Long-term isoflurane anesthesia induces cognitive deficits via AQP4 depolarization mediated blunted glymphatic inflammatory proteins clearance.

Perioperative neurocognitive disorders (PND) refer to cognitive deterioration that occurs after surgery or anesthesia. Prolonged isoflurane exposure has potential neurotoxicity and induces PND, but the mechanism is unclear. The glymphatic system clears harmful metabolic waste from the brain. This study sought to unveil the functions of glymphatic system in PND and explore the underlying molecular mechanisms. The PND mice model was established by long term isoflurane anesthesia. The glymphatic function was assessed by multiple in vitro and in vivo methods. An adeno-associated virus was used to overexpress AQP4 and TGN-020 was used to inhibit its function. This research revealed that the glymphatic system was impaired in PND mice and the blunted glymphatic transport was closely associated with the accumulation of inflammatory proteins in the hippocampus. Increasing AQP4 polarization could enhance glymphatic transport and suppresses neuroinflammation, thereby improve cognitive function in the PND model mice. However, a marked impaired glymphatic inflammatory proteins clearance and the more severe cognitive dysfunction were observed when decreasing AQP4 polarization. Therefore, long-term isoflurane anesthesia causes blunted glymphatic system by inducing AQP4 depolarization, enhanced the AQP4 polarization can alleviate the glymphatic system malfunction and reduce the neuroinflammatory response, which may be a potential treatment strategy for PND.

Low-Data Drug Design with Few-Shot Generative Domain Adaptation.

Developing new drugs for emerging diseases, such as COVID-19, is crucial for promoting public health. In recent years, the application of artificial intelligence (AI) has significantly advanced drug discovery pipelines. Generative models, such as generative adversarial networks (GANs), exhibit the potential for discovering novel drug molecules by relying on a vast number of training samples. However, for new diseases, only a few samples are typically available, posing a significant challenge to learning a generative model that produces both high-quality and diverse molecules under limited supervision. To address this low-data drug generation issue, we propose a novel molecule generative domain adaptation paradigm (Mol-GenDA), which transfers a pre-trained GAN on a large-scale drug molecule dataset to a new disease domain using only a few references. Specifically, we introduce a molecule adaptor into the GAN generator during the fine tuning, allowing the generator to reuse prior knowledge learned in pre-training to the greatest extent and maintain the quality and diversity of the generated molecules. Comprehensive downstream experiments demonstrate that Mol-GenDA can produce high-quality and diverse drug candidates. In summary, the proposed approach offers a promising solution to expedite drug discovery for new diseases, which could lead to the timely development of effective drugs to combat emerging outbreaks.

NIR-dependent photothermal-photodynamic synergistic antibacterial mechanism for titanium carbide nanosheets intercalated and delaminated by tetramethylammonium hydroxide.

The infectious disease epidemics caused by pathogens are a serious and growing worldwide public health problem. More seriously, the multiple resistant bacteria extensively spread in hospitals or communities due to antibiotic abuse. In this paper, we fabricate two-dimensional Ti3C2 nanosheets with excellent biocompatibility and photothermal-photodynamic synergistic antibacterial activity against E. coli and S. aureus based on the strategy of tetramethylammonium hydroxide (TMAOH)-driven intercalation and delamination. Compared with the traditional Ti3C2 nanosheets exfoliated by HF or situ HF (HCl + LiF), the photothermal-photodynamic Ti3C2 nanosheets show higher synergistic antibacterial efficiency. In addition, the antibacterial mechanism demonstrates that biofilm disruption and leakage of bacterial contents contribute to reactive oxygen species reaction (ROS) and photothermal antibacterial activity irradiated by NIR after most Ti3C2 nanosheets adhering to target bacteria. In conclusion, the Ti3C2 nanosheets have great potential as an effective antibacterial material without causing drug resistance, relying on intercalating and delaminating by TMAOH.

Robust Flow Estimation Algorithm of Multichannel Ultrasonic Flowmeter Based on Random Sampling Least Squares.

The multi-path ultrasonic flowmeter is widely used in engineering practice, and the flow algorithm is important for its accuracy. The least-squares estimation method is simple and efficient and has good engineering application value. In practical applications, noises are inevitably introduced to the measurement process because of the flowmeter itself or flow-field interference. The results of classical least squares will deviate from reality because it lacks robustness. In this regard, two flow algorithms of multi-path ultrasonic flowmeter are proposed based on least-squares and random-sampling consensus algorithms, which are widely used in the image field. The two algorithms can resist gross errors effectively by avoiding the interference of external points in the sampling points. To verify the effectiveness of the proposed algorithms, we take the double-bend flow field, which is a typical damaged flow field in engineering, as the research object, and then we compare the four algorithms. It can be seen that the two flow algorithms have higher accuracy and better robustness in the presence of interference noise.

Enhancement of astrocytic gap junctions Connexin43 coupling can improve long-term isoflurane anesthesia-mediated brain network abnormalities and cognitive impairment.

AIM: Astrocytes are connected by gap junctions Connexin43 (GJs-Cx43) forming an extensive intercellular network and maintain brain homeostasis. Perioperative neurocognitive disorder (PND) occurs frequently after anesthesia/surgery and worsens patient outcome, but the neural circuit mechanisms remain unclear. This study aimed to determine the effects of the GJs-Cx43-mediated astrocytic network on PND and ascertain the underlying neural circuit mechanism. METHODS: Male C57BL/6 mice were treated with long-term isoflurane exposure to construct a mouse model of PND. We also exposed primary mouse astrocytes to long-term isoflurane exposure to simulate the conditions of in vivo cognitive dysfunction. Behavioral tests were performed using the Y-maze and fear conditioning (FC) tests. Manganese-enhanced magnetic resonance imaging (MEMRI) and resting-state functional magnetic resonance imaging (rs-fMRI) were used to investigate brain activity and functional connectivity. Western blot and flow cytometry analysis were used to assess protein expression. RESULTS: Reconfiguring the astrocytic network by increasing GJs-Cx43 expression can modulate 22 subregions affected by PND in three ways: reversed activation, reversed inhibition, and intensified activation. The brain functional connectivity analysis further suggests that PND is a brain network disorder that includes sleep-wake rhythm-related brain regions, contextual and fear memory-related subregions, the hippocampal-amygdala circuit, the septo-hippocampal circuit, and the entorhinal-hippocampal circuit. Notably, remodeling the astrocytic network by upregulation of GJs-Cx43 can partially reverse the abnormalities in the above circuits. Pathophysiological degeneration in hippocampus is one of the primary hallmarks of PND pathology, and long-term isoflurane anesthesia contributes to oxidative stress and neuroinflammation in the hippocampus. However, promoting the formation of GJs-Cx43 ameliorated cognitive dysfunction induced by long-term isoflurane anesthesia through the attenuation of oxidative stress in hippocampus. CONCLUSION: Enhancing GJs-Cx43 coupling can improve brain network abnormalities and cognitive impairment induced by long-term isoflurane anesthesia, its mechanisms might be associated with the regulation of oxidative stress and neuroinflammation.

Summary of best evidence for enhanced recovery after surgery for patients undergoing lung cancer operations.

According to the cancer burden report released by the International Agency for Research on Cancer (IARC) in 2020, the mortality rate of lung cancer is 18%, ranking first in the world, and its morbidity and mortality rates are highest in China. Pneumonectomy is the preferred treatment for lung cancer patients, but surgery carries a significant risk of perioperative complications, which may affect the patient's functional recovery and quality of life. So, the rehabilitation of the large number of lung cancer patients in China requires greater attention. A number of studies have shown that the enhanced recovery after surgery (ERAS) protocol can reduce the risk of death, readmission rate, adjuvant chemotherapy time, postoperative pain level, anesthesia medication amount, length of stay, and hospitalization expenses. Foreign literature has successively issued guidelines to improve recovery among lung cancer patients, but Chinese-specific literature for patients undergoing lung cancer surgery or thoracic surgery remains inadequate. Some Chinese expert consensus have only considered part of the content of ERAS in thoracic surgery. To summary the evidence of the ERAS program for lung cancer surgery patients at home and abroad basing on evidence-based medicine is necessary. Therefore, this study used evidence-based practical thinking as a guide to (1) evaluate, integrate, and summarize relevant evidence guidelines and data resources at home and abroad so as to construct an enhanced recovery program for lung cancer patients suitable for Chinese national conditions and (2) provide a scientific basis for future research and practice in related fields.

Connexin 43 gap junction-mediated astrocytic network reconstruction attenuates isoflurane-induced cognitive dysfunction in mice.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common complication following anesthesia and surgery. General anesthetic isoflurane has potential neurotoxicity and induces cognitive impairments, but the exact mechanism remains unclear. Astrocytes form interconnected networks in the adult brain through gap junctions (GJs), which primarily comprise connexin 43 (Cx43), and play important roles in brain homeostasis and functions such as memory. However, the role of the GJ-Cx43-mediated astrocytic network in isoflurane-induced cognitive dysfunction has not been defined. METHODS: 4-month-old male C57BL/6 mice were exposure to long-term isoflurane to induce cognitive impairment. To simulate an in vitro isoflurane-induced cognitive dysfunction-like condition, primary mouse astrocytes were subjected to long-term isoflurane exposure. Cognitive function was assessed by Y-maze and fear conditioning tests. Western blot was used to determine the expression levels of different functional configurations of Cx43. The morphology of the GJs-Cx43 was evaluated by immunofluorescence staining. Levels of IL-1ß and IL-6 were examined by ELISA. The ability of GJs-Cx43-mediated intercellular communication was examined by lucifer yellow dye transfer assay. Ethidium bromide uptake assays were used to measure the activity of Cx43 hemichannels. The ultrastructural morphology of astrocyte gap junctions and tripartite synapse were observed by transmission electron microscopy. RESULTS: After long-term isoflurane anesthesia, the GJs formed by Cx43 in the mouse hippocampus and primary mouse astrocytes were significantly reduced, GJs function was impaired, hemichannel activity was enhanced, the levels of IL-1ß and IL-6 were increased, and mice showed significant cognitive impairment. After treatment with the novel GJ-Cx43 enhancer ZP1609, GJ-Cx43-mediated astrocytic network function was enhanced, neuroinflammation was alleviated, and ameliorated cognition dysfunction induced by long-term isoflurane exposure. However, ZP1609 enhances the astrocytic network by promoting Cx43 to form GJs without affecting hemichannel activity. Additionally, our data showed that long-term isoflurane exposure does not alter the structure of tripartite synapse. CONCLUSION: Our results reveal a novel mechanism of the GJ-Cx43-mediated astrocytic network involved in isoflurane-induced neuroinflammation and cognitive impairments, which provides new mechanistic insight into the pathogenesis of POCD and identifies potential targets for its treatment.

Suppressing vanadium dissolution of V2O5via in situ polyethylene glycol intercalation towards ultralong lifetime room/low-temperature zinc-ion batteries.

Zinc-ion batteries (ZIBs) are a main focus worldwide for their potential use in large-scale energy storage due to their abundant resources, environmental friendliness, and high safety. However, the cathode materials of ZIBs are limited, requiring a stable host structure and fast Zn2+ channel diffusion. Here, we develop a strategy for the intercalation of polyethylene glycol (PEG) to facilitate Zn2+ intercalation and to suppress the dissolution of vanadium in V2O5. In particular, PEG-V2O5 shows a high capacity of 430 mA h g-1 at a current density of 0.1 A g-1 as well as excellent 100 mA h g-1 specific capacity after 5000 cycles, with a high current density of 10.0 A g-1. A reversible capacity of 81 mA h g-1 can even be achieved with a low temperature of -20 °C at a current density of 2.0 A g-1 after 3500 cycles. The superior electrochemical performance comes from the intercalation of PEG molecules, which can improve kinetic transport and structural stability during the cycling process. The Zn2+ storage mechanism, which provides essential guidelines for the development of high-performance ZIBs, can be found through various ex situ characterization technologies and density functional density calculations.

Ex Vivo and In Vivo Monitoring and Characterization of Thermal Lesions by High-Intensity Focused Ultrasound and Microwave Ablation Using Ultrasonic Nakagami Imaging.

The feasibility of ultrasonic Nakagami imaging to evaluate thermal lesions by high-intensity focused ultrasound and microwave ablation was explored in ex vivo and in vivo liver models. Dynamic changes of the ultrasonic Nakagami parameter in thermal lesions were calculated, and ultrasonic B-mode and Nakagami images were reconstructed simultaneously. The contrast-to-noise ratio (CNR) between thermal lesions and normal tissue was used to estimate the contrast resolution of the monitoring images. After thermal ablation, a bright hyper-echoic region appeared in the ultrasonic B-mode and Nakagami images, identifying the thermal lesion. During thermal ablation, mean values of Nakagami parameter showed an increasing trend from 0.72 to 1.01 for the ex vivo model and 0.54 to 0.72 for the in vivo model. After thermal ablation, mean CNR values of the ultrasonic Nakagami images were 1.29 dB (ex vivo) and 0.80 dB (in vivo), significantly higher ( ) than those for B-mode images. Thermal lesion size, assessed using ultrasonic Nakagami images, shows a good correlation to those obtained from the gross-pathology images (for the ex vivo model: length, = 0.96; width, = 0.90; for the in vivo model: length, = 0.95; width, = 0.85). This preliminary study suggests that ultrasonic Nakagami parameter may have a potential use in evaluating the formation of thermal lesions with better image contrast. Moreover, ultrasonic Nakagami imaging combined with B-mode imaging may be utilized as an alternative modality in developing monitoring systems for image-guided thermal ablation treatments.

In vivo monitoring of microwave ablation in a porcine model using ultrasonic differential attenuation coefficient intercept imaging.

In this study, the feasibility of using ultrasonic differential attenuation coefficient intercept (Δα0) imaging to evaluate thermal lesions induced by microwave ablation (MWA) was explored using an in vivo porcine model. The attenuation coefficient intercept (Δα0 is estimated by subtracting an initial value of Δα0 images. Receiver operating characteristic (ROC) curves and the area under ROC curve (AUC) were employed to statistically assess the predictability of ultrasonic imaging. Ultrasonic Δα0 values were approximately 0.13 dB/cm and 0.16 dB/cm in a normal liver and kidney, respectively, increasing to 2.9 dB/cm and 2.55 dB/cm in ablated regions after MWA. The CNR values of the ultrasonic Δα0 images (0.9 dB and 0.6 dB in the liver and kidney, respectively) were significantly higher (p < 0.05) than the values of B-mode images (0.6 dB and 0.3 dB). The AUC value of the ultrasonic Δα0 image was higher than the B-mode image value, 0.95 compared with 0.88. This in vivo study suggests that ultrasonic Δα0 imaging has the potential to evaluate thermal lesions with high accuracy and better image contrast for monitoring MWA.

Feasibility of Using Ultrasonic Nakagami Imaging for Monitoring Microwave-Induced Thermal Lesion in Ex Vivo Porcine Liver.

The feasibility of using ultrasonic Nakagami imaging to evaluate thermal lesions induced by microwave ablation (MWA) in ex vivo porcine liver was explored. Dynamic changes in echo amplitudes and Nakagami parameters in the region of the MWA-induced thermal lesion, as well as the contrast-to-noise ratio (CNR) between the MWA-induced thermal lesion and the surrounding normal tissue, were calculated simultaneously during the MWA procedure. After MWA exposure, a bright hyper-echoic region appeared in ultrasonic B-mode and Nakagami parameter images as an indicator of the thermal lesion. Mean values of the Nakagami parameter in the thermal lesion region increased to 0.58, 0.71 and 0.91 after 1, 3 and 5 min of MVA. There were no significant differences in envelope amplitudes in the thermal lesion region among ultrasonic B-mode images obtained after different durations of MWA. Unlike ultrasonic B-mode images, Nakagami images were less affected by the shadow effect in monitoring of MWA exposure, and a fairly complete hyper-echoic region was observed in the Nakagami image. The mean value of the Nakagami parameter increased from approximately 0.47 to 0.82 during MWA exposure. At the end of the postablation stage, the mean value of the Nakagami parameter decreased to 0.55 and was higher than that before MWA exposure. CNR values calculated for Nakagami parameter images increased from 0.13 to approximately 0.61 during MWA and then decreased to 0.26 at the end of the post-ablation stage. The corresponding CNR values calculated for ultrasonic B-mode images were 0.24, 0.42 and 0.17. This preliminary study on ex vivo porcine liver suggested that Nakagami imaging have potential use in evaluating the formation of MWA-induced thermal lesions. Further in vivo studies are needed to evaluate the potential application.