Abnormalities of structural covariance of insular subregions in drug-naïve OCD patients.

The insula plays a significant role in the neural mechanisms of obsessive-compulsive disorder. Previous studies have identified functional and structural abnormalities in insula in obsessive-compulsive disorder patients. The predictive coding model in the context of interoception can explain the psychological and neuropathological manifestations observed in obsessive-compulsive disorder. The model is based on the degree of laminar differentiation of cerebral cortex. The interindividual differences in a local measure of brain structure often covary with interindividual differences in other brain regions. We investigated the anatomical network involving the insula in a drug-naïve obsessive-compulsive disorder sample. We recruited 58 obsessive-compulsive disorder patients and 84 matched health controls. The cortical thickness covariance maps between groups were compared at each vertex. We also evaluated the modulation of Yale-Brown Obsessive-Compulsive Scale scores and obsessive-compulsive disorder duration on thickness covariance. Our findings indicated that the thickness covariance seeded from granular and dysgranular insula are different compared with controls. The duration and severity of obsessive-compulsive disorder can modulate the thickness covariance of granular and dysgranular insula with posterior cingulate cortex and rostral anterior cingulate cortex. Our results revealed aberrant insular structural characteristics and cortical thickness covariance in obsessive-compulsive disorder patients, contributing to a better understanding of the involvement of insula in the pathological mechanisms underlying obsessive-compulsive disorder.

Integrating single-cell and multi-omic approaches reveals Euphorbiae Humifusae Herba-dependent mitochondrial dysfunction in non-small-cell lung cancer.

Euphorbiae Humifusae Herba (EHH) is a pivotal therapeutic agent with diverse pharmacological effects. However, a substantial gap exists in understanding its pharmacological properties and anti-tumour mechanisms. This study aimed to address this gap by exploring EHH's pharmacological properties, identifying NSCLC therapy-associated protein targets, and elucidating how EHH induces mitochondrial disruption in NSCLC cells, offering insights into novel NSCLC treatment strategies. String database was utilized to explore protein-protein interactions. Subsequently, single-cell analysis and multi-omics further unveiled the impact of EHH-targeted genes on the immune microenvironment of NSCLC, as well as their influence on immunotherapeutic responses. Finally, both in vivo and in vitro experiments elucidated the anti-tumour mechanisms of EHH, specifically through the assessment of mitochondrial ROS levels and alterations in mitochondrial membrane potential. EHH exerts its influence through engagement with a cluster of 10 genes, including the apoptotic gene CASP3. This regulatory impact on the immune milieu within NSCLC holds promise as an indicator for predicting responses to immunotherapy. Besides, EHH demonstrated the capability to induce mitochondrial ROS generation and perturbations in mitochondrial membrane potential in NSCLC cells, ultimately leading to mitochondrial dysfunction and consequent apoptosis of tumour cells. EHH induces mitochondrial disruption in NSCLC cells, leading to cell apoptosis to inhibit the progress of NSCLC.

Bulk-like Pt(100)-oriented Ultrathin Surface: Combining the Merits of Single Crystals and Nanoparticles to Boost Oxygen Reduction Reaction.

Single crystal surfaces with highly coordinated sites very often hold high specific activities toward oxygen reduction reaction (ORR) and others. Transposing their high specific activity to practical high-surface-area electrocatalysts remains challenging. Here, ultrathin Pt(100) alloy surface is constructed via epitaxial growth. The surface shows 3.1-6.9 % compressive strain and bulk-like characteristics as demonstrated by site-probe reactions and different spectroscopies. Its ORR activity exceeds that of bulk Pt3 Ni(100) and Pt(111) and presents a 19-fold increase in specific activity and a 13-fold increase in mass activity relative to commercial Pt/C. Moreover, the electrochemically active surface area (ECSA) is increased by 4-fold compared to traditional thin films (e.g. NSTF), which makes the catalyst more tolerant to voltage loss at high current densities under fuel cell operation. This work broadens the family of extended surface catalysts and highlights the knowledge-driven approach in the development of advanced electrocatalysts.

Construction of circRNA-miRNA-mRNA network and identification of novel potential biomarkers for non-small cell lung cancer.

BACKGROUND: The underlying circular RNAs (circRNAs)-related competitive endogenous RNA (ceRNA) mechanisms of pathogenesis and prognosis in non-small cell lung cancer (NSCLC) remain unclear. METHODS: Differentially expressed circRNAs (DECs) in two Gene Expression Omnibus datasets (GSE101684 and GSE112214) were identified by utilizing R package (Limma). Circinteractome and StarBase databases were used to predict circRNA associated-miRNAs and mRNAs, respectively. Then, protein-protein interaction (PPI) network of hub genes and ceRNA network were constructed by STRING and Cytoscape. Also, analyses of functional enrichment, genomic mutation and diagnostic ROC were performed. TIMER database was used to analyze the association between immune infiltration and target genes. Kaplan-Meier analysis, cox regression and the nomogram prediction model were used to evaluate the prognostic value of target genes. Finally, the expression of potential circRNAs and target genes was validated in cell lines and tissues by quantitative real-time PCR (qRT-PCR) and Human Protein Atlas (HPA) database. RESULTS: In this study, 15 DECs were identified between NSCLC tissues and adjacent-normal tissues in two GEO datasets. Following the qRT-PCR corroboration, 7 DECs (hsa_circ_0002017, hsa_circ_0069244, hsa_circ_026337, hsa_circ_0002346, hsa_circ_0007386, hsa_circ_0008234, hsa_circ_0006857) were dramatically downregulated in A549 and SK-MES-1 compared with HFL-1 cells. Then, 12 circRNA-sponged miRNAs were screened by Circinteractome and StarBase, especially, hsa-miR-767-3p and hsa-miR-767-5p were significantly up-regulated and relevant to the prognosis. Utilizing the miRDB and Cytoscape, 12 miRNA-target genes were found. Functional enrichment, genomic mutation and diagnostic analyses were also performed. Among them, FNBP1, AKT3, HERC1, COL4A1, TOLLIP, ARRB1, FZD4 and PIK3R1 were related to the immune infiltration via TIMER database. The expression of ARRB1, FNBP1, FZD4, and HERC1 was correlated with poor overall survival (OS) in NSCLC patients by cox regression and nomogram. Furthermore, the hub-mRNAs were validated in cell lines and tissues. CONCLUSION: We constructed the circRNA-miRNA-mRNA network that might provide novel insights into the pathogenesis of NSCLC and reveal promising immune infiltration and prognostic biomarkers.

Comparative molecular profiling of distant metastatic and non-distant metastatic lung adenocarcinoma.

Most lung cancer deaths are caused by a distant disseminated disease rather than primary tumors. Understanding the biology behind distant metastasis (DM) is crucial for the effective prediction and reduction of recurrence rates. Genome-wide analysis of the tumor provides a new way to explore the pathogenesis and molecular diagnosis of metastasis in lung adenocarcinoma. In our study, a total of 215 eligible lung adenocarcinoma patients were enrolled. The DNA was extracted from formalin-fixed paraffin-embedded (FFPE) samples from the primary tumors of these patients. Comprehensive molecular profiling was performed using a panel covering the exome of lung cancer-associated driver genes based on targeted next-generation sequencing. Tumor gene alterations were analyzed to investigate the differences in molecular features between lung adenocarcinomas with or without DM. Patients with DM of lung adenocarcinoma had significantly more variations in overall copy number (defined as Copy Number Alteration (CNA) load and Copy Number Instability (CNI) score). Interestingly, the study of the relationship between copy number variation and other molecular features verified that the degree of copy number variation has a positive correlation with mutations of DNA damage repair pathway (DDR). Thus, the additional analysis further revealed that metastatic patients accumulated more mutations in the DDR pathway, suggesting that impaired function of the DDR pathway and copy number variations play important roles in the invasion process of cancer cells. A comprehensive genetic analysis of lung adenocarcinoma revealed significant genomic changes between DM and non-DM patients. This finding may shed new light on the elucidation of lung cancer invasion mechanisms, and provide potential predictors for metastatic lung cancer.

Treatment of Advanced Non-small-Cell Lung Cancer with Qi-Nourishing Essence-Replenishing Chinese Herbal Medicine Combined with Chemotherapy.

BACKGROUND: To evaluate the effect of qi-nourishing essence-replenishing Chinese herbal medicine combined with chemotherapy in survival of advanced non-small-cell lung cancer(NSCLC) patients with essence and qi deficiency. METHODS: A prospective multi-centered randomized controlled study was conducted, and 266 advanced NSCLC patients were enrolled. 126 patients in control group received Vinorelbine plus cisplatin(NP) chemotherapy combined with symptom-oriented Chinese herbs medication(without qi-nourishing essence-replenishing herbs);140 patients in experimental group received NP chemotherapy combined with qi-nourishing essence-replenishing Chinese herbal medication(Kangliu Zengxiao Decoction and modified Feiyanning Decoction, during and after chemotherapy respectively). RESULTS: One patient in control and 2 in experimental group were excluded for failure to complete two cycles of chemotherapy. During follow-up, 17 and 7 patients in control and experimental group were excluded respectively(4 and 4 for taking Gefetinib after disease progression, 4 and 2 for receiving other chemotherapeutic regimens, 9 and 1 for lost to follow-up). 239 patients were included in the final analysis (131 in experimental group and 108 in control). Median overall survival in experimental group was significantly longer than control group (14.87vs.12.97 months,P = 0.027). In experimental and control group, 1-year, 3-year, 5-year, 7-year, and 9-year survival rates were 57% vs. 53%, 17% vs. 8%, 10% vs. 2%, 6% vs. 0%, and 6% vs. 0%, respectively. CONCLUSION: Qi-nourishing essence-replenishing Chinese herbal medicine combined with chemotherapy improves survival of advanced NSCLC patients with essence and qi deficiency.

Cerium oxide immobilized reduced graphene oxide hybrids with excellent microwave absorbing performance.

Microwave absorbing materials with high absorption over a broad bandwidth when they have a small thickness are strongly desired due to their widespread applications. Herein, cerium oxide immobilized reduced graphene oxide (CeO2-rGO) hybrids with excellent microwave absorbing performance have been fabricated by a versatile one-step hydrothermal approach. Modern measurement techniques, including X-ray diffraction, Raman spectroscopy, electronic microscopy, X-ray photoelectron spectroscopy and vector network analysis, have been conducted to characterize the chemical composition, microstructure and electromagnetic performance of the as-obtained hybrids. Morphological analysis reveals that the CeO2 nanocrystals are homogeneously immobilized onto the rGO surface without any significant agglomeration. Interestingly, significant enhancement in the microwave absorbing performance has been observed for all the CeO2-rGO hybrids. For example, a CeO2-rGO hybrid with a 10 : 1 mass ratio of CeO2 to GO exhibits a minimum reflection loss (RL) of -45.94 dB, which is 73.35 times and 6.14 times that of the lone CeO2 and rGO, respectively. Moreover, the CeO2-rGO hybrid shows a broadband absorption feature with an effective absorption bandwidth (RL < -10 dB) of 4.5 GHz, and can be exploited for practical application in a frequency range of 3.68-18.00 GHz via tuning of the thickness. Investigation of the structure-property correlation indicates that such enhancements are attributed to conductive loss, polarization loss and multiple reflections which are mainly derived from the unique CeO2-rGO based architecture. In addition, the higher oxygen vacancy concentration of CeO2 in hybrids can promote electron transfer between CeO2 and rGO, leading to microwave attenuation enhancement. It is expected that these CeO2-rGO hybrids can be used as new microwave absorbers.

ZEB1 Promotes Chemoresistance to Cisplatin in Ovarian Cancer Cells by Suppressing SLC3A2.

Ovarian cancer is one of the deadliest gynecological malignancies in women. Chemoresistance has been a major obstacle for ovarian cancer treatment. Zinc finger E-box-binding homeobox 1 (ZEB1) is an important regulator of tumor development in various types of cancer. Abnormal expression of SLC3A2 (CD98hc), a type 2 transmembrane cell surface molecule, has been described in several cancers. This study was designed to investigate the role of ZEB1 and SLC3A2 in the chemoresistance to cisplatin in ovarian cancer cells. We found that ZEB1 was increased in cisplatin-resistant SKOV3/DPP cells. Downregulation of ZEB1 significantly decreased cell viability in response to cisplatin, increased cis-platin-induced apoptosis, and decreased migration and invasion in the presence of cisplatin. In addition, downregulation of ZEB1 decreased the volume and weight of implanted tumors. SLC3A2 was decreased in cisplatin-resistant SKOV3/DPP cells. Upregulation of SLC3A2 significantly decreased cell viability in response to cisplatin, increased cisplatin-induced apoptosis, and decreased migration and invasion in the presence of cisplatin. Moreover, upregulation of SLC3A2 decreased the volume and weight of implanted tumors. Downregulation of ZEB1 resulted in a significant increase of SLC3A2 expression. Moreover, downregulation of SLC3A2 significantly inhibited ZEB1 knockdown-mediated inhibition of cisplatin-resistance. ZEB1-mediated regulation of SLC3A2 was involved in the chemoresistance to cisplatin in ovarian cancer cells. Overall, we provide new insights into the mechanism of chemoresistance to cisplatin in ovarian cancer cells. ZEB1/SLC3A2 may be promising therapeutic targets for enhancement of the sensitivity of ovarian cancer cells to cisplatin-mediated chemotherapy.

[Effect of Shuanghuang Shengbai Granule on Wnt Signal Transduction Pathway in Tumor-bearing Mice with Chemotherapy Induced Myelosuppression].

Objective To observe the regulation of Shuanghuang Shengbai Granule (SHSBG) on regulating Wnt signaling pathway in tumor-bearing mice with chemotherapy induced myelosuppression. Methods Chemotherapy induced myelosuppression model was established in Lewis lung tumor bearing mice by intraperitoneal injection of cyclophosphamide (CTX). And then they were intervened by SHSBG. Routine white blood cell (WBC) count, red blood cell (RBC) count, platelet count, and tumor mass were calculated. Ratios of bone marrow hematopoietic stem cell (Sca, CD34 double positive cells) were detec- ted by flow cytometry. mRNA expression of main genes in Wnt signaling pathway (Wnt, ß-catenin, Frizzted, DSH, GSK3) were detected using real time fluorescent quantitative PCR. Results The number of WBC and ratio of hematopoietic stem cells in the treatment group were higher than those in the model group (P<0. 05). Expressions of Wnt, ß-catenin, Frizzted, DSH, and GSK3 mRNA in the bone marrow were higher in the treatment group than in the model group (P <0. 05). Expressions of Wnt, ß-catenin, Frizzted, and DSH mRNA expression in tumors were lower in the treatment group than in the model group (P <0. 05). There was no statistical difference in counts of RBC and platelet, tumor mass, or GSK3 mR- NA expression among all groups (P >0. 05). Conclusions The mechanism for SHSBG treating myelo-suppression was related to regulating Wnt signaling pathway. Besides, it had dual regulation effect on Wnt signaling pathway, up-regulating expressions of main genes in Wnt signaling pathway while inhibiting ex- pressions of partial genes in tumors.

Resting-state functional connectivity of goal-directed and habitual-learning systems: The efficacy of cognitive-behavioral therapy for obsessive-compulsive disorder.

BACKGROUND: There is an imbalance between goal-directed and habitual-learning system in patients with obsessive-compulsive disorder (OCD). At present, the relationship between cognitive behavior therapy (CBT) as a first-line therapy and goal-directed and habitual-learning disorder is still unclear. We attempted to discuss the effect of CBT treatment in patients with OCD, using abnormalities in goal-directed and habitual-learning-related brain regions at baseline as predictive factors. METHODS: A total of 71 subjects, including 35 OCD patients and 36 healthy controls, were recruited. The OCD patients underwent 8 weeks of cognitive-behavioral therapy (CBT). These patients were divided into two groups based on treatment response (Nresponders = 18, Nnonresponders = 17). Further subgroup analysis was conducted based on disease duration (Nshort = 17, Nlong = 18) and age of onset (Nearly = 14, Nlate = 21). We collected resting-state ROI-ROI functional connectivity data and apply repeated-measures linear mixed-effects models to investigate the differences of different subgroups. RESULTS: CBT led to symptom improvement in OCD patients, with varying degrees of effectiveness across subgroups. The orbitofrontal cortex (OFC) and insula, key regions for goal-directed behavior and habitual-learning, respectively, showed significant impacts on CBT efficacy in subgroups with different disease durations and ages of onset. CONCLUSION: The findings suggest that the goal-directed system may influence the efficacy of CBT through goal selection, maintenance, and emotion regulation. Furthermore, we found that disease duration and age of onset may affect treatment outcomes by modulating functional connectivity between goal-directed and habitual-learning brain regions.

Resting-state functional connectivity of amygdala subregions predicts treatment outcome for cognitive behavioral therapy in obsessive-compulsive disorder at a 4-month follow-up.

BACKGROUND: Cognitive behavioral therapy (CBT) is considered as the first-line treatment for obsessive-compulsive disorder (OCD). However, the underlying neural mechanisms through which CBT exerts its effects in OCD remain unclear. This study aims to investigate whether the improvement of clinical symptoms in OCD patients after CBT treatment is associated with changes in resting-state functional connectivity (FC) of the amygdala subregion, and whether these changes can be served as potential predictors of four-months treatment efficacy. METHODS: We collected resting-state functional magnetic resonance imaging (rs-fMRI) data from 57 OCD patients and 50 healthy subjects at baseline. In the patient group, rs-fMRI was also obtained after completion of an 8-week CBT treatment and 4 months post-treatment. A whole-brain rsFC analysis was conducted using the amygdala subregion as the seed point. We analyzed the FC patterns in relation to 4 months clinical outcomes to elucidate the long-term efficacy of CBT in OCD patients. RESULTS: Treatment responseat at pre-treatment was found to be associated with reduced rsFC between the left basolateral amygdala(BLA)and left superior temporal gyrus(STG) at baseline. Lower pre-treatment FC were negatively correlated with the severity of OCD symptoms as measured by the Yale-Brown Obsessive Compulsive Severity Scale (Y-BOCS). Moreover, the area under the receiver operating characteristic (ROC) curve for the FC between the left BLA and STG at the end of treatment was 73.0% and 70.4% for the effective-ineffective and remitted or unremitted groups, respectively. At the 4-month follow-up, the area under the ROC curve for the effective-ineffective and remitted or unremitted groups was 83.9% and 76.5%, respectively. CONCLUSION: These findings suggest that brain functional activity in patients with OCD can predict treatment response to CBT, and longitudinal changes in relevant brain functional activity following CBT treatment are associated with treatment response in OCD.

A density correction method for radioactive waste drum based on SRGS technology.

The segmented ringed gamma scanning (SRGS) technique represents an advancement in segmented gamma scanning (SGS) technology used for detecting the density of radioactive waste drums, offering enhanced measurement accuracy. However, significant occur errors in the reconstruction of matrix densities due to the non-uniform distribution of density in radioactive waste and the conical beam emitted from the transmission source collimator. This paper proposes a density correction method based on dichotomy to address this issue. The efficacy of this method was verified through both simulations and experiments on a sample containing five different materials, utilizing 137Cs and 60Co for transmission and emission measurements, respectively. The experimental results demonstrate that the errors in the corrected matrix densities are reduced, falling within a margin of 16.8%. Additionally, the corrected reconstruction error of the activity is approximately 25% of the uncorrected results.

Monolithic integrated optoelectronic chip for vector force detection.

Sensors with a small footprint and real-time detection capabilities are crucial in robotic surgery and smart wearable equipment. Reducing device footprint while maintaining its high performance is a major challenge and a significant limitation to their development. Here, we proposed a monolithic integrated micro-scale sensor, which can be used for vector force detection. This sensor combines an optical source, four photodetectors, and a hemispherical silicone elastomer component on the same sapphire-based AlGaInP wafer. The chip-scale optical coupling is achieved by employing the laser lift-off techniques and the flip-chip bonding to a processed sapphire substrate. This hemispherical structure device can detect normal and shear forces as low as 1 mN within a measurement range of 0-220 mN for normal force and 0-15 mN for shear force. After packaging, the sensor is capable of detecting forces over a broader range, with measurement capabilities extending up to 10 N for normal forces and 0.2 N for shear forces. It has an accuracy of detecting a minimum normal force of 25 mN and a minimum shear force of 20 mN. Furthermore, this sensor has been validated to have a compact footprint of approximately 1.5 mm2, while maintaining high real-time response. We also demonstrate its promising potential by combining this sensor with fine surface texture perception in the fields of compact medical robot interaction and wearable devices.

Extracellular vesicles produced by 3D cultured MSCs promote wound healing by regulating macrophage activation through ANXA1.

The conundrum of wound healing has transformed into an imminent medical challenge. Presently, cell-free therapy centered around extracellular vesicles (EVs) has become a pivotal and promising research avenue. EVs generated from three-dimensional (3D) cell cultures have been previously established to possess enhanced tissue regeneration potential, although the underlying mechanisms remain elusive. In this study, we observed higher expression of annexin ANXA1 in 3D-cultured EVs. Remarkably, 3D-EVs with elevated ANXA1 expression demonstrated a more potent capacity to promote macrophage polarization from the M1 phenotype to the M2 phenotype. Concurrently, they exhibited superior abilities to enhance cell migration and tube formation, facilitating expedited wound healing in animal experiments. Conversely, the application of an ANXA1 inhibitor counteracted the positive effects of 3D-EVs. Taken together, our data validate that extracellular vesicles derived from 3D-cultured MSCs regulate macrophage polarization via ANXA1, thereby fostering wound healing.

[Effect of bufalin combined gefitinib on lung cancer H1975 cells and its mechanisms research].

OBJECTIVE: To observe the effect of bufalin combined Gefitinib on lung cancer H1975 cells, and to explore its potential mechanisms for anti-tumor. METHODS: The cytostatic effects of bufalin (1 -100 nmol/L), gefitinib (0.1-20 micromol/L), and bufalin plus gefitinib on H1975 cells were evaluated by MTT assay. Their effects on apoptosis of H1975 cells were determined by flow cytometry (FCM). Their effects on expressions of epidermal growth factor receptor (EGFR) and Met signal pathway related proteins in H1975 cells were detected by Western blot. RESULTS: Results of MTT assay showed that gefitinib over 5 micromol/L could inhibit H1975 cells. But combined therapy of bufalin and gefitinib could potently inhibit the growth of H1975 cells. Results of FCM showed the apoptotic rate was 61.64% +/- 5.61% in the bufalin plus gefitinib group, obviously higher than that of the bufalin group (18.34% +/- 3.42%) and the gefitinib group (7.32% +/- 1.08%), showing statistical difference (P < 0.01). Results of Western blot showed the protein expressions of p-EGFR, p-Met, p-Akt, and p-mTOR in H1975 cells could be markedly down-regulated by bufalin plus gefitinib. CONCLUSIONS: Combination of bufalin and gefitinib potently inhibited the growth of H1975 cells, and induced cell apoptosis. The potential mechanism for anti-tumor might be involved in blocking EGFR-PI3k/Akt pathway.

Integrating network pharmacology prediction and experimental investigation to verify ginkgetin anti-invasion and metastasis of human lung adenocarcinoma cells via the Akt/GSK-3ß/Snail and Wnt/ß-catenin pathway.

Introduction: Lung cancer, one of the most frequent malignancies, has a high death rate and an increased number of new cases globally. Ginkgo biloba has been used for many years in the treatment of lung cancer. Ginkgetin is the key active ingredient extracted from Ginkgo biloba. However, the mechanism by which ginkgetin inhibits the invasive metastasis of lung cancer is unclear. Methods: We used a network pharmacology approach to obtain the molecular mechanism by which ginkgetin inhibits lung cancer metastasis. Then we analyzed potential target proteins between ginkgetin and lung cancer. Finally, we validated with molecular docking and experimental validation. Results: By analyzing the intersecting genes of lung cancer and ginkgetin, there were 79 intersecting genes, which were mainly involved in the positive regulation of cell migration, with the cancer pathway being one of the most enriched pathways. The results of in vitro experiments showed that GK had a large inhibitory effect on cell invasion and metastasis of A549 and H1299. In vivo animals GK had a great inhibitory effect on metastasis of LLC. Conclusion: This study identified the potential related GK molecular targets and signaling pathways in treating human lung cancer using network pharmacological approaches. Experiments confirmed that GK inhibits the Akt/GSK-3ß/Snail and Wnt/ß-catenin cascade initiation in A549, H1299 and LLC cells, preventing metastasis. This study's results align with the hypotheses derived from the network pharmacology analysis.

Identification and validation of a novel cuproptosis-related stemness signature to predict prognosis and immune landscape in lung adenocarcinoma by integrating single-cell and bulk RNA-sequencing.

Background: Cancer stem cells (CSCs) play vital roles in lung adenocarcinoma (LUAD) recurrence, metastasis, and drug resistance. Cuproptosis has provided a novel insight into the treatment of lung CSCs. However, there is a lack of knowledge regarding the cuproptosis-related genes combined with the stemness signature and their roles in the prognosis and immune landscape of LUAD. Methods: Cuproptosis-related stemness genes (CRSGs) were identified by integrating single-cell and bulk RNA-sequencing data in LUAD patients. Subsequently, cuproptosis-related stemness subtypes were classified using consensus clustering analysis, and a prognostic signature was constructed by univariate and least absolute shrinkage operator (LASSO) Cox regression. The association between signature with immune infiltration, immunotherapy, and stemness features was also investigated. Finally, the expression of CRSGs and the functional roles of target gene were validated in vitro. Results: We identified six CRSGs that were mainly expressed in epithelial and myeloid cells. Three distinct cuproptosis-related stemness subtypes were identified and associated with the immune infiltration and immunotherapy response. Furthermore, a prognostic signature was constructed to predict the overall survival (OS) of LUAD patients based on eight differently expressed genes (DEGs) with cuproptosis-related stemness signature (KLF4, SCGB3A1, COL1A1, SPP1, C4BPA, TSPAN7, CAV2, and CTHRC1) and confirmed in validation cohorts. We also developed an accurate nomogram to improve clinical applicability. Patients in the high-risk group showed worse OS with lower levels of immune cell infiltration and higher stemness features. Ultimately, further cellular experiments were performed to verify the expression of CRSGs and prognostic DEGs and demonstrate that SPP1 could affect the proliferation, migration, and stemness of LUAD cells. Conclusion: This study developed a novel cuproptosis-related stemness signature that can be used to predict the prognosis and immune landscape of LUAD patients, and provided potential therapeutic targets for lung CSCs in the future.

[Effects of isopsoralen on tibial fracture and vascular healing in mice].

OBJECTIVE: To explore effects of isopsoralen (ISO) with different doses on fracture and vascular healing in mice. METHODS: Sixty 2-month-old male C57BL/6 mices with body mass of (20±2) g were selected and divided into 4 groups by random number table method:model group (model), low dose group (isopsoralen-low dose, ISO-L), medium dose group (isopsoralen-medium dose, ISO-M) and high dose group (isopsoralen-high dose, ISO-H), with 15 animals in each group. The right tibial fracture model was established. After operation, ISO-L group, ISO-M group and ISO-H group were given ISO concentration of 10 mg·kg-1, 20 mg·kg-1 and 40 mg·kg-1, respectively. Model group was given same volume of normal saline once a day for 28 days. Weighed once a week. X-ray was performed on 7, 14, 21 and 28 days, respectively, and modified I.R. Garrett scoring method was used to evaluate callus growth. After 28 days, the main organs were stripped and weighed, and organ coefficients were calculated. Hematoxylin eosin staining (HE staining) was performed on the organs to observe whether there were pathological structural changes. Micro-computed tomography (Micro-CT) was used to scan fracture area and conduct three-dimensional reconstruction to obtain the effect map, and quantify bone volume fraction (bone volume/total volume, BV/TV). After decalcification, the tibia was embedded in paraffin wax and sectioned. The healing and shape of fracture end were observed by HE staining and ferruxin solid green staining. The right tibia was removed and decalcified after intravascular infusion of Microfil contrast agent. Micro-CT was used to scan the callus microvessels in the fracture area, and the vascular volume fraction and vessel diameter were quantified. RESULTS: After 28 days of administration, there was no significant difference in body mass and organ coefficient among all groups (P>0.05), and no significant pathological changes were found in HE staining of organs. The results of X-ray and improved I.R. Garrett score showed that ISO-M group was higher than that of Model group at 28 days (P<0.05). Scores of ISO-H group at 14, 21 and 28 days were higher than those of the other 3 groups (P<0.05). Micro-CT results showed intracavitary callus in ISO-M group was significantly reduced, which was lower than that in Model group (P<0.05), most of the callus in ISO-H group were subsided, and BV/TV in ISO-H group was lower than that in the other 3 groups (P<0.05). The results of HE staining and ferrubens solid green staining showed fracture area of ISO-H group was closed, continuous laminar bone had appeared, and the fracture healing process was higher than that of other groups. Angiographic results showed vascular volume fraction in ISO-H and ISO-M groups was higher than that in Model and ISO-L groups (P<0.05), and the vascular diameter in ISO-H and ISO-M groups was higher than that in Model and ISO-L groups (P<0.05). CONCLUSION: In the concentration range of 10-40 mg·kg-1, ISO has no obvious toxic and side effects, and could improve bone microstructure, promote formation of callus microvessels, and accelerate healing of fracture ends in a concentration-dependent manner.

Delayed denervation-induced muscle atrophy in Opg knockout mice.

Recent evidence has shown a crucial role for the osteoprotegerin/receptor activator of nuclear factor κ-B ligand/RANK (OPG/RANKL/RANK) signaling axis not only in bone but also in muscle tissue; however, there is still a lack of understanding of its effects on muscle atrophy. Here, we found that denervated Opg knockout mice displayed better functional recovery and delayed muscle atrophy, especially in a specific type IIB fiber. Moreover, OPG deficiency promoted milder activation of the ubiquitin-proteasome pathway, which further verified the protective role of Opg knockout in denervated muscle damage. Furthermore, transcriptome sequencing indicated that Opg knockout upregulated the expression of Inpp5k, Rbm3, and Tet2 and downregulated that of Deptor in denervated muscle. In vitro experiments revealed that satellite cells derived from Opg knockout mice displayed a better differentiation ability than those acquired from wild-type littermates. Higher expression levels of Tet2 were also observed in satellite cells derived from Opg knockout mice, which provided a possible mechanistic basis for the protective effects of Opg knockout on muscle atrophy. Taken together, our findings uncover the novel role of Opg in muscle atrophy process and extend the current understanding in the OPG/RANKL/RANK signaling axis.

Altered brain functional network topology in Obsessive-Compulsive Disorder: A comparison of patients with varying severity of depressive symptoms and the impact on psychosocial functioning.

BACKGROUND: Obsessive-compulsive disorder (OCD) is associated with psychosocial impairment, which can be exacerbated by depressive symptoms. In this study, we employed graph theory analysis to investigate the association among neuroimaging, clinical features, and psychosocial functioning in OCD patients, with a specific focus on the differential impact of depressive symptoms. METHODS: 216 OCD patients were divided into two subgroups based on depressive symptoms. Resting-state functional MRI data were acquired from a subset of 106 OCD patients along with 77 matched healthy controls (HCs). We analyzed the topological characteristics of the entire brain and the cognition-related subnetworks and performed Pearson correlation analyses to further explore the relationship with psychosocial functioning. RESULTS: OCD patients with more severe depressive symptoms exhibited greater impairment across all dimensions of psychosocial functioning. Graph theory analysis revealed more pronounced reductions in network efficiency within the entire brain, the default mode network (DMN), and the cingulo-opercular network (CON) among patients with non or mild depressive symptoms. Lower nodal efficiency and degree centrality of the right superior temporal gyrus (STG) were found in OCD patients and these variables were positively correlated with psychosocial functioning impairment. CONCLUSIONS: This study revealed that the presence of depressive symptoms generally exacerbated psychosocial functioning impairment in OCD patients. Abnormalities in the functional integration of the entire brain, the DMN, and the CON in OCD patients may comprise the basis of cognitive deficits, while dysfunction of the right STG may affect the psychosocial functioning through its role in emotion, intention perception, and insight.