Preoperative Frailty Assessment Predicts Postoperative Mortality, Delirium and Pneumonia in Elderly Lung Cancer Patients: A Retrospective Cohort Study.

BACKGROUND: The purpose of this study was to investigate the predictive value of the 5-factor modified frailty index (mFI-5) for postoperative mortality, delirium and pneumonia in patients over 65 years of age undergoing elective lung cancer surgery. METHODS: Data were collected from a single-center retrospective cohort study conducted in a general tertiary hospital from January 2017 to August 2019. In total, the study included 1372 elderly patients aged over 65 who underwent elective lung cancer surgery. They were divided into frail group (mFI-5, 2-5), prefrail group (mFI-5, 1) and robust group (mFI-5, 0) on the basis of mFI-5 classification. The primary outcome was postoperative 1-year all-cause mortality. Secondary outcomes were postoperative pneumonia and postoperative delirium. RESULTS: Frailty group had the highest incidence of postoperative delirium (frailty 31.2% versus prefrailty 1.6% versus robust 1.5%, p < 0.001), postoperative pneumonia (frailty 23.5% versus prefrailty 7.2% versus robust 7.7%, p < 0.001), and postoperative 1-year mortality (frailty 7.0% versus prefrailty 2.2% versus robust 1.9%. p < 0.001). Frail patients have significantly longer length of hospitalization than those in the robust group and prefrail patients (p < 0.001). Multivariate analysis showed a clear link between frailty and increased risk of postoperative delirium (aOR 2.775, 95% CI 1.776-5.417, p < 0.001), postoperative pneumonia (aOR 3.291, 95% CI 2.169-4.993, p < 0.001) and postoperative 1-year mortality (aOR 3.364, 95% CI, 1.516-7.464, p = 0.003). CONCLUSIONS: mFI-5 has potential clinical utility in predicting postoperative death, delirium and pneumonia incidence in elderly patients undergoing radical lung cancer surgery. Frailty screening of patients (mFI-5) may provide benefits in risk stratification, targeted intervention efforts, and assist physicians in clinical decision-making.

Global research trends in CRISPR-related technologies associated with extracellular vesicles from 2015 to 2022: a bibliometric, dynamic, and visualized study.

PURPOSE: This study aims to explore the emerging trends, dynamic development, and research hotspots of clustered regularly interspaced short palindromic repeats (CRISPR) technology associated with extracellular vesicles during the past 7 years and demonstrate them by visualization. METHODS: A total of 219 records related to CRISPR technology associated with extracellular vesicles from 2015 to 2022 in the Web of Science Core Collection (WoSCC) database were collected. R language, VOSviewer, CiteSpace, and GraphpadPrism software packages were used to analyze the history of this research, the general characteristics of the literature, and keywords. Finally, the hotspots and latest trends in CRISPR technology associated with extracellular vesicles are predicted. RESULTS: A total of 219 articles were collected for this study. The production of publications about CRISPR technology associated with extracellular vesicles has increased annually. Researchers from China, the USA, and Germany made the most important contributions to this trend, while RLUK Research Libraries UK offers the largest amount of literature in this field. Shenzhen University, Nanjing Medicine University, and Peking University exhibited the closest cooperation. Additionally, active topics burst during different periods, as identified according to 317 keywords belonging to 39 disciplines. Keywords were clustered into seven research subareas, namely exosome, nanovesicles, DNA, gene editing, gene therapy, cancer therapy, and endometrial stromal cells. The alluvial map of keywords reveals that the most enduring concepts are gene therapy, nanovesicles, etc., while the emerging keywords are genome, protein delivery, plasma, etc. CONCLUSIONS: We reviewed 219 previous publications and conducted the first bibliometric study of CRISPR technology related to extracellular vesicles from 2015 to 2022. This comprehensive summary constructed a knowledge map and demonstrates the trends in this area. The current trends and potential hotpots for this topic are also identified, which will be a great help for researchers in the future.

Dvl2 facilitates the coordination of NF-κB and Wnt signaling to promote colitis-associated colorectal progression.

Colitis-associated colorectal cancer (CAC) arises due to prolonged inflammation and has distinct molecular events compared with sporadic colorectal cancer (CRC). Although inflammatory NF-κB signaling was activated by pro-inflammatory cytokines (such as TNFα) in early stages of CAC, Wnt/ß-catenin signaling later appears to function as a key regulator of CAC progression. However, the exact mechanism responsible for the cross-regulation between these 2 pathways remains unclear. Here, we found reciprocal inhibition between NF-κB and Wnt/ß-catenin signaling in CAC samples, and the Dvl2, an adaptor protein of Wnt/ß-catenin signaling, is responsible for NF-κB inhibition. Mechanistically, Dvl2 interacts with the C-terminus of tumor necrosis factor receptor 1 (TNFRI) and mediates TNFRI endocytosis, leading to NF-κB signal inhibition. In addition, increased infiltration of the pro-inflammatory cytokine interleukin-13 (IL-13) is responsible for upregulating Dvl2 expression through STAT6. Targeting STAT6 effectively decreases Dvl2 levels and restrains colony formation of cancer cells. These findings demonstrate a unique role for Dvl2 in TNFRI endocytosis, which facilitates the coordination of NF-κB and Wnt to promote CAC progression.

Drebrin promotes lung adenocarcinoma cell migration through inducing integrin ß1 endocytosis.

Lung adenocarcinoma (LUAD) is the most common type of lung cancers, which remains the leading cause of cancer-related death worldwide. Drebrin can promote cell migration and invasion with poor prognosis, but its roes in LUAD tumor progression remains unknown. We showed that the expression of Drebrin was upregulated in clinical LUAD samples. A Kaplan-Meier survival analysis showed that a high expression of Drebrin predicated poor prognosis in LUAD. In vitro, Drebrin promoted anchorage-independent growth and migration of LUAD cells. Drebrin interacted with dynamin through CT domain, and served as an adaptor to promote LUAD cell migration through inducing integrin ß1 endocytosis. Thus, this study demonstrated the critical role of Drebrin in LUAD and associated mechanism.

Multivalence Charge Transfer in Doped and Codoped Photocatalytic TiO2.

The present work reports data for the mineralogical and chemical properties of anatase thin films individually doped or codoped with chromium and vanadium, fabricated by sol-gel spin coating on glass substrates and annealing at 450 °C for 2 h. X-ray photoelectron spectroscopy data indicated the presence of Ti(4+), Ti(3+), Cr(3+), and possibly Cr(4+) in the Cr-doped thin films; Ti(4+), Ti(3+), V(3+), V(4+), and possibly V(5+) in the V-doped thin films; and Ti(4+), Ti(3+), Cr(3+), Cr(4+), V(3+), V(4+), and possibly V(5+) in the codoped thin films. While the thermodynamically stable valences Ti(4+), Cr(3+), and V(5+) would be expected to have formed, the presence of the nonequilibrium valences Ti(3+), Cr(4+), V(3+), and V(4+) is considered to have resulted from intervalence charge transfer for the Cr-doped and V-doped systems but from multivalence charge transfer (MVCT) for the codoped system. The latter phenomenon, which is introduced as a new conceptual term, describes the nature of the mutual exchange of electrons during valence changes of both dopant (Cr, V) and matrix (Ti) ions during annealing. In the present case, MVCT appears to be a transient metastable condition that acts during annealing, but subsequent UV irradiation can alter its effects.

Optimizing energy efficiency in induction skull melting process: investigating the crucial impact of melting system structure.

Induction skull melting (ISM) technology could melt metals with avoiding contamination from crucible. A long-standing problem of ISM is that the low charge energy utilization and inhomogeneous fields have obstructed its application in many critical metal materials and manufacturing processes. The present work investigated the problem through the structure optimization strategy and established a numerical electromagnetic-field model to evaluate components' eddy current loss. Based on the model, the effect of crucible and inductor structure on charge energy utilization, etc. was studied. Furtherly, the charge energy utilization was increased from 27.1 to 45.89% by adjusting the system structure. Moreover, structure modifications are proposed for enhancing electromagnetic intensity and uniformity, charge soft contact and uniform heating. The work constructed a basis for framing new solutions to the problem through ISM device structure optimization.

Sevoflurane exerts antidepressant-like effects via the BDNF-TrkB pathway.

Depression has emerged as the predominant psychiatric affliction affecting individuals. Prior research has substantiated the antidepressant properties exhibited by numerous anesthetics. Sevoflurane, a widely utilized inhalant anesthetic in clinical practice, remains relatively uncharted in terms of its specific antidepressant effects. In this study, we used open field test, forced swimming test and novelty-suppressed feeding test to investigate the anxiety and depression-like behaviors in C57BL/6 mice following the inhalation of sevoflurane. We then used western blotting to scrutinized the expression levels of proteins associated with the brain-derived neurotrophic factor (BDNF)-tryosine receptor kinase B (TrkB) pathway in the hippocampus and prefrontal cortex. To further investigate whether sevoflurane exerts antidepressant-like effects via the BDNF-TrkB pathway, we downregulated TrkB expression by administering siRNA into the lateral ventricle. We found that the inhalation of 2.5 % sevoflurane exerted a significant antidepressant-like effect, accompanied by an elevation in p-TrkB expression levels in the hippocampus and prefrontal cortex. Intriguingly, this antidepressant-like effect was abrogated following the downregulation of TrkB expression through the microinjection of siRNA into the lateral ventricle. In conclusion, this study provides evidence supporting the notion that sevoflurane exerts its antidepressant-like effect via the BDNF-TrkB signaling pathway.

Prelimbic cortical pyramidal neurons to ventral tegmental area projections promotes arousal from sevoflurane anesthesia.

AIMS: General anesthesia has been used in surgical procedures for approximately 180 years, yet the precise mechanism of anesthetic drugs remains elusive. There is significant anatomical connectivity between the ventral tegmental area (VTA) and the prelimbic cortex (PrL). Projections from VTA dopaminergic neurons (VTADA ) to the PrL play a role in the transition from sevoflurane anesthesia to arousal. It is still uncertain whether the prelimbic cortex pyramidal neuron (PrLPyr ) and its projections to VTA (PrLPyr -VTA) are involved in anesthesia-arousal regulation. METHODS: We employed chemogenetics and optogenetics to selectively manipulate neuronal activity in the PrLPyr -VTA pathway. Electroencephalography spectra and burst-suppression ratios (BSR) were used to assess the depth of anesthesia. Furthermore, the loss or recovery of the righting reflex was monitored to indicate the induction or emergence time of general anesthesia. To elucidate the receptor mechanisms in the PrLPyr -VTA projection's impact on anesthesia and arousal, we microinjected NMDA receptor antagonists (MK-801) or AMPA receptor antagonists (NBQX) into the VTA. RESULTS: Our findings show that chemogenetic or optogenetic activation of PrLPyr neurons prolonged anesthesia induction and promoted emergence. Additionally, chemogenetic activation of the PrLPyr -VTA neural pathway delayed anesthesia induction and promoted anesthesia emergence. Likewise, optogenetic activation of the PrLPyr -VTA projections extended the induction time and facilitated emergence from sevoflurane anesthesia. Moreover, antagonizing NMDA receptors in the VTA attenuates the delayed anesthesia induction and promotes emergence caused by activating the PrLPyr -VTA projections. CONCLUSION: This study demonstrates that PrLPyr neurons and their projections to the VTA are involved in facilitating emergence from sevoflurane anesthesia, with the PrLPyr -VTA pathway exerting its effects through the activation of NMDA receptors within the VTA.

Bibliometric study and visualization of cellular senescence associated with osteoarthritis from 2009 to 2023.

BACKGROUND: Osteoarthritis is a common degenerative joint disease that is highly prevalent in the elderly population. Along with the occurrence of sports injuries, osteoarthritis is gradually showing a younger trend. Osteoarthritis has many causative factors, and its pathogenesis is currently unknown. Cellular senescence is a stable form of cell cycle arrest exhibited by cells in response to external stimuli and plays a role in a variety of diseases. And it is only in the last decade or so that cellular senescence has gradually become cross-linked with osteoarthritis. However, there is no comprehensive bibliometric analysis in this field. The aim of this study is to present the current status and research hotspots of cellular senescence in the field of osteoarthritis, and to predict the future trends of cellular senescence in osteoarthritis research from a bibliometric perspective. METHODS: This study included 298 records of cellular senescence associated with osteoarthritis from 2009 to 2023, with data from the Web of Science Core Collection database. CiteSpace, Scimago Graphica software, VOSviewer, and the R package "bibliometrix" software were used to analyze regions, institutions, journals, authors, and keywords to predict recent trends in cellular senescence related to osteoarthritis research. RESULTS: The number of publications related to cellular senescence associated with osteoarthritis is increasing year by year. China and the United States contribute more than 70% of the publications and are the mainstay of research in this field. Central South University is the most active institution with the largest number of publications. International Journal of Molecular Sciences is the most popular journal in the field with the largest number of publications, while Osteoarthritis and Cartilage is the most cited journal. Loeser, Richard F. is not only the most prolific author, but also the most frequently cited author, contributing greatly to the field. CONCLUSION: In the last decade or so, this is the first bibliometric study that systematically describes the current status and development trend of research on cellular senescence associated with osteoarthritis. The study comprehensively and systematically summarizes and concludes the research hotspots and development trends, providing valuable references for researchers in this field.

GABAergic neurons in the nucleus accumbens core mediate the antidepressant effects of sevoflurane.

General anaesthetics have been widely applied to induce reversible loss and recovery of consciousness in clinical practice and have been shown to have reliably safe profiles. Since brief exposure to general anaesthetics can result in long-lasting and global changes in neuronal structures and function, these drugs also exhibit strong therapeutic potential for mood disorders. Preliminary and clinical studies have suggested that the inhalational anaesthetic drug sevoflurane might relieve symptoms of depression. However, the antidepressant effects of sevoflurane and the underlying mechanisms remain elusive. In the present study, we confirmed that the antidepressant and anxiolytic effects of inhaling 2.5% sevoflurane for 30 min were comparable to those of ketamine and could be sustained for 48 h. Activation of GABAergic (γ-aminobutyric acidergic) neurons in the nucleus accumbens core by chemogenetics was shown to mimic the antidepressant effects of inhaled sevoflurane, whereas inhibition of these neurons significantly prevented these effects. Considered together, these results suggested that sevoflurane might exert rapid and long-lasting antidepressant effects via modulation of neuronal activities in the nucleus accumbens core nucleus.

Activation of the ERK1/2 pathway mediates the neuroprotective effect provided by calycosin treatment.

Calycosin is a natural product extracted from some plant families and exhibits various biological properties. But the effect of calycosin on cerebral ischemia-reperfusion injury has not been fully elucidated. In this study, the neuroprotective effect of calycosin treatment on the differentiated SH-SY5Y cells exposed to OGD was evaluated using MTT and flow cytometry. Rats that were pretreatment with calycosin were subjected to MCAO, neurological behavior scores and brain infarct volume were evaluated. The protein expression of pERK/ERK were assessed using Western blot. siRNA-pERK and U0126 were administered to investigate the impact of the ERK pathway on calycosin preconditioning. The results demonstrated the neuronal viability in the calycosin-treated SH-SY5Y cells increased significantly, and the rate of apoptosis decreased compared with the Oxygen-glucose deprivation only SH-SY5Y cells. Calycosin pretreatment reduced infarct volume and improved neurological outcome in rats subjected to MCAO. Administration of calycosin increased the ratio of pERK/ERK expression, which was down-regulated in ischemia-reperfusion group. Down-regulation of pERK/ERK significantly attenuated the neuroprotective effect induced by calycosin pretreatment in vitro and in vivo. We concluded calycosin treatment could induce a neuroprotective effect against ischemia, which was related to the regulation of the ERK1/2 pathway.

Ventrolateral periaqueductal gray GABAergic neurons promote arousal of sevoflurane anesthesia through cortico-midbrain circuit.

The mechanism of general anesthesia remains elusive. The ventrolateral periaqueductal gray (vlPAG) in the midbrain regulates sleep and awake states. However, the role of vlPAG and its circuits in anesthesia is unclear. We utilized opto/chemogenetics, righting reflex, and electroencephalographic recording to assess consciousness changes. We employed fiber photometry to measure the activity of neurons and neurotransmitters. As a result, photometry recording showed that the activity of GABA neurons in vlPAG decreased during sevoflurane anesthesia and was reactivated after anesthesia. Activating GABAergic neurons in vlPAG promoted arousal during anesthesia, while inhibiting them delayed this process. Furthermore, medial prefrontal cortex (mPFC) to vlPAG pyramidal neurons projections and vlPAG to ventral tegmental area (VTA) GABAergic projections played a prominent role in the anesthesia-awake transition. GABA neurotransmitter activity of VTA synchronized with mPFC-vlPAG pyramidal neuron projections. Therefore, the cortico-midbrain circuits centered on vlPAG GABAergic neurons exert an arousal-promoting effect during sevoflurane anesthesia.

Mental health changes in elderly patients undergoing non-cardiac surgery during the COVID-19 pandemic in China.

BACKGROUND: The COVID-19 pandemic has a heavy impact on the mental health of elderly surgical patients worldwide. In particular, the elderly patients faced considerable psychological stress due to various environmental and medical factors during the outbreak. This study aims to examine changes in mental health trends among non-cardiac surgical patients aged 65 and above in China during the COVID-19 pandemic. METHODS: This multi-center, convenient sampling, longitudinal observational study was conducted from April 1, 2020 to April 30, 2022. Primary outcome was the prevalence of postoperative depression. Secondary outcome was the prevalence of postoperative anxiety. Follow-up was conducted separately at 7 days and 30 days after surgery. Depression symptoms were assessed using the Patient Health Questionnaire 9 (PHQ-9) scale. Anxiety symptoms were assessed using Generalized Anxiety Disorder-7 (GAD-7) scale, with scores of ≥5 defining positive depression or anxiety symptoms. Multivariate logistic regression analysis was used to investigate risk factors of mental health status in more elderly patients undergoing non-cardiac surgery. RESULTS: A total of 4639 patients were included, of whom 2279 (46.0 %) were male, 752 (15.2 %) were over the age of 75, and 4346 (93.7 %) were married. The monthly prevalence trends demonstrated that compared to the outbreak period, a significant reduction in the prevalence of depression and anxiety symptoms in elderly patients who underwent surgery during the post-pandemic period. In post-pandemic period, a statistically significant decrease in the prevalence of all severity depression and anxiety patients was noted at the 7-day follow-up, but no significant decrease was observed for severe depression and anxiety in the 30-day follow-up. In COVID-19 low-risk area, a significant overall decrease in prevalence of mental health was observed during the post-pandemic period compared to the outbreak period, including 7-day depression, 7-day anxiety, 30-day depression, and 30-day anxiety (all with P < 0.001). Female and patients with ≥2 comorbidities appeared to be more susceptible to postoperative depression and anxiety during the pandemic. LIMITATION: The absence of data from the early days of the COVID-19 outbreak. CONCLUSIONS: This study analyzed the prevalence of depression and anxiety in elderly non-cardiac patients during and after the COVID-19 pandemic, focusing on dimensions such as severity, risk-areas, gender, and comorbidity. Our findings revealed a significant decrease in the prevalence of depression and anxiety in elderly surgery patients during the post-pandemic period.

Intermediate-Temperature Tensile Behavior of a Hot-Rolled Mg-Li-Al-Cd-Zn Alloy.

Developing light structure materials that work stably at elevated temperatures is a long-standing challenge for many application fields, particularly in the development of aerospace equipment. Zn/Cd alloying elements were prospected to improve the stability of the lightest Mg-Li based alloys; however, little is known about the intermediate-temperature mechanical properties of such alloys. The present work investigated the tensile behaviors of a cold-rolled Mg-Li-Al-Cd-Zn alloy in a temperature range of 30-150 °C. The results indicate that the alloy can host a tensile strength σUTS of 108~121 MPa, a yield strength σYP of 97~109 MPa and elongation εB of 14-15 % at 150 °C, dependent on the tensile direction. The mechanical properties intensively are modulated by temperature through the competition between work hardening and softening. Work hardening due to dislocation blocking by the precipitated MgLi2X phase dominated the deformation at low temperatures, while softening that resulted from dynamic recrystallization was the main effect at high temperatures. Correspondingly, a quasi-cleavage mechanism dominated the fracture at temperatures near room temperature, and microvoid coalescence worked at high temperatures above 100 °C. Our results offer a new experimental understanding of the elevated-temperature mechanical behaviors of Mg-Li alloys and will advance the development of new light magnesium alloys with high stability.

Decellularized Human Umbilical Cord Wharton Jelly Scaffold Improves Tendon Regeneration in a Rabbit Rotator Cuff Tendon Defect Model.

BACKGROUND: Owing to limited self-healing capacity, failure of rotator cuff tendon healing is a common complication after surgery. Biological scaffolds have garnered attention owing to their potential to enhance healing outcomes. PURPOSE: To verify the effect of the decellularized umbilical cord Wharton jelly (DUCWJ) scaffold as a bridging scaffold in a rabbit model of acute rotator cuff tendon defect. STUDY DESIGN: Controlled laboratory study. METHODS: We fabricated a DUCWJ scaffold using a physicochemical decellularized method, evaluating changes in the umbilical cord Wharton jelly before and after decellularization. Scanning electron microscopy and biomechanical testing were performed to determine the microstructure and mechanical properties. We assessed cytocompatibility and cell regulatory behavior of the scaffold toward tendon stem/progenitor cells (TSPCs). A supraspinatus tendon defect was created in 54 New Zealand White rabbits, allocated to the DUCWJ scaffold repair group and the negative control group (without scaffold). Histology, reverse transcription polymerase chain reaction, and biomechanical tensile strength were assessed at 4, 8, and 12 weeks postoperatively. RESULTS: Decellularization completely removed cells from the umbilical cord Wharton jelly, retained a considerable amount of glycosaminoglycan and collagen, and preserved the microstructure and tensile strength. The DUCWJ scaffold facilitated migration and proliferation of TSPCs in vitro. Tendon-related gene expression revealed that the DUCWJ scaffold could maintain the tenocyte phenotype of TSPCs. In the in vivo study, the DUCWJ scaffold improved tendon healing and enhanced the biomechanical strength of repaired tendons. Histological evaluation scores of the DUCWJ group were significantly higher than those of the negative control at 4, 8, and 12 weeks after surgery (P < .05). In repaired tendon tissues, reverse transcription polymerase chain reaction findings revealed that the DUCWJ scaffold stimulated tendon development and maturation. Furthermore, an overall increase in ultimate load and tensile modulus was noted over time; the DUCWJ group presented better results than the negative control group (P < .05). CONCLUSION: The DUCWJ scaffold has an excellent 3-dimensional porous structure, good biocompatibility, and fundamental biomechanical characteristics, and it promotes migration, attachment, and proliferation of TSPCs. The in vivo animal study demonstrated that the DUCWJ scaffold has potential for tendon regeneration in an acute rotator cuff tendon defect model. CLINICAL RELEVANCE: DUCWJ scaffolds have potential as a regenerative material to augment rotator cuff healing in the clinical setting.

Inhibition of HIF-1α-AQP4 axis ameliorates brain edema and neurological functional deficits in a rat controlled cortical injury (CCI) model.

Traumatic brain injury (TBI) is an important cause of death in young adults and children. Till now, the treatment of TBI in the short- and long-term complications is still a challenge. Our previous evidence implied aquaporin 4 (AQP4) and hypoxia inducible factor-1α (HIF-1α) might be potential targets for TBI. In this study, we explored the roles of AQP4 and HIF-1α on brain edema formation, neuronal damage and neurological functional deficits after TBI using the controlled cortical injury (CCI) model. The adult male Sprague Dawley rats were randomly divided into sham and TBI group, the latter group was further divided into neutralized-AQP4 antibody group, 2-methoxyestradiol (2-ME2) group, and their corresponding control, IgG and isotonic saline groups, respectively. Brain edema was examined by water content. Hippocampal neuronal injury was assessed by neuron loss and neuronal skeleton related protein expressions. Spatial learning and memory deficits were evaluated by Morris water maze test and memory-related proteins were detected by western blot. Our data showed that increased AQP4 protein level was closely correlated with severity of brain edema after TBI. Compared with that in the control group, both blockage of AQP4 with neutralized-AQP4 antibody and inhibition of HIF-1α with 2-ME2 for one-time treatment within 30-60 min post TBI significantly ameliorated brain edema on the 1st day post-TBI, and markedly alleviated hippocampal neuron loss and spatial learning and memory deficits on the 21st day post-TBI. In summary, our preliminary study revealed the short-term and long-term benefits of targeting HIF-1α-AQP4 axis after TBI, which may provide new clues for the selection of potential therapeutic targets for TBI in clinical practice.

Integrated bioactive scaffold with aptamer-targeted stem cell recruitment and growth factor-induced pro-differentiation effects for anisotropic meniscal regeneration.

Reconstruction of the knee meniscus remains a significant clinical challenge owing to its complex anisotropic tissue organization, complex functions, and limited healing capacity in the inner region. The development of in situ tissue-engineered meniscal scaffolds, which provide biochemical signaling to direct endogenous stem/progenitor cell (ESPC) behavior, has the potential to revolutionize meniscal tissue engineering. In this study, a fiber-reinforced porous scaffold was developed based on aptamer Apt19S-mediated mesenchymal stem cell (MSC)-specific recruitment and dual growth factor (GF)-enhanced meniscal differentiation. The aptamer, which can specifically recognize and recruit MSCs, was first chemically conjugated to the decellularized meniscus extracellular matrix (MECM) and then mixed with gelatin methacrylate (GelMA) to form a photocrosslinkable hydrogel. Second, connective tissue growth factor (CTGF)-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) and transforming growth factor-ß3 (TGF-ß3)-loaded PLGA microparticles (MPs) were mixed with aptamer-conjugated MECM to simulate anisotropic meniscal regeneration. These three bioactive molecules were delivered sequentially. Apt19S, which exhibited high binding affinity to synovium-derived MSCs (SMSCs), was quickly released to facilitate the mobilization of ESPCs. CTGF incorporated within PLGA NPs was released rapidly, inducing profibrogenic differentiation, while sustained release of TGF-ß3 in PLGA MPs remodeled the fibrous matrix into fibrocartilaginous matrix. The in vitro results showed that the sequential release of Apt19S/GFs promoted cell migration, proliferation, and fibrocartilaginous differentiation. The in vivo results demonstrated that the sequential release system of Apt/GF-scaffolds increased neomeniscal formation in rabbit critical-sized meniscectomies. Thus, the novel delivery system shows potential for guiding meniscal regeneration in situ.

Dopaminergic Neurons in the Ventral Tegmental-Prelimbic Pathway Promote the Emergence of Rats from Sevoflurane Anesthesia.

Dopaminergic neurons in the ventral tegmental area (VTA) play an important role in cognition, emergence from anesthesia, reward, and aversion, and their projection to the cortex is a crucial part of the "bottom-up" ascending activating system. The prelimbic cortex (PrL) is one of the important projection regions of the VTA. However, the roles of dopaminergic neurons in the VTA and the VTADA-PrL pathway under sevoflurane anesthesia in rats remain unclear. In this study, we found that intraperitoneal injection and local microinjection of a dopamine D1 receptor agonist (Chloro-APB) into the PrL had an emergence-promoting effect on sevoflurane anesthesia in rats, while injection of a dopamine D1 receptor antagonist (SCH23390) deepened anesthesia. The results of chemogenetics combined with microinjection and optogenetics showed that activating the VTADA-PrL pathway prolonged the induction time and shortened the emergence time of anesthesia. These results demonstrate that the dopaminergic system in the VTA has an emergence-promoting effect and that the bottom-up VTADA-PrL pathway facilitates emergence from sevoflurane anesthesia.

Identification of the OA-related metabolism-related genes, corresponding transcription factors, relevant pathways, and specific bioactive small molecules.

Metabolic alteration of articular cartilage is associated with the pathogenesis of Osteoarthritis (OA). This study aims to identify the metabolism-related genes, corresponding transcription factors (TFs), and relevant pathways. Overall, RNA sequencing profiles of articular cartilage were collected from the GEO database. Metabolism-related genes and OA-related hallmarks were collected from the MSigDB v7.1. Differential expression analysis, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and Gene Set Variation Analysis (GSVA) were conducted to identify pathways or hallmarks that were related to the pathogenesis of OA. The Pearson correlation analysis was used to establish the regulatory network among transcription factors, metabolism-related genes, and hallmarks. To further confirm the regulation of the identified transcription factors, Chromatin Immunoprecipitation-sequencing (ChIP-seq) was conducted, and single-cell sequencing was used to locate the cell clusters. Connectivity Map (CM) analysis were also conducted to identify the potential specific bioactive small molecules targeting the metabolic alteration of osteoarthritis. scTPA database was used to detect activated signaling pathways. Collectively, a total of 74 and 38 differentially expressed metabolism-related genes and TFs were retrieved. Skeletal system development, extracellular matrix, and cell adhesion molecule binding were important pathways in GO analysis. Human papillomavirus infection, PI3K-Akt signaling pathway, and Human T-cell leukemia virus 1 infection were the top 3 pathways in KEGG. 7 and 12 hallmarks were down- and up-regulated in GSVA, respectively. Ten bioactive small molecules may be potential treatments of OA by regulating the metabolism of articular cartilage. ChIP-seq analysis showed high relativity between transcription factors and their target genes. Furthermore, single-cell sequencing confirms the high expression of identified transcription factors in chondrocytes. To conclude, we established a comprehensive network integrated with transcription factors, metabolism-related genes, and hallmarks.