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OBJECTIVE Spontaneous basal ganglia hemorrhage is a common type of intracerebral hemorrhage (ICH) with no definitive treatment. Minimally invasive endoscopic evacuation is a promising therapeutic approach for ICH. In this study the authors examined prognostic factors associated with long-term functional dependence (modified Rankin Scale [mRS] score ≥ 4) in patients who had undergone endoscopic evacuation of basal ganglia hemorrhage. METHODS In total, 222 consecutive patients who underwent endoscopic evacuation between July 2019 and April 2022 at four neurosurgical centers were enrolled prospectively. Patients were dichotomized into functionally independent (mRS score ≤ 3) and functionally dependent (mRS score ≥ 4) groups. Hematoma and perihematomal edema (PHE) volumes were calculated using 3D Slicer software. Predictors of functional dependence were assessed using logistic regression models. RESULTS Among the enrolled patients, the functional dependence rate was 45.50%. Factors independently associated with long-term functional dependence included female sex, older age (≥ 60 years), Glasgow Coma Scale score ≤ 8, larger preoperative hematoma volume (OR 1.02), and larger postoperative PHE volume (OR 1.03, 95% CI 1.01–1.05). A subsequent analysis evaluated the effect of stratified postoperative PHE volume on functional dependence. Specifically, patients with large (≥ 50 to < 75 ml) and extra-large (≥ 75 to 100 ml) postoperative PHE volumes had 4.61 (95% CI 0.99–21.53) and 6.75 (95% CI 1.20–37.85) times greater likelihood of long-term dependence, respectively, than patients with a small postoperative PHE volume (≥ 10 to < 25 ml). CONCLUSIONS A large postoperative PHE volume is an independent risk factor for functional dependence among basal ganglia hemorrhage patients after endoscopic evacuation, especially with postoperative PHE volume ≥ 50 ml.

In the process of promoting the internal audit work, we can find the operation and management of the enterprise, which is affected by the internal audit work. Therefore, it can be seen that the internal audit plays an important role, and it is also a necessary link in the internal management of the enterprise. With the development of China’s current economic market and the corresponding transformation, energy enterprises are facing serious development problems in the process of operation and management. The existence of these problems is concentrated in the internal audit management, mainly because many internal auditors fail to clearly recognize the necessity of establishing a good internal audit during the development of energy enterprises, which will inevitably have a negative impact on the development of enterprises. In addition, internal audit has not been fully recognized and concerned by all leaders, so the emergence of these situations will lead to the difficulty of internal audit in playing its real role to a certain extent. Therefore, in this paper, the author will start from the energy enterprises, study the financial audit method innovation of energy enterprises in Qinghai Province based on the panel data regression model, discuss the problems faced by internal design in enterprise management, and focus on how to effectively solve this problem, hoping to provide more reference for energy enterprises to carry out financial audit in the future.

The thermal management system is one of the important assemblies that ensure the secure operation of electric vehicles (EVs). Using intelligent algorithms to optimize the control strategy of the thermal management system can reduce energy consumption under the premise of effective heat dissipation of EVs. This paper attempts to construct the control strategy of EV thermal management system by coupling the modified genetic algorithm (MGA) and support vector regression (SVR). Firstly, the double-population adaptive mutation method and a novel optimization process are adopted to obtain MGA. Afterward, the performance of MGA is verified by four benchmark functions compared with three typical algorithms, which are genetic algorithm (GA), double-population genetic algorithm (DPGA), and quantum genetic algorithm (QGA). The results demonstrate that the accuracy and stability of MGA are obviously better than the other three algorithms. Secondly, MGA is applied to modify parameters of SVR kernel function, and the accuracy of MGA-SVR algorithm is verified by the Auto-MPG and Computer Hardware data sets. The mean square deviations of the SVR algorithm test set are 0.0186 and 0.0806, respectively, and the mean square deviations of the MGA-SVR algorithm test set are 0.0099 and 0.0054, respectively, which fully shows that MGA-SVR have more accurate forecasting capabilities. Finally, the thermal management system model of EV is built by the one-dimensional simulation software KULI. Under the Chinese working condition, fan speed which meets the cooling requirements of the motor and controller is obtained from the KULI model, and the database is constructed. Then, MGA-SVR is trained by database and employed to predict fan speed under the Chinese working condition and obtain control strategy of the thermal management system. Compared with traditional control strategy, the thermal management system based on MGA-SVR control strategy can not only meet the radiating requirements, but also effectively reduce the power consumption of fans.

Objective: To evaluate the efficacy of Tian dan shu gan rehabilitation exercise in improving the short-term survival quality of patients after percutaneous coronary intervention (PCI) and explore whether patients’ symptoms, physical function, cognitive function, and psychosocial function are improved after this exercise. Methods: Patients with acute myocardial infarction who underwent PCI in Yueyang Hospital of Integrated Traditional Chinese and Western Medicine Affiliated to Shanghai University of Traditional Chinese Medicine from August to November 2020 were selected. A total of 110 patients were selected by the convenience sampling method. Patients in the control group were given routine nursing measures after PCI for coronary heart disease, and patients in the experimental group received Tian dan shu gan rehabilitation exercise in addition to routine nursing. Results: After 3 wk, the quality of life in the experimental group was improved compared with that in the control group, and the differences in symptom scores, physical functions, cognitive functions, and psychosocial functions were statistically significant (P < 0.01). After 3 wk of Tian dan shu gan rehabilitation exercise, patients with body mass index (BMI) between 27 and 29.9 had the highest score of body function, which was statistically significantly better compared with that of other groups (P < 0.001). Patients who had remained bachelors for a long period of time had the highest score of symptoms, which was statistically significant compared with the other groups (P < 0.001). The nursing satisfaction of the experimental group was 96.3%. Conclusions: Tian dan shu gan rehabilitation exercise was effective in improving the short-term quality of life of patients with acute myocardial infarction after PCI, and the nursing satisfaction rate was high, use of which should be further extended to more clinical patients.

Cyclic dinucleotides (CDNs) as stimulator of interferon genes (STING) agonists capable of inducing strong antitumor innate immune response are highly promising for tumor immunotherapy. The efficacy of these CDNs is, however, reduced greatly by their fast clearance, poor cell uptake and inefficient cytosolic transportation. Here, we report that reduction-responsive biodegradable chimaeric polymersomes (CPs) markedly enhance tumor retention and cytosolic delivery of a synthetic CDN, ADU-S100, and bolster STING pathway activation in the tumor microenvironment and tumor draining lymph nodes, giving significantly better tumor repression and survival of B16F10 melanoma-bearing mice compared with free CDN control. The superiority of CPs-mediated CDN delivery is further verified in combination therapy with low-dose fractionated radiation, which brings about clearly stronger and longer-term immunotherapeutic effects and protection against tumor re-challenge. The development of nano-STING agonists that are able to overcome the delivery barriers of CDNs represents an effective strategy to potentiate cancer immunotherapy.

Recent single-cell studies of cancer in both mice and humans have identified the emergence of a myofibroblast population specifically marked by the highly restricted leucine-rich-repeat-containing protein 15 (LRRC15)1–3. However, the molecular signals that underlie the development of LRRC15+ cancer-associated fibroblasts (CAFs) and their direct impact on anti-tumour immunity are uncharacterized. Here in mouse models of pancreatic cancer, we provide in vivo genetic evidence that TGFβ receptor type 2 signalling in healthy dermatopontin+ universal fibroblasts is essential for the development of cancer-associated LRRC15+ myofibroblasts. This axis also predominantly drives fibroblast lineage diversity in human cancers. Using newly developed Lrrc15–diphtheria toxin receptor knock-in mice to selectively deplete LRRC15+ CAFs, we show that depletion of this population markedly reduces the total tumour fibroblast content. Moreover, the CAF composition is recalibrated towards universal fibroblasts. This relieves direct suppression of tumour-infiltrating CD8+ T cells to enhance their effector function and augments tumour regression in response to anti-PDL1 immune checkpoint blockade. Collectively, these findings demonstrate that TGFβ-dependent LRRC15+ CAFs dictate the tumour-fibroblast setpoint to promote tumour growth. These cells also directly suppress CD8+ T cell function and limit responsiveness to checkpoint blockade. Development of treatments that restore the homeostatic fibroblast setpoint by reducing the population of pro-disease LRRC15+ myofibroblasts may improve patient survival and response to immunotherapy.

Billions of cells undergo apoptosis every day in the human body, resulting in the generation of a large number of apoptotic vesicles (apoVs) to maintain organ and tissue homeostasis. However, the characteristics and function of pluripotent stem cell (PSC)-derived apoVs (PSC-apoVs) are largely unknown. In this study, we showed that human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) produced larger numbers of apoVs than human umbilical cord mesenchymal stem cells (UMSCs) do when induced by staurosporine. In addition to expressing the general apoV markers cleaved caspase 3, Annexin V, calreticulin, ALIX, CD63 and TSG101, ESC-apoVs inherited pluripotent-specific molecules SOX2 from ESCs in a caspase 3-dependent manner. Moreover, ESC-apoVs could promote mouse skin wound healing via transferring SOX2 into skin MSCs via activating Hippo signaling pathway. Collectively, these findings reveal that apoVs are capable of inheriting pluripotent molecules from ESCs to energize adult stem cells, suggesting the potential to use PSC-apoVs for clinical applications. STATEMENT OF SIGNIFICANCE: Apoptotic vesicles (apoVs) are essential to maintain organ and tissue homeostasis. However, the characteristics and function of pluripotent stem cell (PSC)-derived apoVs (PSC-apoVs) are largely unknown. This study showed that PSC-apoVs produced 100 times more apoVs than human umbilical cord mesenchymal stem cells (UMSCs). Despite expressing the general apoV makers, PSC-apoVs inherited pluripotent-specific molecule SOX2 from PSCs in a caspase 3-dependent manner. Moreover, PSC-apoVs promote mouse skin wound healing via transferring SOX2 into skin MSCs, thus activating Hippo signaling pathway. These findings reveal that apoVs are capable of inheriting pluripotent molecules from PSCs to energize adult stem cells, thus providing a cell-free strategy for clinical applications of PSCs.

Sialic acid-bound immunoglobulin lectin 15 (Siglec-15) plays a crucial role in many kinds of tumors. The relationship between Siglec-15 and the prognosis of osteosarcoma patients and its role in the apoptosis and pyroptosis of osteosarcoma cells are not sufficiently understood. Our study aimed to investigate the function of Siglec-15 in osteosarcoma cells and its effect on tumor cell proliferation, apoptosis and pyroptosis.The Siglec-15 expression in pathological sections of osteosarcoma patients was analyzed and the overall survival time related to the expression of Siglec-15 was further analyzed. Next, we detected the expression of Siglec-15 in osteosarcoma cells and downregulated the expression of Siglec-15 by small interfering RNA (siRNA). The proliferation, apoptosis and pyroptosis of osteosarcoma cells were studied by proliferation and apoptosis kits and Western blotting. Furthermore, the Siglec-15 signaling pathway was examined, which may be involved in the observed cellular effects.We demonstrated the expression of Siglec-15 in osteosarcoma cells. SiRNA-mediated downregulation of Siglec-15 was successful. We found that knockdown of Siglec-15 in osteosarcoma cell lines significantly inhibited proliferation while promoting apoptosis. Further investigation showed that the expression of proliferation-related proteins was downregulated and that apoptosis- and pyroptosis-related proteins were upregulated. In addition, we found that Siglec-15 may inhibit proliferation while inducing apoptosis and pyroptosis via the (Signal Transducer and Activator of Transcription 3) STAT3/Bcl-2 pathway in osteosarcoma.In this study, we demonstrated that the ablation of Siglec-15 in osteosarcoma inhibited proliferation and promoted apoptosis and pyroptosis by targeting the Siglec-15/STAT3/Bcl-2 pathway.

Xanthotoxin (XAT) is a natural furanocoumarins, a bioactive psoralen isolated from the fruit of the Rutaceae plant Pepper, which has received increasing attention in recent years due to its wide source and low cost. By collecting and compiling literature on XAT, the results show that XAT exhibits significant activity in the treatment of various diseases, including neuroprotection, skin repair, osteoprotection, organ protection, anticancer, antiinflammatory, antioxidative stress and antibacterial. In this paper, we review the pharmacological activity and potential molecular mechanisms of XAT for the treatment of related diseases. The data suggest that XAT can mechanistically induce ROS production and promote apoptosis through mitochondrial or endoplasmic reticulum pathways, regulate NF-κB, MAPK, JAK/STAT, Nrf2/HO-1, MAPK, AKT/mTOR, and ERK1/2 signaling pathways to exert pharmacological effects. In addition, the pharmacokinetics properties and toxicity of XAT are discussed in this paper, further elucidating the relationship between structure and efficacy. It is worth noting that data from clinical studies of XAT are still scarce, limiting the use of XAT in the clinic, and in the future, more in-depth studies are needed to determine the clinical efficacy of XAT.

In Qinghai-Tibet Plateau, crops are commonly subjected to freeze–thaw and salt stress factors simultaneously, and allelopathy is common, which affects the growth of highland barley (Hordeum vulgare L.), the largest food crop in Tibet. In order to explore the effects of artemisinin, salt and freeze–thaw (FAS) stress on physiological characteristics of highland barley seedlings, hydroponic experiment was carried out with the addition of 20 mg/L artemisinin and 150 mM NaCl as well as the simulation of freeze–thaw environment. The results suggested that under combined stress, the soluble protein content in combined stresses of artemisinin, FAS increased by 97.8%, the variation of relative conductivity in FAS group was lower than that in combined salt and freeze–thaw stress (FS), the relative water content decreased significantly (P

ObjectiveTraumatic brain injury (TBI) is a global social, economic, and health challenge that is associated with premature death and long-term disability. In the context of rapid development of urbanization, the analysis of TBI rate and mortality trend could provide abundant diagnosis and treatment suggestions, which helps to form future reference on public health strategies.MethodsIn this study, as one of major neurosurgical centers in China, we focused on the regime shift of TBI based on 18-year consecutive clinical data and evaluated the epidemiological features. In our current study, a total of 11,068 TBI patients were reviewed.ResultsThe major cause of TBI was road traffic injuries (44.%), while the main type of injury was cerebral contusion (n = 4,974 [44.94%]). Regarding to temporal changes, a decreasing trend in TBI incidence for patients under 44 years old was observed, while an increasing trend for those aged over 45 years was indicated. Incidences of RTI and assaults decreased, while ground level fall presented increasing incidences. The total number of deaths was 933 (8.43%), with a decreasing trend in overall mortality since 2011. Age, cause of injury, GCS at admission, Injury Severity Score, shock state at admission, trauma-related diagnoses and treatments were significantly associated with mortality. A predictive nomogram model for poor prognosis was developed based on patient's GOS scores at discharge.ConclusionsThe trends and characteristics of TBI patients changed with rapid development of urbanization in the past 18 years. Further larger studies are warranted to verify its clinical suggestions.

Objective: patients with moderate traumatic brain injury (TBI) are under the threat of intracranial hypertension(IHT), which is an important cause of death and unfavorable outcome of TBI patients. However, it is unclear which moderate TBI patients will develop IHT and when to receive ICP-lowering treatment or even invasive ICP monitoring after admission. The purpose of the present study was to develop and validate a prediction model that estimates the risk of IHT in moderate TBI patients with lower GCS (9-11) by admission data. Methods: baseline data collected on admission of 296 moderate TBI patients with GCS score of 9-11 were collected and analyzed. Multi-variable logistic regression modeling with backward stepwise elimination was used to develop a prediction model for IHT. The discrimination efficacy, calibration efficacy, and clinical utility of the prediction model were evaluated. Finally, the prediction model was validated in a separate cohort of 74 patients from 3 hospitals. Results: four independent prognostic factors for IHT were identified: GCS score of 9, Marshall diffuse injury type IV and nonevacuated mass lesion, ISS≥18and location of contusion (frontal and temporal contusion). A prediction model was established and shown as a nomogram. The C-statistic of the prediction model in internal validation was 84.30% (95% confidence interval [CI]: 0.794–0.892). External validation was performed in a separate cohort of 85 patients. The area under the curve for the prediction model was 82.70% (95% CI: 0.726~0.928). Conclusions: A prediction model based on patient parameters collected on admission was found to be highly sensitive in distinguishing moderate TBI patients with lower GCS score of 9-11 who would suffer IHT. The high discriminative ability of the prediction model supports its use in identifying moderate TBI patients with lower GCS score of 9-11 who need ICP-lowering therapy or invasive ICP monitoring.

The COVID-19 pandemic has posed severe challenges that require collaborative efforts from multi-sector organizations. Guided by an institutional theory framework that considers how both organizational fields and national level contexts affect organizations’ social partnership communication, the current study examines the COVID-19-related social partnership communication network on social media. The cross-national study using semantic network analysis and exponential random graph models (ERGMs) first maps the meaning of COVID-19 social partnership network, and then investigates the role of organizational fields and a country’s political system, economic system, educational system, and cultural system on the formation of interorganizational communication ties surrounding the relief efforts of COVID-19. Results reveal the importance of the political system—such as the presence of populist government, economic disparity, and uncertainty avoidance cultural orientation in shaping the social media-based social partnership communication network. In addition, NGOs from multiple issue areas are actively engaged in the network, whereas corporations from manufacturing and financial industries are active players.

To clarify the technical pearls of cavernous sinus molding technique with hemostatic agent injection during endoscopic endonasal pituitary surgery.All patients pretreated with cavernous sinus hemostatic agent injection molding technique for hemostasis in endoscopic endonasal surgery for pituitary adenoma resection between November 2017 and June 2021 were included. A small incision was made in the cavernous sinus wall before intracavernous manipulation. The hemostatic agent was injected with gentle pressure. It spread along the venous channels and established partial molding of the cavernous sinus. Intraoperative bleeding, surgical field score, and complications were evaluated.Thirty-eight patients with pituitary adenoma requiring cavernous sinus manipulation were pretreated with this technique. Technically, the tailored thin blunt metal tube with its 1 cm head end bended up 45° were the best instrument to accomplish injection. Multi-spot injections were preferred to control different compartments of the cavernous sinus, which both had a better effect in bleeding control and helped to reduce the influence of trigemino-cardiac reflex. Postoperative complications, including temporal lobe edema, hemorrhage, and exophthalmos were not observed.Pretreating cavernous sinus with hemostatic agent injection molding technique during endoscopic endonasal pituitary surgery is a practical, effective and safe method for intracavernous bleeding control.

We consider a parsimonious framework of jump-diffusion models for price dynamics with stochastic price volatilities and stochastic jump intensities in continuous time. They account for conditional heteroscedasticity and also incorporate key features appearing in financial time series of price volatilities and jump intensities, such as persistence of contemporaneous jumps (cojumps), mean reversion and feedback effects. More precisely, the stochastic variance and stochastic intensity are jointly modelled by a generalised bivariate shot-noise process sharing common jump arrivals with any non-negative jump-size distributions. This framework covers many classical and important models in the literature. The main contribution of this paper is that, we develop a very efficient scheme for its exact simulation based on perfect decomposition where neither numerical inversion nor acceptance/rejection scheme is required, which means that it is not only accurate but also the efficiency would not be sensitive to the parameter choice. Extensive numerical implementations and tests are reported to demonstrate the accuracy and effectiveness of this scheme. Our algorithm substantially outperforms the classical discretisation scheme. Moreover, we unbiasedly estimate the prices of discrete-barrier European options to show the applicability and flexibility of our algorithms.

Traditional vaccination relies on subcutaneous injection or intramuscular injection, which requires professional medical personnel and is accompanied by the risk of needle-related diseases and injuries. Therefore, to promote immunization coverage and reduce costs, it is necessary to provide a new method of vaccine administration. Dissolving microneedle (DMN) has been proposed as an alternative to hypodermic needles, providing prospects for self-inoculation and increasing immunogenicity by directly targeting skin dendritic cells. This study reported the successful preparation and characterization of Bletilla striata polysaccharide microneedles (BMNs) and investigated the potential of this natural material-based DMN as a vaccine carrier. The prepared BMNs exhibited more excellent mechanical properties and stability compared with microneedles made of hyaluronic acid and polyvinyl alcohol. BMNs had good cell compatibility, low bacterial skin permeability, slight irritation to the skin, and no infection or inflammation in the body. In addition, as shown by circular dichroism, the molecular structure of the antigen ovalbumin (OVA) loaded in BMN did not change during storage for 21 days. The Franz diffusion cell experiment showed 76.74% of OVA was released to the skin within 3 h. These encouraging findings indicate that the BMNs can be a promising tool for effective vaccine delivery.

Rac1 can affect the migration of neural crest cells by regulating the polymerization of actin and the membrane formation process. But the role of the Rac1 signaling pathway in the pathogenesis of Hirschsprung's disease (HSCR) remains unclear. In order to investigate the mechanism of the abnormal protein phosphorylation of Rac1, Lim-kinase 1 (Limk1) and Cofilin involved in the pathogenesis of HSCR. The protein phosphorylation levels of these proteins were detected by Western blot in 30 samples of HSCR narrow segment, 30 samples of transitional segment tissues, and 14 samples of normal intestinal tissues. Subsequently, in the SH-SY5Y human neuroblastoma cell line, a Rac1, Limk1, and Cofilin inhibitor group, a Rac1 overexpression group (PDGF-BB group), a Rac1 overexpression group + a Limk1 inhibitor group (P-B group), a Rac1 overexpression group + a Cofilin inhibitor group (P-C group) were established. The results showed that the expressions of p-Rac1, p-Limk1, and p-Cofilin in HSCR narrow segment and transitional segment were lower than those in normal intestine (p 0.05). The expression levels of p-Rac1, p-Limk1, and p-Cofilin in the relative inhibitor group were significantly lower than those in the control group (p 0.05), and the proliferation and migration levels in the control group and Rac1 overexpression group were significantly higher than those in the Rac1, Limk1, and Cofilin inhibitor group (p 0.05). In conclusion, the decreased phosphorylation of the Rac1/Limk1/Cofilin signaling pathway in HSCR could inhibit the proliferation and migration of SH-SY5Y cells, and this might be associated with the pathogenesis of HSCR.

Moderate traumatic brain injury (mTBI) is a heterogeneous entity that is poorly defined in the literature. Patients with mTBI have a high rate of neurological deterioration (ND), which is usually accompanied by poor prognosis and no definitive methods to predict. The purpose of this study is to develop and validate a prediction model that estimates the ND risk in patients with mTBI using data collected on admission. Data for 479 patients with mTBI collected retrospectively in our department were analyzed by logistic regression models. Bivariable logistic regression identified variables with a

Our research intended to investigate the roles of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) in acute myocardial infarction (AMI) via delivery of microRNA (miR)-302d-3p. AMI mouse models were established. EVs isolated from MSCs with miR-302d-3p mimic were injected near the infarct area or co-cultured with hypoxic cardiomyocytes to evaluate their effects. The expression of NF-κB pathway-related genes and inflammatory factors was determined. AMI mice exhibited downregulated miR-302d-3p and elevated MD2 and BCL6 levels. BCL6 was negatively targeted by miR-302d-3p and could bind to MD2 promoter to upregulate MD2 expression. MSCs-EVs, MSCs-EVs carrying miR-302d-3p, or BCL6 or MD2 silencing inactivated the NF-κB pathway and alleviated infarcted area, myocardial fibrosis, inflammation, apoptosis, and cardiac dysfunction in AMI mice. Besides, MSCs-EVs, MSCs-EVs carrying miR-302d-3p, or BCL6 or MD2 silencing diminished viability and inflammation but augmented apoptosis of hypoxic cardiomyocytes. Conclusively, MSCs-EVs carrying miR-302d-3p repressed inflammation and cardiac remodeling after AMI via BCL6/MD2/NF-κB axis.

This paper addresses a detailed analysis of the ice–structure interaction process of the phase-locked ice crushing (PLC) against offshore structures. Directly measured ice load, structure response data, and in situ observation from the field measurements on the Molikpaq lighthouse and jacket platform were used in the study. This paper summarizes a new ductile damage-collapse (DDC) failure mechanism for the PLC process. The DDC mechanism shows that the ice failure is a discrete ductile crushing process rather than a ductile–brittle transition process. The analysis identifies that the ice has a failure length in PLC and this failure length plays an important role in understanding the interaction. It reveals that PLC can occur on most vertical-sided offshore structures when the velocity of the ice sheet falls within the range of the failure length divided by the natural period of the structure. This paper proposes that this relationship between ice failure length and the natural period of the structure can be used as one of the PLC occurrence conditions. The DDC failure mechanism provides a basis for another technical route to solve the PLC problem.

Mitochondrial dysfunction and oxidative stress are important mechanisms for secondary injury after traumatic brain injury (TBI), which result in progressive pathophysiological exacerbation. Although the Fibronectin type III domain-containing 5 (FNDC5) was reported to repress oxidative stress by retaining mitochondrial biogenesis and dynamics, while its possible role in the secondary injury after TBI remain obscure. In the present study, we observed thatthe level of plasma irisin (the cleavage product of FNDC5) significantly correlated with the neurological outcomes ofTBI patients. Knockout of FNDC5increased the lesion volume and exacerbated apoptosis and neurological deficitsafter TBI in mice, whileFNDC5 overexpression yielded a neuroprotective effect. Moreover, FNDC5 deficiency disrupted mitochondrial dynamics and function. Activation of Sirtuin 3 (SIRT3) alleviated FNDC5 deficiency-induced disruption of mitochondrial dynamics and bioenergetics. In neuron-specific SIRT3 knockout mice, FNDC5failed to attenuateTBI-induced mitochondrial damage and brain injuries. Mechanically, FNDC5 deficiency led to reduced SIRT3 expression via enhanced ubiquitin degradation of transcription factor Nuclear factor erythroid 2-related factor 2 (NRF2), which contributed to the hyperacetylation and inactivation of key regulatory proteins of mitochondrial dynamics and function, including OPA1 and SOD2. Finally, engineered RVG29-conjugated nanoparticles were generated to selectively and efficiently deliver irisin to the brain of mice, which yielded a satisfactory curative effect against TBI. In conclusion, FNDC5/irisin exerts a protective role against acute brain injury by promoting SIRT3-dependent mitochondrial quality control and thus represents a potential target for neuroprotection after TBI.

Purpose:Glioblastoma (GBM) is one of the most aggressive and lethal cancer types in humans. The standard treatment approach is surgery followed by chemoradiation. However, the molecular mechanisms of innate tumor radioresistance remain poorly understood.Experimental Design:We tested the expression of Smoothened (Smo) in primary and recurrent GBM tissues and cells. Then, we determined radiation effectiveness against primary and recurrent GBM cells. Lastly, the functional role of Smo in GBM radioresistance was further confirmed by in vitro and in vivo experiments.Results:We reported that Smo was significantly upregulated in recurrent GBM cell lines and tumor tissues following radiation treatment. Higher Smo expression indicated poor prognosis of GBM patients after radiation treatment. Smo had radioresistance effects in both GBM cells and human tumor xenografts. The mechanisms underlying these effects involved the attenuation of DNA damage repair caused by IR. Importantly, we found that the effect of Smo on radioresistance was mediated by Claspin polyubiquitination and proteasomal degradation, leading to the regulation of ATR–Chk1 signaling. Moreover, we found that Smo reduced Claspin polyubiquitination and proteasomal degradation by promoting USP3 transcription. Furthermore, we demonstrated that the Smo inhibitor GDC-0449 induced radiosensitivity to GBM.Conclusions:These data suggest that Smo confers radiation resistance in GBM by promoting USP3 transcription, leading to the activation of Claspin-dependent ATR–Chk1 signaling. These findings identify a potential mechanism of GBM resistance to radiation and suggest a potential therapeutic target for radiation resistance in GBM.

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Osteoarthritis (OA) is a disabling disease with significant morbidity worldwide. OA attacks the large synovial joint, including the peripheral joints and temporomandibular joint (TMJ). As a representative of peripheral joint OA, knee OA shares similar symptoms with TMJ OA. However, these two joints also display differences based on their distinct development, anatomy, and physiology. Extracellular vesicles (EVs) are phospholipid bilayer nanoparticles, including exosomes, microvesicles, and apoptotic bodies. EVs contain proteins, lipids, DNA, micro-RNA, and mRNA that regulate tissue homeostasis and cell-to-cell communication, which play an essential role in the progression and treatment of OA. They are likely to partake in mechanical response, extracellular matrix degradation, and inflammatory regulation during OA. More evidence has shown that synovial fluid and synovium-derived EVs may serve as OA biomarkers. More importantly, mesenchymal stem cell-derived EV shows a therapeutic effect on OA. However, the different function of EVs in these two joints is largely unknown based on their distinct biological characteristic. Here, we reviewed the effects of EVs in OA progression and compared the difference between the knee joint and TMJ, and summarized their potential therapeutic role in the treatment of OA.