at 12 months (T1), and the revised Chinese version of the Post-Traumatic Growth Inventory (PTGI-R) and the Connor and Davidson's Resilience Scale (CD-RISC) at 18 months (T2) after the tornado, respectively. RESULTS: It indicated that parental attachment at T1 has direct and positive effect on PTG at T2, and resilience at T2 fully mediated the relationship between parental attachment at T1 and PTG at T2. CONCLUSION: The findings revealed that parental attachment and resilience are two key resources that promote adolescent's PTG, and parental attachment acts through resilience to promote PTG in adolescents.

[Moxibustion of 45 ℃ at "Zusanli" (ST36) improves vascular endothelial oxidative stress in hyperlipidemia rats].

OBJECTIVE: To explore the antioxidant effect of moxibustion on vascular endothelial function and the under-lying mechanism. METHODS: Forty male SD rats were randomly divided into blank, model, moxibustion and endothelial nitric oxide synthase (eNOS) inhibitor groups, with 10 rats in each group. Hyperlipidemia rat model was established by high fat diet for 8 weeks. Rats in the moxibustion group received 45 ℃ moxibustion at "Zusanli" (ST36) for 10 min once daily for consecutive 4 weeks. Rats in the eNOS inhibitor group received intraperitoneal injection of eNOS inhibitor L-NAME (1 mg/100 g) at the same time of moxibustion intervention. The morphology of abdominal aorta endothelium was observed by HE staining. Lipid deposition in abdominal aorta was observed by oil red O staining. The contents of total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) in serum and reactive oxygen species (ROS), nitric oxide (NO), superoxide dismutase (SOD), oxidized LDL lipoprotein (ox-LDL), endothelin-1 (ET-1), eNOS, malondialdehyde (MDA) in serum and abdominal aorta were determined by ELISA. The expression of eNOS in abdominal aorta was detected by immunofluorescence. RESULTS: HE staining of the abdominal aorta showed no significant pathological abnormality in the blank group; the endovascular cortex was rough, and the inner, media and outer membrane were rough in the model group; the nucleus and surrounding tissue structure were clear and the vascular wall was smooth in the moxibustion group; abdominal aorta texture was rough in the eNOS inhibitor group. Compared with the blank group, the area of oil red O staining in abdominal aorta increased (P<0.05); the contents of serum TC, TG and LDL-C increased (P<0.01, P<0.05) while HDL-C decreased (P<0.05); the contents of ET-1 in serum and abdominal aorta were increased (P<0.01, P<0.05) while the contents of NO and eNOS were decreased (P<0.05, P<0.001); the contents of ROS, ox-LDL and MDA in serum and abdominal aorta were increased (P<0.001, P<0.01, P<0.000 1) while the content of SOD in abdominal aorta was decreased (P<0.000 1); the expression level of eNOS in abdominal aorta was decreased (P<0.05) in the model group. Compared with the model group, the area of oil red O staining in abdominal aorta decreased (P<0.05); the contents of TC, TG and LDL-C in serum decreased (P<0.05) while HDL-C increased (P<0.05); the contents of ET-1 in serum and abdominal aorta were decreased (P<0.01, P<0.05) while the contents of NO and eNOS in abdominal aorta were increased (P<0.001, P<0.01); the contents of ROS and MDA in serum and abdominal aorta were decreased (P<0.001, P<0.01, P<0.05), the content of ox-LDL was decreased (P<0.01) and the content of SOD was increased (P<0.000 1) in abdominal aorta; the expression level of eNOS in abdominal aorta was increased (P<0.05) in the moxibustion group. Compared with the moxibustion group, the contents of serum TC, LDL-C and MDA in the eNOS inhibitor group were increased (P<0.05); the contents of ET-1, ROS, ox-LDL and MDA in abdominal aorta were increased (P<0.05), the contents of NO, eNOS and SOD were decreased (P<0.05); the expression level of eNOS in abdominal aorta was decreased (P<0.05). CONCLUSION: 45 ℃ moxibustion at ST36 can protect and repair vascular endothelial injury in abdominal aorta of hyperlipidemia rats and improve the oxidative stress of vascular endothelium.

Azidobenziodazolones as Azido Sources for the Enantioselective Copper-Catalyzed Azidation of N-Unprotected 3-Trifluoromethylated Oxindoles.

Both azido (N3) and trifluoromethyl (CF3) groups are key moieties of numerous valuable molecules that are extensively applied in drug discovery, chemical biology, and synthetic chemistry. However, the asymmetric construction of chiral quaternary stereocenters bearing both N3 and CF3 groups is still unexplored. Herein, we report a kind of bench-stable and easily adjustable benziodazolone-based azidating reagents. These reagents were used to achieve an enantioselective copper-catalyzed azidation of N-unprotected 3-trifluoromethylated oxindoles to provide diverse enantioenriched 3-N3-3-CF3 oxindoles.

Repopulated retinal microglia promote Müller glia reprogramming and preserve visual function in retinal degenerative mice.

Rationale: Müller glia (MG) play a key role in maintaining homeostasis of the retinal microenvironment. In zebrafish, MG reprogram into retinal progenitors and repair the injured retina, while this MG regenerative capability is suppressed in mammals. It has been revealed that microglia in zebrafish contribute to MG reprogramming, whereas those in mammals are over-activated during retinal injury or degeneration, causing chronic inflammation, acceleration of photoreceptor apoptosis, and gliosis of MG. Therefore, how to modulate the phenotype of microglia to enhance MG reprogramming rather than gliosis is critical. Methods: PLX3397, a colony-stimulating factor 1 receptor inhibitor, was applied to deplete microglia in the retinas of retinal degeneration 10 (rd10) mice, and withdrawal of PLX3397 was used to induce the repopulated microglia (Rep-MiG). The protective roles of the Rep-MiG on the degenerative retina were assessed using a light/dark transition test, and scotopic electroretinogram recordings. Immunofluorescence, western blot, transcriptomic sequencing, and bioinformatics analysis were performed to investigate the effects and mechanisms of microglia on MG reprogramming. Results: Following PLX3397 withdrawal, Rep-MiG replenished the entire retina with a ramified morphology and significantly improved the retinal outer nuclear layer structure, the electroretinography response, and the visual behavior of rd10 mice. Coincidentally, MG were activated, de-differentiated, and showed properties of retina progenitors in a spatial correlation with Rep-MiG. Morphological and transcriptomic analyses revealed Rep-MiG significantly enhanced protease inhibitor activity and suppressed extracellular matrix (ECM) levels during retinal degeneration. Conclusions: It suggested that Rep-MiG with the homeostasis characteristic stimulated the progenitor cell-like properties of MG, probably through regulating ECM remodeling, which protected photoreceptors and improved visual function of rd10 mice. It might be a potential protocol to reprogram MG and delay mammal retinal degeneration.

Self-supervised contrastive learning using CT images for PD-1/PD-L1 expression prediction in hepatocellular carcinoma.

Background and purpose: Programmed cell death protein-1 (PD-1) and programmed cell death-ligand-1 (PD-L1) expression status, determined by immunohistochemistry (IHC) of specimens, can discriminate patients with hepatocellular carcinoma (HCC) who can derive the most benefits from immune checkpoint inhibitor (ICI) therapy. A non-invasive method of measuring PD-1/PD-L1 expression is urgently needed for clinical decision support. Materials and methods: We included a cohort of 87 patients with HCC from the West China Hospital and analyzed 3094 CT images to develop and validate our prediction model. We propose a novel deep learning-based predictor, Contrastive Learning Network (CLNet), which is trained with self-supervised contrastive learning to better extract deep representations of computed tomography (CT) images for the prediction of PD-1 and PD-L1 expression. Results: Our results show that CLNet exhibited an AUC of 86.56% for PD-1 expression and an AUC of 83.93% for PD-L1 expression, outperforming other deep learning and machine learning models. Conclusions: We demonstrated that a non-invasive deep learning-based model trained with self-supervised contrastive learning could accurately predict the PD-1 and PD-L1 expression status, and might assist the precision treatment of patients withHCC, in particular the use of immune checkpoint inhibitors.