Elimination of GGTA1, CMAH, ß4GalNT2 and CIITA genes in pigs compromises human versus pig xenogeneic immune reactions.

BACKGROUND: Pig organ xenotransplantation is a potential solution for the severe organ shortage in clinic, while immunogenic genes need to be eliminated to improve the immune compatibility between humans and pigs. Current knockout strategies are mainly aimed at the genes causing hyperacute immune rejection (HAR) that occurs in the first few hours while adaptive immune reactions orchestrated by CD4 T cell thereafter also cause graft failure, in which process the MHC II molecule plays critical roles. METHODS: Thus, we generate a 4-gene (GGTA1, CMAH, ß4GalNT2, and CIITA) knockout pig by CRISPR/Cas9 and somatic cell nuclear transfer to compromise HAR and CD4 T cell reactions simultaneously. RESULTS: We successfully obtained 4KO piglets with deficiency in all alleles of genes, and at cellular and tissue levels. Additionally, the safety of our animals after gene editing was verified by using whole-genome sequencing and karyotyping. Piglets have survived for more than one year in the barrier, and also survived for more than 3 months in the conventional environment, suggesting that the piglets without MHC II can be raised in the barrier and then gradually mated in the conventional environment. CONCLUSIONS: 4KO piglets have lower immunogenicity, are safe in genomic level, and are easier to breed than the model with both MHC I and II deletion.

NPS-2143 inhibit glioma progression by suppressing autophagy through mediating AKT-mTOR pathway.

Gliomas are the most common tumours in the central nervous system. In the present study, we aimed to find a promising anti-glioma compound and investigate the underlying molecular mechanism. Glioma cells were subjected to the 50 candidate compounds at a final concentration of 10 µM for 72 h, and CCK-8 was used to evaluate their cytotoxicity. NPS-2143, an antagonist of calcium-sensing receptor (CASR), was selected for further study due to its potent cytotoxicity to glioma cells. Our results showed that NPS-2143 could inhibit the proliferation of glioma cells and induce G1 phase cell cycle arrest. Meanwhile, NPS-2143 could induce glioma cell apoptosis by increasing the caspase-3/6/9 activity. NPS-2143 impaired the immigration and invasion ability of glioma cells by regulating the epithelial-mesenchymal transition process. Mechanically, NPS-2143 could inhibit autophagy by mediating the AKT-mTOR pathway. Bioinformatic analysis showed that the prognosis of glioma patients with low expression of CASR mRNA was better than those with high expression of CASR mRNA. Gene set enrichment analysis showed that CASR was associated with cell adhesion molecules and lysosomes in glioma. The nude mice xenograft model showed NPS-2143 could suppress glioma growth in vivo. In conclusion, NPS-2143 can suppress the glioma progression by inhibiting autophagy.

Novel PTCH1 Mutation Causes Gorlin-Goltz Syndrome.

OBJECTIVE: To analyse the aetiology and pathogenesis of Gorlin-Goltz syndrome (GS; also known as nevoid basal cell carcinoma syndrome [NBCCS] or basal cell nevus syndrome [BCNS]) in a Chinese family. METHODS: Whole-exome sequencing (WES) was performed on genomic DNA samples from the subjects in a family, followed by the investigation of pathogenesis via bioinformatic approaches and conformational analysis. RESULTS: A novel heterozygous non-frameshift deletion patched 1 (PTCH1) [NM_000264: c.3512_3526del (p.1171_1176del)] was identified by WES and further validated by Sanger sequencing. Bioinformatic and conformational analysis showed that the mutation caused altered PTCH1 protein structure, which may be related to functional abnormalities. CONCLUSION: This study expands the mutation spectrum of PTCH1 in GS and facilitates the early diagnosis and screening of GS. PTCH1 [c.3512_3526del (p.1171_1176del)] may cause structural abnormalities and functional disabilities, leading to GS in families.

Daurisoline suppress glioma progression by inhibiting autophagy through PI3K/AKT/mTOR pathway and increases TMZ sensitivity.

Glioma is one of the most common primary malignant tumors of the central nervous system. Temozolomide (TMZ) is the only effective chemotherapeutic agent, but it easily develops resistance and has unsatisfactory efficacy. Consequently, there is an urgent need to develop safe and effective compounds for glioma treatment. The cytotoxicity of 30 candidate compounds to glioma cells was detected by the CCK-8 assay. Daurisoline (DAS) was selected for further investigation due to its potent anti-glioma effects. Our study revealed that DAS induced glioma cell apoptosis through increasing caspase-3/6/9 activity. DAS significantly inhibited the proliferation of glioma cells by inducing G1-phase cell cycle arrest. Meanwhile, DAS remarkably suppressed the migration and invasion of glioma cells by regulating epithelial-mesenchymal transition. Mechanistically, our results revealed that DAS impaired the autophagic flux of glioma cells at a late stage by mediating the PI3K/AKT/mTOR pathway. DAS could inhibit TMZ-induced autophagy and then significantly promote TMZ chemosensitivity. Nude mice xenograft model revealed that DAS could restrain glioma proliferation and promote TMZ chemosensitivity. Thus, DAS is a potential anti-glioma drug that can improve glioma sensitivity to TMZ and provide a new therapeutic strategy for glioma in chemoresistance.

Personality traits predict treatment outcome of an antidepressant in untreated adolescents with depression: An 8-week, open-label, flexible-dose study.

BACKGROUND: Antidepressant response in adults with major depressive disorder (MDD) is probably influenced by personality dimensions. However, personality dimensions in depression and their association with antidepressant treatment in adolescents are relatively unknown. We sought to investigate whether personality traits (PTs) can influence antidepressant treatment response in adolescents with depression. METHODS: Eighty-two adolescents with MDD who had completed the 8 weeks of treatment with selective serotonin reuptake inhibitors (SSRI) were enrolled. The Revised NEO Five-Factor Inventory (NEO-FFI-R) was used to measure their personality at baseline, and the 17-item Hamilton Depression Rating Scale (HAMD-17) and Children's Depression Rating Scale-Revised (CDRS-R) were used to evaluate depressive symptoms at baseline and 8 weeks. Moreover, logistic regression was performed to investigate the relationship between personality dimensions and antidepressant response. Receiver operating characteristic analyses were employed to determine the accuracy of a PT-based model in predicting the antidepressant response rate. RESULTS: Adolescents with MDD had significantly different PTs at baseline. Multivariable logistic regression analysis showed that extroversion scores were associated with response to antidepressant treatment, the lower the extroversion score, the better the response to antidepressant treatment, after correcting for variables with significant differences and trends or all potential confounding variables. It was also found that the combination of disease duration, extraversion-gregariousness, and agreeableness-trust effectively predicted antidepressant response in adolescents with MDD, with a sensitivity of 79.4 % and specificity of 68.7 %. CONCLUSION: Personality dysfunction in adolescents is associated with MDD. The antidepressant treatment response is influenced by the degree of extroversion in adolescents with MDD.

Improve meat production and virus resistance by simultaneously editing multiple genes in livestock using Cas12iMax.

The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated gene (Cas) system is continually optimized to achieve the most efficient gene editing effect. The Cas12iMax, a Cas12i variant, exhibits powerful DNA editing activity and enriches the gene editing toolbox. However, the application of Cas12iMax in large domestic animals has not yet been reported. To verify the efficiency and feasibility of multiple gene editing in large animals, we generated porcine fibroblasts with simultaneous knockouts of IGF2, ANPEP, CD163, and MSTN via Cas12iMax in one step. Phenotypically stable pigs were created through somatic cell nuclear transfer technology. They exhibited improved growth performance and muscle quality. Furthermore, we simultaneously edited three genes in bovine fibroblasts. A knockout of MSTN and PRNP was created and the amino acid Q-G in CD18 was precisely substituted. Meanwhile, no off-target phenomenon was observed by sum-type analysis or off-target detection. These results verified the effectiveness of Cas12iMax for gene editing in livestock animals and demonstrated the potential application of Cas12iMax in the field of animal trait improvement for agricultural production.

Single-cell transcriptomic analysis reveals transcriptional and cell subpopulation differences between human and pig immune cells.

BACKGROUND: The pig is a promising donor candidate for xenotransplantation. Understanding the differences between human and swine immune systems is critical for addressing xenotransplant rejection and hematopoietic reconstitution. The gene transcriptional profile differences between human and pig immune cell subpopulations have not been studied. To assess the similarities and differences between pigs and humans at the levels of gene transcriptional profiles or cell subpopulations are important for better understanding the cross-species similarity of humans and pigs, and it would help establish the fundamental principles necessary to genetically engineer donor pigs and improve xenotransplantation. OBJECTIVE: To assess the gene transcriptional similarities and differences between pigs and humans. METHODS: Two pigs and two healthy humans' PBMCs were sorted for 10 × genomics single-cell sequence. We generated integrated human-pig scRNA-seq data from human and pig PBMCs and defined the overall gene expression landscape of pig peripheral blood immune cell subpopulations by updating the set of human-porcine homologous genes. The subsets of immune cells were detected by flow cytometry. RESULTS: There were significantly less T cells, NK cells and monocytes but more B cells in pig peripheral blood than those in human peripheral blood. High oxidative phosphorylation, HIF-1, glycolysis, and lysosome-related gene expressions in pig CD14+ monocytes were observed, whereas pig CD14+ monocytes exhibited lower levels of cytokine receptors and JAK-STAT-related genes. Pig activated CD4+T cells decreased cell adhesion and inflammation, while enriched for migration and activation processes. Porcine GNLY+CD8+T cells reduced cytotoxicity and increased proliferation compared with human GNLY+CD8+T cells. Pig CD2+CD8+γδT cells were functionally homologous to human CD2+CD4+ γδT cells. Pig CD2-CD8-γδT cells expressed genes with quiescent and precursor characteristics, while CD2-CD8+γδT cells expressed migration and memory-related molecules. Pig CD24+ and CD5+B cells are associated with inflammatory responses. CONCLUSION: Our research with integrated scRNA-seq assays identified the different distribution of pig immune cell subpopulations and the different transcriptional profiles of human and pig immune cells. This study enables a deeper understanding of the development and function of porcine immune cells.

Three-dimensional surface motion capture of multiple freely moving pigs using MAMMAL.

Understandings of the three-dimensional social behaviors of freely moving large-size mammals are valuable for both agriculture and life science, yet challenging due to occlusions in close interactions. Although existing animal pose estimation methods captured keypoint trajectories, they ignored deformable surfaces which contained geometric information essential for social interaction prediction and for dealing with the occlusions. In this study, we develop a Multi-Animal Mesh Model Alignment (MAMMAL) system based on an articulated surface mesh model. Our self-designed MAMMAL algorithms automatically enable us to align multi-view images into our mesh model and to capture 3D surface motions of multiple animals, which display better performance upon severe occlusions compared to traditional triangulation and allow complex social analysis. By utilizing MAMMAL, we are able to quantitatively analyze the locomotion, postures, animal-scene interactions, social interactions, as well as detailed tail motions of pigs. Furthermore, experiments on mouse and Beagle dogs demonstrate the generalizability of MAMMAL across different environments and mammal species.

Characterisation of X chromosome status of human extended pluripotent stem cells.

Different pluripotent cell types have been established by capturing pluripotency in different states. Human extended pluripotent stem cells (hEPSCs), recently established by two independent studies, have the capability of differentiating into both embryonic and extraembryonic lineages, as well as forming human blastoids, showing great potential for early human development modeling and regenerative medicine. Considering that X chromosome status in female human pluripotent stem cells is dynamic and heterogeneous, and often leads to functional consequences, we characterized it in hEPSCs. We derived hEPSCs from primed human embryonic stem cells (hESCs) with defined X chromosome status (pre- or post-X chromosome inactivation) using two previously published methods. We showed that hEPSCs derived using both methods had highly similar transcription profiles and X chromosome status. However, the X chromosome status of hEPSCs is largely determined by the primed hESCs from which they were derived, suggesting a lack of complete reprogramming of X chromosome during primed to extended/expanded pluripotency conversion. Furthermore, we found that the X chromosome status of hEPSCs affected their ability to differentiate into embryonic or extraembryonic lineage cells. Taken together, our work characterized the X chromosome status of hEPSCs, providing important information for the future application of hEPSCs.

Drug­resistant Acinetobacter baumannii: From molecular mechanisms to potential therapeutics (Review).

Bacterial drug resistance is increasingly becoming an important problem that needs to be solved urgently in modern clinical practices. Infection caused by Acinetobacter baumannii is a serious threat to the life and health of patients. The drug resistance rate of Acinetobacter baumannii strains is increasing, thus research on the drug resistance of Acinetobacter baumannii has also seen an increase. When patients are infected with drug-resistant Acinetobacter baumannii, the availability of suitable antibiotics commonly used in clinical practices is becoming increasingly limited and the prognosis of patients is worsening. Studying the molecular mechanism of the drug resistance of Acinetobacter baumannii is fundamental to solving the problem of drug-resistant Acinetobacter baumannii and potentially other 'super bacteria'. Drug resistance mechanisms primarily include enzymes, membrane proteins, efflux pumps and beneficial mutations. Research on the underlying mechanisms provides a theoretical basis for the use and development of antibiotics and the development of novel treatment methods.

Pharmacokinetics and bioequivalence studies of fluvoxamine maleate tablets in healthy Chinese subjects.

Fluvoxamine is a selective serotonin reuptake inhibitor commonly used for various types of depression. The purpose of this study was to evaluate the pharmacokinetics and bioequivalence of fluvoxamine maleate tablets orally on an empty stomach and after a meal in healthy adult Chinese subjects and to preliminarily evaluate their safety. A single-center, randomized, open-label, two-drug, two-period, crossover, single-dose trial protocol was designed. Sixty healthy Chinese participants were enrolled and randomly classified into fasting (n = 30) and fed groups (n = 30). Each week, subjects took fluvoxamine maleate tablets 50 mg orally once as a test preparation or as a reference preparation on an empty stomach/after meals. To evaluate the bioequivalence of test and reference tables, the concentration of fluvoxamine maleate in the plasma of the subjects at different time points after administration was detected by liquid chromatography-tandem mass spectrometry, and pharmacokinetic parameters including the maximum plasma drug concentration (Cmax ), the time to reach maximum concentration (Tmax ), the area under the plasma concentration-time curve from time 0 to the last measurable concentration (AUC0-t ) and the area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞ ) were calculated. Our data revealed that the 90% confidence intervals of the geometric mean ratio of the test or reference drugs for the Cmax , AUC0-t and AUC0-∞ fell within the acceptance range for bioequivalence (92.30-102.77%). The absorption, measured by AUC, did not show a significant difference between the two groups. There were no suspected serious adverse reactions or serious adverse events over the entire trial. Our results demonstrated that the test and reference tablets were bioequivalent under fasting and fed conditions.

Comparison of endoscopic and open surgery in life-threatening large spontaneous supratentorial intracerebral hemorrhage: A propensity-matched analysis.

BACKGROUND: Conventionally, open surgery (OS), including standard craniotomy (SC) and decompressive craniectomy (DC) with hematoma evacuation, is adopted to treat life-threatening large spontaneous supratentorial intracerebral hemorrhage (ICH). Recently, endoscopic surgery (ES), a minimally invasive surgical treatment, has gained increased popularity. However, the safety and efficacy of ES for life-threatening large ICH is uncertain. AIM: The aim of this study was to evaluate the effectiveness and safety of ES for life-threatening large ICH and compare it with traditional OS. METHODS: We retrospectively analyzed the clinical and imaging data of consecutive supratentorial ICH patients with preoperative Glasgow Coma Scale (GCS) score ⩽ 8, who underwent ES or OS between May 2015 and October 2021. To minimize bias in case selection, propensity score matching was performed (ratio 1:2, caliper o.2). The primary outcome was a prognosis-based dichotomized (favorable or unfavorable) outcome of the 5-point Glasgow Outcome Scale (GOS) at 6 months. Favorable outcome was defined as a GOS score of 4 to 5 at 6 months. Sensitivity analysis was also performed to ensure the robustness of the findings. RESULTS: Of 695 patients who underwent surgical treatment for spontaneous ICH, 191 patients were identified to be eligible, with 58 patients in the ES group and 133 patients in the OS group. Propensity score matching improved covariate balance and generated a comparable cohort (53 ES and 106 OS) for all analyses. The ES group had a higher incidence of the primary outcome of favorable outcome at 6 months (ES 20/53 (37.7%) vs. OS 22/106 (20.8%); propensity score-matched relative risk (RR) (95% CI) = 1.74 (1.13-2.68); p = 0.013). Sensitivity analysis showed the result was stable. CONCLUSION: ES is a safe treatment for life-threatening large spontaneous supratentorial ICH patients and may achieve better outcomes than OS.

Effect analysis of vertebroplasty combined with posterior decompression and internal fixation in the treatment of spinal metastases with neurological symptoms / 国际外科学杂志

Objective:To analyze the efficacy of vertebroplasty combined with posterior decompression and internal fixation in the treatment of spinal metastases with neurological symptoms.Methods:This study was a retrospective analysis of 32 cases with neurological symptoms caused by spinal metastatic tumor in the Department of Orthopedics, Beijing Friendship Hospital, Capital Medical University from June 2016 to January 2022. All 32 patients (20 males, 12 females) aged between 39 to 85 years were enrolled in this study, with a mean age of (64.8±11.9) years. Surgery time, bleeding volume, modified Tokuhashi score, spinal instability neoplastic score (SINS) were collected. The visual analogue score (VAS), Oswestry disability index (ODI), Karnofsky performance scale (KPS) and American spinal cord injury association (ASIA) score before surgery, 1 month after surgery, 3 months after surgery and 6 months after surgery were collected and analyzed. Measurement data with normal distribution were represented as mean±standard deviation( ± s), and the comparison before and after surgery was conducted using repeated-measures analysis of variance test. Measurement data with skewed distribution were represented as M( Q1, Q3). Results:All 32 patients were followed up for 6 months. The operation time was (209.6±49.0) min, and the blood loss was (462.9±298.3) mL. 14 patients(43.8%) were treated with blood transfusion. The modified Tokuhashi score was 8.09±2.89, and the SINS was 8.81±1.97. The VAS score before surgery, postoperative 1, 3, 6 months were 7.47±0.98, 3.87±0.87, 2.91±0.73 and 2.34±0.60, respectively. ODI score before surgery, postoperative 1, 3, 6 months were 79.13±9.50, 39.14±6.31, 34.43±6.42 and 31.08±4.80, respectively. KPS score before surgery, postoperative 1, 3, 6 months were 49.69±14.70, 64.68±15.02, 71.88±12.81 and 75.63±10.76, respectively. The ASIA grading at 6 months follow-up was improved compared to preoperative baseline. Postoperative complications occurred in 4 cases, including nerve root injury (1 case), bone cement leakage in paravertebral soft tissue (1cases), bone cement leakage in paravertebral vein(1case) and acute thoracic epidural hematoma (1case).Conclusion:Vertebroplasty combined with posterior decompression and internal fixation can effectively relieve pain, relieve the compression of spinal cord and nerve, recover nerve functions, and improve the quality of life of patients with spinal metastatic tumor.

Treatment advice of small molecule antiviral drugs for elderly COVID-19 / 中国药理学通报

COVID-19 has been prevalent for three years. The virulence of SARS-CoV-2 is weaken as it mutates continuously. However, elderly patients, especially those with underlying diseases, are still at high risk of developing severe infections. With the continuous study of the molecular structure and pathogenic mechanism of SARS-CoV-2, antiviral drugs for COVID-19 have been successively marketed, and these anti-SARS-CoV-2 drugs can effectively reduce the severe rate and mortality of elderly patients. This article reviews the mechanism, clinical medication regimens, drug interactions and adverse reactions of five small molecule antiviral drugs currently approved for marketing in China, so as to provide advice for the clinical rational use of anti-SARS-CoV-2 in the elderly.

Mechanism of pterostilbene reducing oxidative damage in endothelial cells in mouse hepatic sinus / 中国药理学通报

Aim To explore the mechanism of the natural phenolic compound pterostilbene(PTE)in the protection of liver ischemic/reperfusion. Methods A total of 40 C57 mice were divided into control group,model group,drug delivery group and treatment group and a 70% liver ischemic/reperfusion(ischemic 60 min)model was established,then primary LSECs were isolated by perfusion and digestion. Hepatic structural disruption was observed by HE staining. The ultrastructure of hepatic sinus endothelial cells was observed by transmission electron microscopy(TEM). The structure of LSECs fenestrae was observed by scanning electron microscopy(SEM). The expression level of heme oxygenase 1(HO-1)in LSECs was detected by Western blot. Results HE staining showed that PTE protected against hepatic ischemic injury. TEM observed that PTE had a protective effect on hepatic sinus endothelial cells,and the number of LSECs fenestrae in the blank control group was larger and the number of fenestrae in the liver I/R model group was reduced. The number of LSECs fenestrae in the liver I/R model group treated with PTE increased compared with the untreated liver I/R model group. Western blot result showed that PTE was able to induce HO-1 expression in LSECs. Conclusions PTE alleviates oxidative damage of endothelial cells in mouse hepatic sinus by inducing HO-1expression,and protects the liver from ischemia/reperfusion injury.

Serotype distribution and antibiotic resistance of Streptococcus pneumoniae isolates collected from unvaccinated children with pneumonia at a province in central Vietnam.

Background and Objectives: Identification of pnemococcal serotypes and antimicrobial resistance provides helpful information for the use of suitable vaccines and antibiotics; however, very limited data is available on these issues in Vietnam. The present study aimed to find the serotype distribution and drug resistance patterns of Streptococcus pneumoniae isolated from unvaccinated children less than 5 years of age with pneumonia at a province in centre Vietnam. Materials and Methods: A total of 126 clinical pnemococcal strains isolated from unvaccinated children less than 5 years of age with pneumonia at the Nghe An province, Vietnam between Nov 2019 and Mar 2021. All strains were identified using conventional microbiological method, VITEK® 2 Compact system, specific PCR and sequencing. The serotypes and antimicrobial resistance patterns of pnemococcal strains were determined using the multiplex PCR assays and VITEK® 2 Compact system. Results: The results showed that, eight different pneumococcal serotypes were identified. The most common serotypes were 19F (67.46%), followed by 23F (10.32%), 19A (9.52%), 6A/B (3.17%), 15A (2.38%), 9V (3.17%), 11A (1.59%) and 14 (0.80%), respectively. More than half of the pneumococcal strains were non-susceptible to penicillin. The resistance rate to ceftriaxone and cefotaxime were 41.3% and 50.8%. The percentage of pneumococci strains resistant to clarithromycin, azithromycin, erythromycin, cotrimoxazole, tetracyclin, and clindamycin were more than 93% of all strains. All pneumococcal serotypes were highly resistant to clarithromycin, azithromycin, erythromycin, cotrimoxazole, and clindamycin. Conclusion: Our findings showed high antibiotic resistance rates of the strains causing pneumococcal pneumonia, mostly macrolide resistance, among unvaccinated children.

Development and Validation of a Prediction Model for Chronic Post-Surgical Pain After Thoracic Surgery in Elderly Patients: A Retrospective Cohort Study.

Purpose: Chronic post-surgical pain (CPSP) is one of the adverse outcomes after surgery, especially in thoracotomy. However, the prevalence of CPSP in elderly adults (≥65 years), is still limited. Therefore, the present study was undertaken to establish and validate the prediction model of CPSP in those patients after thoracic surgery, including thoracotomy and video-assisted thoracoscopic surgery. Patients and Methods: This retrospective, observational single-center cohort study was conducted in Nanfang Hospital, Southern Medical University, which randomly and consecutively collected 577 elderly patients who underwent thoracic surgery between January 1, 2017, and December 31, 2020. According to the Akaike information criterion, the prediction model was built based on all the data and was validated by calibration with 500 bootstrap samples. Results: The mean age of participants was 69.09±3.80 years old, and 63.1% were male. The prevalence of CPSP was 26.9%. Age more than 75 years, BMI, blood loss, longer length of hospital stays, and higher pre-operative neutrophil count were associated with CPSP. Except for these factors, we incorporated history of drinking to build up the prediction model. The areas under the curve (AUCs) of the prediction models were 0.66 (95% CI, 0.61-0.71) and 0.64 (95% CI, 0.59-0.69) in the observational and validation cohorts, respectively. And the calibration curve of the predictive model showed a good fit between the predicted risk of CPSP and observed outcomes in elderly patients. Conclusion: The present developed model may help clinicians to find high-risk elderly patients with CPSP after thoracic surgery and take corresponding measures in advance to reduce the incidence of CPSP and improve their life quality.

Reduced nucleus accumbens functional connectivity in reward network and default mode network in patients with recurrent major depressive disorder.

The nucleus accumbens (NAc) is considered a hub of reward processing and a growing body of evidence has suggested its crucial role in the pathophysiology of major depressive disorder (MDD). However, inconsistent results have been reported by studies on reward network-focused resting-state functional MRI (rs-fMRI). In this study, we examined functional alterations of the NAc-based reward circuits in patients with MDD via meta- and mega-analysis. First, we performed a coordinated-based meta-analysis with a new SDM-PSI method for all up-to-date rs-fMRI studies that focused on the reward circuits of patients with MDD. Then, we tested the meta-analysis results in the REST-meta-MDD database which provided anonymous rs-fMRI data from 186 recurrent MDDs and 465 healthy controls. Decreased functional connectivity (FC) within the reward system in patients with recurrent MDD was the most robust finding in this study. We also found disrupted NAc FCs in the DMN in patients with recurrent MDD compared with healthy controls. Specifically, the combination of disrupted NAc FCs within the reward network could discriminate patients with recurrent MDD from healthy controls with an optimal accuracy of 74.7%. This study confirmed the critical role of decreased FC in the reward network in the neuropathology of MDD. Disrupted inter-network connectivity between the reward network and DMN may also have contributed to the neural mechanisms of MDD. These abnormalities have potential to serve as brain-based biomarkers for individual diagnosis to differentiate patients with recurrent MDD from healthy controls.