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Myocardial infarction (MI)-induced ventricular arrhythmia is the most common cause of death in patients with type 2 diabetes mellitus (T2DM). Patients with T2DM are two to four times more likely to die from MI than non-diabetic patients. Withdrawal of cardiac vagal activity is an important trigger for MI-induced ventricular arrhythmias in T2DM. Our recent study found that T2DM-elevated hydrogen peroxide (H2O2) levels in cardiac vagal postganglionic (CVP) neurons contribute to the withdrawal of cardiac vagal activity and ventricular arrhythmogenesis through inhibition of N-type Ca2+ channels (Cav2.2) in CVP neurons. The repressor element 1-silencing transcription factor (REST) is crucial to inhibit the expression of Cav2.2-α. In general, mature neuronal cells do not express the REST in the physiological condition. Here, we tested whether H2O2 induces REST expression in CVP neurons, which successively inhibits the expression of Cav2.2 in CVP neurons, causes cardiac vagal dysfunction, and triggers MI-evoked ventricular arrhythmias in T2DM rats. Our in vitro experiments demonstrated that protein expression of REST is high, whereas Cav2.2-α expression is low in undifferentiated NG108-15 cells. Differentiation of NG108-15 cells for twenty-one days significantly reduced REST expression and increased Cav2.2-α expression. Additionally, treatment with exogenous H2O2 (1 μM) in differentiated NG108-15 cells markedly increased REST expression and decreased Cav2.2-α expression. Similarly, a high level of REST protein and a low level of Cav2.2-α protein were confirmed in CVP neurons from T2DM rats than those from age-matched sham rats. In vivo transfection of REST shRNA (2 μl, 1×107 TU/ml) into the CVP neurons significantly decreased REST expression and increased Cav2.2-α expression in CVP neurons from T2DM rats. REST shRNA also improved cardiac vagal function, measured by heart rate variability, and reduced the cumulative duration of MI-evoked ventricular arrhythmias in conscious rats. These data suggested that H2O2-REST signaling pathway could be a key factor to mediate cardiac vagal dysfunction and affect the occurrence of ventricular arrhythmias in T2DM. This study was supported by the NIH-NHLBI (R01HL144146 to YLL). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Withdrawal of cardiac vagal activity is associated with ventricular arrhythmias-related sudden cardiac death and high mortality in T2DM patients. Although vagal nerve stimulation (VNS) has emerged as a promising therapy for ventricular arrhythmias, VNS-induced off-target side effects due to a lack of organ specificity severely limit its prescription in the clinic. To avoid the limitations of the VNS, we employed an optogenetic technique that combines with a miniaturized bio-optoelectronic implant with genetic targeting strategies to achieve cardiac-specific vagal activation in T2DM rats. We hypothesize that optogenetic activation in cardiac vagal postganglionic (CVP) neurons can restore vagal control of cardiac function, and further reduce susceptibility to ventricular arrhythmias in T2DM. Rat T2DM was induced by a high-fat diet plus streptozotocin injection. AAV-channelrhodopsin-2 (ChR2, 2 μl, 5x1012 vg/ml), an excitatory light-sensitive opsin gene, was in vivo transfected into CVP neurons located in the atrioventricular ganglion (AVG). At three weeks after opsin gene (i.e., AAV-ChR2) transfection, continual optogenetic stimulation in CVP neurons was applied twice daily (10 Hz, 50% duty cycle, 5 mW for 1 hour) by illuminating a LED probe that is controlled and powered wirelessly in conscious rats. Our data from immunofluorescence staining showed that microinjection of AAV-ChR2 into the AVG induced expression of ChR2-mcherry in almost all CVP neurons. Optogenetic activation of CVP neurons resulted in a negative inotropic reaction on the left ventricular systolic pressure in a frequency-dependent manner in anesthetized rats. Data from spectral analysis of heart rate variability demonstrated that optogenetic stimulation gradually restored T2DM-reduced high-frequency power (an index of cardiac vagal activation) from one to three days after optogenetic therapy in vivo, whereas it has no effect on low-frequency power (an index of cardiac sympathetic activation). Additionally, data from 24-hour continuous ECG recording in conscious rats demonstrated that optogenetic stimulation in CVP neurons improved the T2DM-impaired heterogeneity of ventricular electrical activity, which was measured by evaluating ventricular arrhythmia-related ECG parameters at three days after optogenetic therapy in vivo. These data suggested that optogenetic activation in CVP neurons might be an effective intervention against cardiac vagal dysfunction-related ventricular arrhythmias in the T2DM state. This study was supported by the Great Plains IDeA-CTR Pilot Grant (to DZ), NIH-NHLBI (R01HL144146 to YLL), and AHA Career Development Award (851929 to DZ). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The tripartite motif (TRIM) protein family has been investigated in multiple human cancers, including gastric cancer (GC). However, the role of TRIM69 in the anoikis resistance and metastasis of GC cells remains to be elucidated. We identified the differentially expressed genes in anoikis-resistant GC cells using RNA-sequencing analysis. The interaction between TRIM69 and PRKCD was analyzed by coimmunoprecipitation and mass spectrometry. Our results have shown that TRIM69 was significantly downregulated in anoikis-resistant GC cells. TRIM69 overexpression markedly suppressed the anoikis resistance and metastasis of GC cells in vitro and in vivo. TRIM69 knockdown had the opposite effects. Mechanistically, TRIM69 interacted with PRKCD through its B-box domain and catalyzed the K48-linked polyubiquitination of PRKCD. Moreover, TRIM69 inhibited BDNF production in a PRKCD-dependent manner. Importantly, overexpression of PRKCD or BDNF blocked the effects of TRIM69 on the anoikis resistance and metastasis of GC cells. Interestingly, a TRIM69−PRKCD+BDNF+ cell subset was positively associated with metastasis in GC patients. TRIM69-mediated suppression of the anoikis resistance and metastasis of GC cells via modulation of the PRKCD/BDNF axis, with potential implications for novel therapeutic approaches for metastatic GC.

B7 homolog 3 (B7‐H3) plays an important role in tumor biology, but the molecular mechanism underlying the role of B7‐H3 in tumor metastasis remains unclear. In this article, our analysis of The Cancer Genome Atlas database suggested that B7‐H3 expression is associated with poor prognosis of patients with clear cell renal cell carcinoma (ccRCC). B7‐H3 knockdown affected the expression of metastasis‐related genes and significantly suppressed the metastasis of ccRCC cells, but it had no significant effect on the proliferation of ccRCC cells. Database analysis revealed a strong positive correlation between B7‐H3 and fibronectin (FN) in ccRCC cells, and further study also confirmed that FN interacts with B7‐H3. Silencing FN expression inhibited the migration and invasion of ccRCC cells, whereas exogenous FN promoted the migration and invasion of ccRCC cells, which was accompanied by activation of kinases [namely, phosphorylated (p)‐phosphoinositide 3‐kinase, p‐protein kinase B, p‐p38 and p‐extracellular regulated protein kinase]. B7‐H3 knockdown abolished the prometastatic effect of FN. In conclusion, our data suggest that B7‐H3 binds to exogenous FN and promotes the metastasis of ccRCC cells., In this study, we explored the clinical significance and prognostic relationship of B7 homolog 3 (B7‐H3) in clear cell renal cell carcinoma (ccRCC). We report the novel discovery that B7‐H3 interacts with plasma fibronectin in promoting ccRCC metastasis. Cotargeting fibronectin and B7‐H3 may have potential as a new therapeutic intervention strategy for ccRCC treatment.

Renal denervation (RDN) is widely investigated in multiple studies of sympathetically driven cardiovascular diseases. While the therapeutic potential of RDN for ventricular arrhythmia has been reported, the mechanisms responsible for the antiarrhythmic effect of RDN are poorly understood. Our recent study showed that macrophage expansion-induced neuroinflammation in the stellate ganglion (SG) was a critical factor for cardiac sympathetic overactivation and ventricular arrhythmogenesis in chronic heart failure (CHF). This study aims to investigate if and how RDN decreases ventricular arrhythmias through attenuating neuroinflammation in cardiac sympathetic postganglionic (CSP) neurons in CHF. CHF was induced by acute surgical ligation of the left coronary artery in rats. Completed bilateral RDN was achieved by surgically cutting all the visible renal nerves around the renal artery and vein and followed by application of 70% ethanol around the vessels. Using immunofluorescence staining and Western blot analysis, we found that expression of granulocyte-macrophage colony-stimulating factor receptor-α subunit (GM-CSFRα), and Iba1 (an activated macrophage marker) in macrophages from the SG were increased in 16-week CHF rats, compared with age matched sham rats. In the ELISA experiment, we observed high levels of GM-CSF in kidney, serum, and SG in CHF rats, which were markedly reduced at 3 weeks after RDN. CHF-elevated macrophage activation and expression of GM-CSFRα in the SG were decreased by RDN. Flow cytometry data confirmed that CHF-increased percentage of macrophages in the SG was reduced at 3 weeks after RDN. Patch-clamp data found that RDN reduced the N-type Ca 2+ currents in CSP neurons from CHF rats (50.5+3.3 pA/pF in CHF rats vs. 28.6+2.2 pA/pF in CHF+RDN rats, P2+ channel signaling axis in CHF.

Introduction Frostbite is thought to result from initial vasoconstriction, ischemia, intracellular ice crystal formation, and inflammation caused by reperfusion injury. Corticosteroids have demonstrated beneficial anti-inflammatory effects in the treatment of other ischemia/reperfusion clinical conditions. The objective of this study was to determine the effect of dexamethasone (dex) on wound healing, inflammatory response, and vasculogenesis in a mouse skin frostbite model. Methods Treatment and control groups of C57/BL6 mice were subjected to frostbite using a previously described model. Treatment with intraperitoneal dex (1 mg·kg-1·d-1) began on the day of frostbite induction and lasted for 7 d. Over 4 wk, we compared wound diameter; morphology by visual inspection, hematoxylin–eosin staining, and Masson’s trichrome staining; density of inflammatory cytokines IL-1β and TNFα using Western blot analysis; and formation of microvasculature using immunofluorescence staining. Data were analyzed using 1-way or 1-way repeated-measures analysis of variance. Results After frostbite injury, morphological images demonstrated epidermal necrosis and loss in the frostbitten skin as well as infiltration of inflammation-related leukocytes. Increased production of inflammatory cytokines and disappearance of the microvasculature also occurred in the frostbitten skin. In comparison to the control group, treatment with dex promoted wound healing as demonstrated by decreased wound diameter; decreased levels of inflammatory cytokines, and accelerated formation of mature microvasculature. Conclusions In this animal model, dex improved wound healing in frostbitten skin and demonstrated both anti-inflammatory effects and stimulation of vasculogenesis. This study suggests that the use of potent anti-inflammatory agents may be an effective strategy for mitigating frostbite injury.

Aims Cardiac sympathetic overactivation is an important trigger of ventricular arrhythmias in patients with chronic heart failure (CHF). Our previous study demonstrated that N-type calcium (Cav2.2) currents in cardiac sympathetic post-ganglionic (CSP) neurons were increased in CHF. This study investigated the contribution of Cav2.2 channels in cardiac sympathetic overactivation and ventricular arrhythmogenesis in CHF. Methods and results Rat CHF was induced by surgical ligation of the left coronary artery. Lentiviral Cav2.2-α shRNA or scrambled shRNA was transfected in vivo into stellate ganglia (SG) in CHF rats. Final experiments were performed at 14 weeks after coronary artery ligation. Real-time polymerase chain reaction and western blot data showed that in vivo transfection of Cav2.2-α shRNA reduced the expression of Cav2.2-α mRNA and protein in the SG in CHF rats. Cav2.2-α shRNA also reduced Cav2.2 currents and cell excitability of CSP neurons and attenuated cardiac sympathetic nerve activities (CSNA) in CHF rats. The power spectral analysis of heart rate variability (HRV) further revealed that transfection of Cav2.2-α shRNA in the SG normalized CHF-caused cardiac sympathetic overactivation in conscious rats. Twenty-four-hour continuous telemetry electrocardiogram recording revealed that this Cav2.2-α shRNA not only decreased incidence and duration of ventricular tachycardia/ventricular fibrillation but also improved CHF-induced heterogeneity of ventricular electrical activity in conscious CHF rats. Cav2.2-α shRNA also decreased susceptibility to ventricular arrhythmias in anaesthetized CHF rats. However, Cav2.2-α shRNA failed to improve CHF-induced cardiac contractile dysfunction. Scrambled shRNA did not affect Cav2.2 currents and cell excitability of CSP neurons, CSNA, HRV, and ventricular arrhythmogenesis in CHF rats. Conclusions Overactivation of Cav2.2 channels in CSP neurons contributes to cardiac sympathetic hyperactivation and ventricular arrhythmogenesis in CHF. This suggests that discovering purely selective and potent small-molecule Cav2.2 channel blockers could be a potential therapeutic strategy to decrease fatal ventricular arrhythmias in CHF.

During tourniquet application, blood flow is restricted to a limb to stop excessive limb hemorrhage in a trauma setting and to create a bloodless operating field in the surgical setting. During tourniquet-related ischemia, aerobic respiration stops, and ATP is depleted, and during subsequent reperfusion, there is an increase in reactive oxygen species (ROS) production and other endogenous substances, which leads to acute ischemia-reperfusion (IR) injuries, including tissue necrosis and skeletal muscle contractile dysfunction. Hyperbaric oxygen (HBO) therapy can increase the arterial oxygen tension in the tissues of patients with general hypoxia/anoxia, including carbon monoxide poisoning, circulatory arrest, and cerebral and myocardial ischemia. Here, we studied the protective effects of HBO pretreatment with 100% oxygen at 2.5 ATA against tourniquet/IR injury in mice. After one hour of HBO therapy with 100% oxygen at 2.5 ATA was administered to C57/BL6 mice, a rubber band was placed at the hip joint of the unilateral hindlimb to induce 3 hours of ischemia and then released for 48 hours of reperfusion. We analyzed gastrocnemius muscle morphology and contractile function and measured the levels of ATP and ROS accumulation in the muscles. HBO pretreatment did not improve tourniquet/IR-injured gastrocnemius muscle morphology and muscle contraction. Tourniquet/IR mice with HBO pretreatment showed no increase in ATP levels in IR tissues, but they did have a decreased amount of ROS accumulation in the muscles, compared to IR mice with no HBO pretreatment. These data suggest that one hour of HBO pretreatment with 100% oxygen at 2.5 ATA increases the antioxidant response to lower ROS accumulation but does not increase ATP levels in IR muscles and improve tourniquet/IR-injured muscle morphology and contractile function.

The tourniquet or femoral artery ligation is widely used to stop extremity hemorrhage or create a bloodless operating field in the combat scenario and civilian setting. However, these procedures with subsequent reperfusion also induce ischemia-reperfusion (IR) injuries. To fully evaluate animal models of limb IR injuries, we compared tourniquet- and femoral artery ligation-induced IR injuries in the hindlimb of mice. In C57/BL6 mice, 3 h of unilateral hindlimb ischemia was induced by placement of a rubber band at the hip joint or a surgical ligation of the femoral artery. The tourniquet or femoral artery ligation was then released, allowing for 24 h of reperfusion. Compared to the femoral artery ligation/IR, the tourniquet/IR induced more severe skeletal muscle damage, including muscle necrosis and interruption of muscle fibers. There was no gastrocnemius muscle contraction in tourniquet/IR, while femoral artery ligation/IR markedly weakened gastrocnemius muscle contraction. Motor nerve terminals disappeared, and endplate potentials (EPPs) were undetectable in tourniquet/IR, whereas femoral artery ligation/IR only induced mild impairment of motor nerve terminals and decreased the amplitude of EPPs. Additionally, western blot data showed that proinflammatory cytokine levels (IL-1β and TNF-α) were higher in the tourniquet/IR than that in femoral artery ligation/IR. Moreover, tourniquet/IR caused significant tissue edema and dilation of lymphatic vessels in the hindlimb, compared to femoral artery ligation/IR. The above data demonstrated that tourniquet/IR-induced acute hindlimb injuries are more severe than those induced by femoral artery ligation/IR. This suggests that future investigators should determine which hindlimb IR model (tourniquet/IR or femoral artery ligation/IR) is optimal depending on the purpose of their study.

Tourniquets are widely used to stop extremity hemorrhage, but their use and subsequent release can result in nerve damage and degeneration, leading to neurological deficits. Increasing evidence has suggested a pivotal role of inflammation in nerve damage and abnormal mechanoreception. In this study, we investigated the therapeutic effects of masitinib (Mas), an anti-neuroinflammatory drug, on the mechanoreception of sensory neurons in a mouse model of tourniquet-induced hind paw ischemia-reperfusion (tourniquet/IR). C57BL/6 mice were subjected to 3 h of ischemia by placing a rubber band at the ankle joint and evaluated for subsequent reperfusion injury on day 1, 3, 7, 14, and 28 based on the experiments. Treatment with Mas (28 mg/kg/day, i.p.) began on the day of IR induction and lasted for 1, 3, 7, 14, or 28 days. Tourniquet/IR caused sensory nerve denervation in the skin of paw pads and abolished the hind paw mechanoreception to mechanical stimulation during the first 3 days of reperfusion. Sensory nerves gradually reinnervated in the skin of paw pads and allodynia began to appear on day 7. The maximum reaction occurred on day 14 and was maintained throughout the study period. Treatment with Mas mitigated nerve damage and improved hind paw mechanoreception to mechanical stimulation by decreasing the production of reactive oxygen species (ROS) during the early stages of tourniquet/IR. Mas also alleviated allodynia and decreased inflammatory cytokines (IL-1β and TNFα) in the skin of paw pads from days 7–28. Our data suggest that treatment with Mas significantly ameliorated paw numbness and allodynia in mouse hind paw tourniquet/IR.

This study built and tested two effective nomograms for the purpose of predicting cancer-specific survival and overall survival of chromophobe renal cell carcinoma (chRCC) patients. Multivariate Cox regression analysis was employed to filter independent prognostic factors predictive of cancer-specific survival and overall survival, and the nomograms were built based on a training set incorporating 2901 chRCC patients in a retrospective study (from 2004 to 2015) downloaded from the surveillance, epidemiology, and end results (SEER) database. The nomograms were verified on a validation cohort of 1934 patients, subsequently the performances of the nomograms were examined according to the receiver operating characteristic curve, calibration curves, the concordance (C-index), and decision curve analysis. The results showed that tumor grade, AJCC and N stages, race, marital status, age, histories of chemotherapy, radiotherapy and surgery were the individual prognostic factors for overall survival, and that AJCC, N and SEER stages, histories of surgery, radiotherapy and chemotherapy, age, tumor grade were individual prognostic factors for cancer-specific survival. According to C-indexes, receiver operating characteristic curves, and decision curve analysis outcomes, the nomograms showed a higher accuracy in predicting overall survival and OSS when compared with TNM stage and SEER stage. All the calibration curves were significantly consistent between predictive and validation sets. In this study, the nomograms, which were validated to be highly accurate and applicable, were built to facilitate individualized predictions of the cancer-specific survival and overall survival to patients diagnosed with chRCC between 2004 and 2015.

Heart failure (HF) is a clinical syndrome characterized by ventricular contractile dysfunction. About 50% of death in patients with HF are due to fetal ventricular arrhythmias including ventricular tachycardia and ventricular fibrillation. Understanding ventricular arrhythmic substrates and discovering effective antiarrhythmic interventions are extremely important for improving the prognosis of patients with HF and reducing its mortality. In this review, we discussed ventricular arrhythmic substrates and current clinical therapeutics for ventricular arrhythmias in HF. Base on the fact that classic antiarrhythmic drugs have the limited efficacy, side effects, and proarrhythmic potentials, we also updated some therapeutic strategies for the development of potential new antiarrhythmic interventions for patients with HF.

An cloud computing platform based on B/S architecture and docker container technology for autonomous driving simulation has been established in this paper. The map editor module of the cloud platform lets users design 3D scenes for simulating and testing automated driving systems. When the customized roadway scene for simulation created, it would be saved as OpenDrive format both for the server of cloud platform and CarMaker’s TestRun which all parameters of the virtual environment (vehicle, road, tires, etc.) are sufficiently defined. Then, based on the application online (APO) communication protocol of CarMaker, the local APO agent service was created. When the 27 parameters of vehicle dynamics received from CarMaker server, they were sent to the cloud platform in real time through UPD protocol. The process of data communication is completed by APO agent. Through the work above, a co-simulation between cloud platform and CarMaker could be successfully established for autonomous driving with seventeen-degree-of-freedom. Through the co-simulation experiment, it is found that the real-time data sampling frequency of the co-simulation is 70Hz, which completes the synchronous simulation of carmaker and cloud platform.

Although peripheral nerve system has intrinsic regeneration potential, recovery from peripheral nerve injury (PNI) is often far from optimal, leading to partial or complete loss of sensorimotor function and neuropathic pain. The failure for PNI repair can be due to multiple reasons. Excessively elevated oxidative stress in injured tissue is one of primary causes for poor nerve regeneration and pain by damaging neurons and myelin structure. In addition, deprivation in various neurotrophic factors (NTFs) in chronic nerve denervation will lose support for nerve regrowth. Here, we developed a multifunctional hyaluronic acid-phenylboronic acid-poly (vinyl alcohol) -heparin (HA-PVA-Hep) hydrogel by mixing cysteamine and phenylboronic acid modified hyaluronic acid, commercially available poly (vinyl alcohol) and maleimide functionalized heparin. This hydrogel is biocompatible, stable, injectable, antioxidative, anti-inflammatory, and capable of sustainably releasing NTFs (i.e. glial cell derived neurotrophic factor-GDNF in this study). The therapeutic effect of HA-PVA-Hep hydrogel to repair acute PNI was tested by using a mouse sciatic nerve crush model. We found the hydrogel effectively improved sensorimotor function during the recovery period and significantly prevented muscular atrophy, protected neurons from injury and promoted nerve regeneration as well as remyelination at 28 days post injury. In addition, the hydrogel could also alleviate PNI-induced pain as hydrogel treatment reversed pain-related changes induced by PNI, including increased expression of a proinflammatory modulator, TNF-α, at injured nerve, activation of microglia and upregulation of pain-sensor receptor, TRPA1 at ipsilateral spinal dorsal horn. Nevertheless, supplementing the hydrogel with GDNF interrupted the PNI recovery process and probably counteracted the pain alleviation effect of the hydrogel. Thus, therapeutic effect of GDNF through local administration on PNI treatment needs to be further determined. In summary, our work provides a hydrogel delivery system with inherent therapeutic effect for PNI therapy.

The complexity of research and development process and the diversity of research methods of intelligent connected vehicles increase the difficulty of establishing, integrating and verifying of virtual simulation experiments. In order to solve the problem of how to quantify the impact of weather environment changes on the virtual lidar in the simulation experiment, this paper first uses the derivation of the lidar range model and the analysis of the influence of atmospheric attenuation on the lidar range. Then, with the help of the empirical model of the attenuation coefficient of rain, snow, and haze, the curve fitting method is used to simplify the influence relationship so that it can be applied to the virtual simulation software of autonomous driving. Finally, the scene verification and evaluation of the quantification method of the lidar in the virtual environment affected by weather changes are carried out. The results show that this method effectively improves the restoration degree of the virtual simulation sensor while ensuring the calculation efficiency.

Aim Tourniquet-induced ischaemia and subsequent reperfusion cause serious ischaemia–reperfusion (IR) injury in the neuromuscular junction (NMJ) and skeletal muscle. Here, we investigated whether dexamethasone (Dex) promotes long-term functional recovery of the NMJ and skeletal muscle in tourniquet-induced hindlimb IR. Methods Unilateral hindlimb of C57/BL6 mice was subjected to 3 h of ischaemia following 6 weeks of reperfusion (6-wk IR). Dex treatment began on the day of IR induction and lasted for different periods. Sciatic nerve-stimulated gastrocnemius muscle contraction was detected in situ. Function of the NMJ was measured in situ using electrophysiological recording of the miniature endplate potential (mEPP) and endplate potential (EPP). Western blot was used to detect protein expression of nicotinic acetylcholine receptors (nAChRs) in gastrocnemius muscles. Results Gastrocnemius muscle contraction in mice with 6-wk IR was about 60% of normal skeletal muscle contraction recorded in age-matched sham mice. The amplitude of the mEPP and EPP was lower in mice with 6-wk IR, compared to sham mice. Dex treatment for 1 or 3 days did not restore the function of the NMJ and improve gastrocnemius muscle contraction in mice with 6-wk IR. Dex treatment for 1 week exerted a maximum effect on improving the function of the NMJ and skeletal muscle, with the effect of Dex gradually lessening with prolonged Dex treatment. There are no significant differences in protein expression of nAChR-α1 and nAChR-β1 subunits in the gastrocnemius muscle among all groups. Conclusion Dex promotes repair of the NMJ and subsequently restores skeletal muscle contractile function in tourniquet-induced 6-wk IR.

As a primary tool in first-line treatment of severe extremity hemorrhage, tourniquet and subsequent reperfusion also induce ischemia-reperfusion (IR) injuries including severe dysfunction of the neuromuscular junction (NMJ). Here, we observed the effect of dexamethasone (Dex) on NMJs suffering from IR-cause damage in mouse hindlimb. Unilateral hindlimb of mice was subjected to 3 h of tourniquet application by placing a rubber band, and then releasing the rubber band for reperfusion during different periods of time (1, 2, 4, and 6 weeks). Dex treatment (1 mg/kg/day, i.p.) began on the day of tourniquet-IR induction and lasted for 7 days. During tourniquet-induced IR, NMJs in gastrocnemius muscles showed significant morphological and functional changes. These changes include that motor nerve terminals gradually regenerated, even reaching that seen in sham mice; nicotinic acetylcholine receptor (nAChR) clusters were gradually fragmented with prolongation of reperfusion; and the amplitude of endplate potentials (EPPs) gradually increased, but it did not restore to the sham level at 6 weeks of tourniquet-induced IR. IL-1β and TNFα were over-produced in gastrocnemius muscles at 1 week, gradually decreased to the sham level at 4 weeks, and returned back to a high level at 6 weeks of tourniquet-induced IR. Treatment with Dex mitigated fragmentation of nAChR clusters, increased the amplitude of EPPs, and decreased levels of TNFα and IL-1β during the first two weeks of tourniquet-induced IR. The present study suggests that anti-inflammation is a potentially important strategy for promoting the morphological and functional recovery processes of NMJs after tourniquet-induced IR injuries.

At present, the complexity of the research and development process of the intelligent connected vehicle and the diversity of research methods increase the difficulty of establishing, integrating and verifying of virtual simulation experiments. In view of the deviation of the virtual vehicle sensor in the simulation experiment to the restoration of the real environment, this paper proposes to use the multi-point positioning method for data calibration, use the least square method to estimate the unknown point position in complex situations, and according to the error size after calibration, specific evaluation criteria are given. Finally, the scene verification and simulation evaluation of the calibration method of the GPS simulation data in the virtual environment and the truth value in the real world were carried out. The results show that this method effectively improves the restoration degree of the virtual simulation sensor to the real environment.

In this study, an injectable and self-healing hydrogel based on the boronic ester dynamic covalent bond between phenylboronic acid modified hyaluronic acid (HA-PBA) and the commercially available poly (vinyl alcohol) (PVA) is prepared and should have multi-functions for biomedical applications. The hydrogels were rapidly formed under mild conditions, and the rheological properties and in vitro degradation were systematically characterized. The HA-based hydrogels possessed good injectability and self-healing properties because of the dynamic bond. Moreover, due to the sensitivity of boronic ester to the biologically relevant concentration of hydrogen peroxide (H2O2), a major reactive oxygen species (ROS), the injectable hydrogel could be used as a H2O2/ROS responsive drug delivery system. The hydrogels supported good viability of encapsulated neural progenitor cells (NPC) and protected NPC from ROS induced damage in vitro when H2O2 was present in the media. The dynamic hydrogels were further applied as bio-inks for 3D printing/bioprinting. Overall, this facilely prepared dynamic hydrogel based on HA-PBA and PVA may have many potential biomedical applications, including drug delivery, 3D culture of cells, and 3D bioprinting.

Clinical trials and animal experimental studies have demonstrated an association of arterial baroreflex impairment with the prognosis and mortality of cardiovascular diseases and diabetes. As a primary part of the arterial baroreflex arc, the pressure sensitivity of arterial baroreceptors is blunted and involved in arterial baroreflex dysfunction in cardiovascular diseases and diabetes. Changes in the arterial vascular walls, mechanosensitive ion channels, and voltage-gated ion channels contribute to the attenuation of arterial baroreceptor sensitivity. Some endogenous substances (such as angiotensin II and superoxide anion) can modulate these morphological and functional alterations through intracellular signaling pathways in impaired arterial baroreceptors. Arterial baroreceptors can be considered as a potential therapeutic target to improve the prognosis of patients with cardiovascular diseases and diabetes.