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Developmental exposure to environmental chemicals (ECs) perturbs establishment and maintenance of the ovarian reserve across the reproductive lifetime, leading to premature follicle depletion and ovarian aging. Considering humans are exposed to a complex mixture of ECs, real-life models assessing their cumulative impact on the ovarian reserve are needed. Biosolids is a source of real-life mixture of ECs. While earlier studies demonstrated that grazing pregnant sheep on biosolids-treated pastures (BTP) did not influence establishment of the ovarian reserve in fetal life, its impact on subsequent depletion of ovarian reserve during reproductive life of offspring is unknown. We hypothesized that developmental exposure to biosolids accelerates depletion of ovarian reserve. Ovaries were collected from F1 juveniles (9.5 weeks) and adults (2.5 years) born to F0 ewes grazed on control inorganic fertilizer pastures or BTP from before conception and throughout gestation. The impact on follicular density, activation rate, and Anti-Müllerian hormone (AMH; mediator of activation) expression by immunohistochemistry was determined. Activation rate was increased in F1 BTP juveniles with a corresponding reduction in primordial follicle density. In contrast, activation rate and ovarian reserve were similar between control and F1 BTP adults. The density of AMH-positive antral follicles was lower in BTP juveniles, whereas AMH expression tended to be higher in antral follicles of BTP adults, consistent with the changes in the ovarian reserve. These findings of detrimental effects of developmental exposure to biosolids during juvenile life that normalizes in adults is supportive of a shift in activation rate likely related to peripubertal hormonal changes., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Aim: Early predictors of morbidity after pancreaticoduodenectomy (PD) can guide tailored postoperative management. Preoperative inflammatory data in patients who underwent PD remained poorly studied in investigating the clinical significance of predicting postpancreatectomy acute pancreatitis (PPAP) and PPAP-associated postoperative pancreatic fistula (POPF)., Methods: The clinical data of 467 patients receiving PD between January 2020 and December 2022 were retrospectively reviewed. Preoperative inflammatory data were stratified according to PPAP, and independent risk factors were analyzed. Multivariate logistic regression and subgroup analyses were conducted to compare risk factors of PPAP-associated POPF and non-PPAP-associated POPF., Results: PPAP occurred in 17.6% of patients. The incidence of other complications increased following PPAP. Among the preoperative inflammatory factors, only interleukin-6 (IL-6) increased (P < 0.001), leading to a higher incidence of PPAP and POPF (P < 0.001; P = 0.002). The area under the curve of IL-6 in predicting PPAP was 0.71 (0.65-0.77; P < 0.001). Abnormal preoperative IL-6 levels (odds ratio [OR]: 5.01; P < 0.001), soft pancreatic texture (OR: 2.15; P = 0.007), and pathology (OR: 2.03; P = 0.012) were independent risk factors for PPAP. The subgroup analysis showed that increased IL-6 (OR: 1.01; P = 0.006) and soft pancreatic texture (OR: 2.05; P = 0.033) resulted in a higher risk of PPAP-associated POPF, while increased IL-8 (OR: 1.01; P = 0.007), older age (OR: 1.05; P = 0.008), and higher body mass index (OR: 1.12; P = 0.021) correlated with non-PPAP-associated POPF., Conclusion: PPAP is common after PD; a high preoperative IL-6 level can predict its occurrence, in addition to associated POPF, which could be due to a preoperative proinflammatory status., (© 2024 The Author(s). Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Polysaccharides and various secondary metabolites are the major bioactive ingredients in Bletilla striata tubers and their biosynthesis and accumulation are influenced by light intensity. However, the mechanisms underlying shading effects remain largely unknown. In the present study, we used a combined analysis of the physiology, metabolome, and transcriptome to investigate the physiological activities and bioactive component accumulation of B. striata under different shading treatments (S0, S50, S70, and S90). The dry weight of shoots and tubers, net photosynthetic rate, and polysaccharide content were highest in S50 and lowest in S90. The content of precursors (sucrose, Glucose-6P, and Mannose-6P) for polysaccharide synthesis significantly increased in S50. However, the expression levels of genes involved in starch biosynthesis decreased in S50. Several structural genes involved in secondary metabolism, including cinnamic acid 4-hydroxylase (C4H), chalcone synthase (CHS), and 1-Deoxy-D-xylulose-5-phosphate synthase (DXS), showed decreased expression in S50. However, the shading effect on the biosynthesis of secondary metabolites (phenylpropanoids, flavonoids, and terpenoids) was inconsistent. Our study provides the molecular mechanisms underlying the effects of shading on the biosynthesis of polysaccharides and secondary metabolites in B. striata and offers a theoretical basis for the artificial cultivation and industrial production of bioactive ingredients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors declare no conflict interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Breast cancer brain metastasis (BCBM) is associated with poor survival outcomes and reduced quality of life. The Graded Prognostic Assessment (GPA) score model serves as a well-established tool for predicting the prognosis of BCBM. Notably, the presence of extracranial metastasis (ECM) is considered as a significant prognostic factor in the breast GPA model. This study aims to further refine other features of ECM to enhance the prognostic prediction for BCBM., Methods: This study included all inpatients diagnosed with BCBM at the Cancer Hospital, Chinese Academy of Medical Sciences, from January 2010 to July 2021. Baseline characteristics of patients were compared based on features of ECM, including the presence, number, location, and control status of metastases. Overall survival (OS) were compared using the Kaplan-Meier method with log-rank tests. Cox regression analyses were conducted to identify significant prognostic factors. The aforementioned ECM features were incorporated into the original Breast-GPA model to enhance its prognostic accuracy. The concordance index (C-index) and restricted mean survival time (RMST) were utilized to evaluate and compare the predictive accuracy of the updated and original survival models., Results: 284 patients with BCBM were included in the study. Kaplan-Meier survival curves suggested that patients without ECM when diagnosed with BCBM showed better survival (p = 0.007). In the subgroups with ECM, more than 3 organs involved, both bone and visceral metastasis and progressive ECM portended dismal OS (p = 0.003, 0.001 and <0.001). Multivariate analysis demonstrated that molecular subtype, presence of ECM, and number of brain metastasis significantly influenced OS after BCBM. By modifying the current GPA model to include more precise characteristics of ECM, the predictive accuracy was further enhanced as indicated by the C-index and RMST curve., Conclusions: More ECM sites, both bone and visceral invasion and uncontrolled ECM were dismal prognostic factors for survival outcomes of BCBM patients. A new Breast-GPA model with better predictive effect was constructed., (© 2024. The Author(s).)

Background: Dysregulation of Rho-associated coiled coil-containing protein kinases (ROCKs) is involved in the metastasis and progression of various malignant tumors. However, how one of the isomers, ROCK1, regulates glycolysis in tumor cells is incompletely understood. Here, we attempted to elucidate how ROCK1 influences pancreatic cancer (PC) progression by regulating glycolytic activity., Methods: The biological function of ROCK1 was analyzed in vitro by establishing a silenced cell model. Coimmunoprecipitation confirmed the direct binding between ROCK1 and c-MYC, and a luciferase reporter assay revealed the binding of c-MYC to the promoter of the PFKFB3 gene. These results were verified in animal experiments., Results: ROCK1 was highly expressed in PC tissues and enriched in the cytoplasm, and its high expression was associated with a poor prognosis. Silencing ROCK1 inhibited the proliferation and migration of PC cells and promoted their apoptosis. Mechanistically, ROCK1 directly interacted with c-MYC, promoted its phosphorylation (Ser 62) and suppressed its degradation, thereby increasing the transcription of the key glycolysis regulatory factor PFKFB3, enhancing glycolytic activity and promoting PC growth. Silencing ROCK1 increased gemcitabine (GEM) sensitivity in vivo and in vitro., Conclusions: ROCK1 promotes glycolytic activity in PC cells and promotes PC tumor growth through the c-MYC/PFKFB3 signaling pathway. ROCK1 knockdown can inhibit PC tumor growth in vivo and increase the GEM sensitivity of PC tumors, providing a crucial clinical therapeutic strategy for PC., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Background: Parkinson's disease (PD) is characterized by loss of selectively vulnerable neurons within the basal ganglia circuit and progressive atrophy in subcortical and cortical regions. However, the impact of neurodegenerative pathology on the topological organization of cortical morphological networks has not been explored. The aims of this study were to investigate altered network patterns of covariance in cortical thickness and complexity, and to evaluate how morphological network integrity in PD is related to motor impairment., Methods: Individual morphological networks were constructed for 50 PD patients and 46 healthy controls (HCs) by estimating interregional similarity distributions in surface-based indices. We performed graph theoretical analysis and network-based statistics to detect PD-related alterations and further examined the correlation of network metrics with clinical scores. Furthermore, support vector regression based on topological characteristics was applied to predict the severity of motor impairment in PD., Results: Compared with HCs, PD patients showed lower local efficiency (p = 0.004), normalized characteristic path length (p = 0.022), and clustering coefficient (p = 0.005) for gyrification index-based morphological brain networks. Nodal topological abnormalities were mainly in the frontal, parietal and temporal regions, and impaired morphological connectivity was involved in the sensorimotor and default mode networks. The support vector regression model using network-based features allowed prediction of motor symptom severity with a correlation coefficient of 0.606., Conclusions: This study identified a disrupted topological organization of cortical morphological networks that could substantially advance our understanding of the network degeneration mechanism of PD and might offer indicators for monitoring disease progression., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Blood exchange therapy, specifically Whole blood exchange (WBE), is increasingly being utilized in clinical settings to effectively treat a range of diseases. Consequently, there is an urgent requirement to establish convenient and clinically applicable animal models that can facilitate the exploration of blood exchange therapy mechanisms. Our study conducted continuous WBE in rats through femoral and tail vein catheterization using dual-directional syringe pumps. To demonstrate the applicability of continuous WBE, drug-induced hemolytic anemia (DIHA) was induced through phenylhydrazine hydrochloride (PHZ) injection. Notability, the rats of DIHA + WBE group all survived and recovered within the subsequent period. After the implementation of continuous WBE therapy day (Day 1), the DIHA + WBE group exhibited a statistically significant increase in red blood cells (RBC) (P = 0.0343) and hemoglobin (HGB) levels (P = 0.0090) compared to DIHA group. The rats in the DIHA + WBE group exhibited a faster recovery rate compared to the DIHA group, indicating the successful establishment of a continuous blood exchange protocol. This experimental approach demonstrates not just promising efficacy in the treatment of DIHA and offers a valuable tool for investigating the underlying mechanisms of blood exchange. Furthermore, it has a great potential to the advancement of biomedical research such as drug delivery exploration., (© 2024. The Author(s).)

Background: The status of the hypothalamic-pituitary-gonadal (HPG) axis is important for assessing the onset of physiological or pathological puberty. The reference standard gonadotropin-releasing hormone (GnRH) stimulation test requires hospital admission and repeated blood samples. A simple noninvasive method would be beneficial., Objectives: To explore a noninvasive method for evaluating HPG axis activation in children using an MRI radiomics model., Study Type: Retrospective., Population: Two hundred thirty-nine children (83 male; 3.6-14.6 years) with hypophysial MRI and GnRH stimulation tests, randomly divided a training set (168 children) and a test set (71 children)., Field Strength/sequence: 3.0 T, 3D isotropic fast spin echo (CUBE) T1-weighted imaging (T 1 WI) sequences., Assessment: Radiomics features were extracted from sagittal 3D CUBE T 1 WI, and imaging signatures were generated using the least absolute shrinkage and selection operator (LASSO) with 10-fold cross-validation. Diagnostic performance for differential diagnosis of HPG status was compared between a radiomics model and MRI features (adenohypophyseal height [aPH] and volume [aPV])., Statistical Tests: Receiver operating characteristic (ROC) and decision curve analysis (DCA). A P value <0.05 was considered statistically significant., Results: Eight hundred fifty-one radiomics features were extracted and reduced to 10 by the LASSO method in the training cohort. The radiomics model based on CUBE T1WI showed good performance in assessment of HPG axis activation with an area under the ROC curve (AUC) of 0.81 (95% CI: 0.71, 0.91) in the test set. The AUC of the radiomics model was significantly higher than that of aPH (0.81 vs. 0.65) but there was no significant difference compared to aPV (0.81 vs. 0.78, P = 0.58). In DCA analysis, the radiomics signature showed higher net benefit over the aPV and aPH models., Data Conclusions: The MRI radiomics model has potential to assess HPG axis activation status noninvasively, potentially providing valuable information in the diagnosis of patients with pathological puberty onset., Evidence Level: 4 TECHNICAL EFFICACY: Stage 2., (© 2023 International Society for Magnetic Resonance in Medicine.)

Given the limitations of the response rate and efficacy of immune checkpoint inhibitors (ICIs) in clinical applications, exploring new therapeutic strategies for cancer immunotherapy is necessary. We found that 5-(3,4,5-trimethoxybenzoyl)-4-methyl-2-(p-tolyl)imidazole (BZML), a microtubule-targeting agent, exhibited potent anticancer activity by inducing mitotic catastrophe in A549/Taxol and L929 cells. Nuclear membrane disruption and nuclease reduction provided favorable conditions for cGAS-STING pathway activation in cells with mitotic catastrophe. Similar results were obtained in paclitaxel-, docetaxel- and doxorubicin-induced mitotic catastrophe in various cancer cells. Notably, the surface localization of CALR and MHC-I and the release of HMGB1 were also significantly increased in cells with mitotic catastrophe, but not in apoptotic cells, suggesting that mitotic catastrophe is an immunogenic cell death. Furthermore, activated CD8 + T cells enhanced the anticancer effects originating from mitotic catastrophe induced by BZML. Inhibiting the cGAS-STING pathway failed to affect BZML-induced mitotic catastrophe but could inhibit mitotic catastrophe-mediated anticancer immune effects. Interestingly, the expression of p-TBK1 first increased and then declined; however, autophagy inhibition reversed the decrease in p-TBK1 expression and enhanced mitotic catastrophe-mediated anticancer immune effects. Collectively, the inhibition of autophagy can potentiate mitotic catastrophe-mediated anticancer immune effects by regulating the cGAS-STING pathway, which explains why the anticancer immune effects induced by chemotherapeutics have not fully exerted their therapeutic efficacy in some patients and opens a new area of research in cancer immunotherapy., Competing Interests: Declaration of competing interest The authors declare that there are no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

We aimed to explore the association between FFP transfusion and outcomes of DC patients with significant coagulopathy. A total of 693 DC patients with significant coagulopathy were analyzed with 233 patients per group after propensity score matching (PSM). Patients who received FFP transfusion were matched with those receiving conventional therapy via PSM. Regression analysis showed FFP transfusion had no benefit in 30-day (HR: 1.08, 95% CI 0.83-1.4), 90-day (HR: 1.03, 95% CI 0.80-1.31) and in-hospital(HR: 1.30, 95% CI 0.90-1.89) mortality, associated with increased risk of liver failure (OR: 3.00, 95% CI 1.78-5.07), kidney failure (OR: 1.90, 95% CI 1.13-3.18), coagulation failure (OR: 2.55, 95% CI 1.52-4.27), respiratory failure (OR: 1.76, 95% CI 1.15-2.69), and circulatory failure (OR: 2.15, 95% CI 1.27-3.64), and even associated with prolonged the LOS ICU (β: 2.61, 95% CI 1.59-3.62) and LOS hospital (β: 6.59, 95% CI 2.62-10.57). In sensitivity analysis, multivariate analysis (HR: 1.09, 95%CI 0.86, 1.38), IPTW (HR: 1.11, 95%CI 0.95-1.29) and CAPS (HR: 1.09, 95% CI 0.86-1.38) showed FFP transfusion had no beneficial effect on the 30-day mortality. Smooth curve fitting demonstrated the risk of liver failure, kidney failure and circulatory failure increased by 3%, 2% and 2% respectively, for each 1 ml/kg increase in FFP transfusion. We found there was no significant difference of CLIF-SOFA and MELD score between the two group on day 0, 3, 7, 14. Compared with the conventional group, INR, APTT, and TBIL in the FFP transfusion group significantly increased, while PaO2/FiO2 significantly decreased within 14 days. In conclusion, FFP transfusion had no beneficial effect on the 30-day, 90-day, in-hospital mortality, was associated with prolonged the LOS ICU and LOS hospital, and the increased risk of liver failure, kidney failure, coagulation failure, respiratory failure and circulatory failure events. However, large, multi-center, randomized controlled trials, prospective cohort studies and external validation are still needed to verify the efficacy of FFP transfusion in the future., (© 2024. The Author(s).)

The endocrinology regulating ovulation of the desired number of oocytes in the ovarian cycle is well described, particularly in mono-ovulatory species. Less is known about the characteristics that make one follicle suitable for ovulation while most other follicles die by atresia. Bromodeoxyuridine (BrdU) injection was used to characterize granulosa cell proliferation rates in developing ovarian follicles in the estrous cycle of mice. This methodology allowed identification of follicle diameters of secondary (80-130 μm), follicle-stimulating hormone (FSH)-sensitive (130-170 μm), FSH-dependent (170-350 μm), and preovulatory (>350 μm) follicles. Few preovulatory-sized follicles were present in the ovaries of mice at estrus, the beginning of the cycle. Progressive increases were seen at metestrus and diestrus, when full accumulation of the preovulatory cohort (~10 follicles) occurred. BrdU pulse-chase studies determined granulosa cell proliferation rates in the 24-48 h before the follicle reached the preovulatory stage. This showed that slow-growing follicles were not able to survive to the preovulatory stage. Mathematical modeling of follicle growth rates determined that the largest follicles at the beginning of the cycle had the greatest chance of becoming preovulatory. However, smaller follicles could enter the preovulatory follicle pool if low numbers of large antral follicles were present at the beginning of the cycle. In this instance, rapidly growing follicles had a clear selection advantage. The developing follicle pool displays heterogeneity in granulosa cell proliferation rates, even among follicles at the same stage of development. This parameter appears to influence whether a follicle can ovulate or become atretic., (© The Author(s) 2023. Published by Oxford University Press.)

Organic-rich shale oil reservoirs with low-medium maturity have attracted increasing attention because of their enormous oil and gas potential. In this work, a series of experiments on pyrolysis of the particle and core samples were carried out in a self-made supercritical water pyrolysis apparatus to evaluate the feasibility and benefits of supercritical water in promoting the transformation efficiency and oil yield of the low-medium maturity organic-rich shale. Core samples had a mass loss of 8.4% under supercritical water pyrolysis, and many microcracks were generated, which increased the pyrolysis efficiency substantially. The oil yield of shale pyrolysis could reach 72.40% under supercritical water conditions at 23 MPa and 400 °C, which was 53.02% higher than that under anhydrous conditions. In supercritical water conditions, oxygen-containing compounds are less abundant than in anhydrous conditions, suggesting that supercritical water can inhibit their formation. Also, supercritical water conditions produced higher yields for light fraction, medium fraction, and heavy fraction shale oil than those under anhydrous conditions. These results indicate that supercritical water pyrolysis is feasible and has excellent advantages for low-medium maturity organic-rich shale., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Background and Aim: Several indicators are recognized in the development of clinically relevant postoperative pancreatic fistula (CR-POPF) after pancreaticoduodenectomy (PD). However, drain fluid volume (DFV) remains poorly studied. We aimed to discover the predictive effects of DFV and guide clinical management., Methods: We retrospectively reviewed the clinical data of patients that received PD between January 2015 and December 2019 in a high-volume center. DFV was analyzed as a potential risk factor and postoperative short-term outcomes as well as drain removal time were compared stratified by different DFV levels. Receiver operating characteristic curves and area under curves (AUC) were compared for DFV alone and DFV combined with drain fluid amylase (DFA). Subgroup analysis of DFV stratified by DFA evaluated the predictability of CR-POPF., Results: CR-POPF occurred in 19.7% of 841 patients. Hypertension, postoperative day 3 (POD3) DFA ≥ 300 U/L, and POD3 DFV ≥ 30 mL were independent risk factors, while pancreatic main duct diameter ≥ 3 mm was a protective factor. POD3 DFV ≥ 30 mL increased the overall occurrences of CR-POPF and major complications (P = 0.017; P = 0.029). POD3 DFV alone presented a low predictive value (AUC 0.602), while POD3 DFV combined with DFA had a high predictive value (AUC 0.759) for CR-POPF. Subgroup analysis showed that the combination of POD3 DFV ≥ 30 mL and DFA ≥ 300 U/L led to higher incidences of CR-POPF (P = 0.003)., Conclusion: CR-POPF is common after PD, and high DFV combined with DFA may predict its occurrence and facilitate appropriate management., (© 2023 The Authors. Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Although the molecular features of pancreatic ductal adenocarcinoma (PDAC) have been well described, the impact of detailed gene mutation subtypes on disease progression remained unclear. This study aimed to evaluate the impact of different TP53 mutation subtypes on clinical characteristics and outcomes of patients with PDAC., Methods: We included 639 patients treated with PDAC in Ruijin Hospital affiliated to Shanghai Jiaotong University School of Medicine between Jan 2019 and Jun 2021. The genomic alterations of PDAC were analyzed, and the association of TP53 mutation subtypes and other core gene pathway alterations with patients' clinical characteristics were evaluated by Chi-squared test, Kaplan-Meier method and Cox regression model., Results: TP53 missense mutation was significantly associated with poor differentiation in KRAS mut PDAC (50.7% vs. 36.1%, P = 0.001). In small-sized (≤ 2 cm) KRAS mut tumors, significantly higher LNs involvement (54.8% vs. 23.5%, P = 0.010) and distal metastic rate (20.5% vs. 2.9%, P = 0.030) were observed in those with TP53 missense mutation instead of truncating mutation. Compared with TP53 truncating mutation, missense mutation was significantly associated with reduced DFS (6.6 [5.6-7.6] vs. 9.2 [5.2-13.3] months, HR 0.368 [0.200-0.677], P = 0.005) and OS (9.6 [8.0-11.1] vs. 18.3 [6.7-30.0] months, HR 0.457 [0.248-0.842], P = 0.012) in patients who failed to receive chemotherapy, while higher OS (24.2 [20.8-27.7] vs. 23.8 [19.0-28.5] months, HR 1.461 [1.005-2.124], P = 0.047) was observed in TP53 missense cases after chemotherapy., Conclusions: TP53 missense mutation was associated with poor tumor differentiation, and revealed gain-of-function properties in small-sized KRAS transformed PDAC. Nonetheless, it was not associated with insensitivity to chemotherapy, highlighting the neoadjuvant therapy before surgery as the potential optimized strategy for the treatment of a subset of patients., (© 2023. The Author(s).)

There are conflicting estimates of the duration of mouse primary follicle development. An accurate determination is needed for studies examining preantral follicle survival and mathematical modeling of folliculogenesis. Primary follicle granulosa cell proliferation rates are low and variable, which may explain the variation in duration estimates. In the present study, female C57Bl6/J mice were exposed to bromodeoxyuridine for 48 hours, to label the proliferating granulosa cells in a large proportion of primary follicles. The bromodeoxyuridine-containing water was then withdrawn and replaced with drug-free water and the mice were euthanized at 0, 1, 3, 6, 10, or 13 days post-bromodeoxyuridine withdrawal. Granulosa cells were bromodeoxyuridine labeled in 48% of primary follicles at day 0, but this decreased to 5% over the 13-day period, as the labeled primary follicles progressed to the secondary follicle stage. Curve-fitting estimated that the last of the bromodeoxyuridine-labeled primary follicles would progress to the secondary stage by 13.7 days. Mathematical models that assumed constant rates of primary follicle proliferation were fitted to the data, but the observed pattern of bromodeoxyuridine-labeled primary follicle disappearance could not be replicated. The level of immunoreactivity for bromodeoxyuridine and proliferating-cell nuclear antigen in primary follicles revealed follicles with no granulosa cell proliferation during the 48-h bromodeoxyuridine-exposure period had resumed proliferation 1 or 3 days later. Therefore, primary follicle granulosa cells proliferate after follicle activation, but proliferation rates gradually increase as the follicle develops. Prior estimates of primary follicle duration are inaccurate due to the assumption that follicles develop at a constant rate., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for the Study of Reproduction.)

Background: Major depressive disorder (MDD) and anxiety were recognized in treating pancreatic ductal adenocarcinoma (PDAC). This longitudinal study identified risk factors for MDD and anxiety and established associations with patients' quality of life (QoL) and survival outcomes., Materials and Methods: We used PHQ-9 and GAD-7 questionnaires to diagnose MDD and anxiety in PDAC patients between October 2021 and March 2022 at a Chinese center. Characteristics and clinical data were analyzed for risk factors and EORTC QLQ-C30 questionnaire was administered for QoL before the first chemotherapy. Furthermore, chemotherapy compliance and 1-year survival were compared during follow-up., Results: MDD and anxiety occurred in 51.8% and 44.7% of 114 patients over the half-year period. Employment at work (odds ratio [OR]: 5.514, p = 0.001; OR: 3.420, p = 0.011) was an independent risk factor, while radical surgery (OR: 0.342, p = 0.034; OR: 0.238, p = 0.004) was a protective factor. Several aspects of decreased QoL were discovered after their onsets. Higher incidences of physical disorders (p = 0.004; p < 0.001), mental disorders (p = 0.001; p < 0.001), anti-therapy emotions (p = 0.002; 0.001), and chemotherapy suspensions (p = 0.001; p = 0.043) were observed. Furthermore, the 1-year mortalities for all patients and those receiving radical surgeries were correlated with MDD (p = 0.007; 0.036) and anxiety (p = 0.010; 0.031)., Conclusions: MDD and anxiety are common in PDAC patients and correlated with poor QoL and survivals. Therefore, appropriate mental management is required in future., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: The hepatobiliary-specific phase can help in early detection of changes in lesion tissue density, internal structure, and microcirculatory perfusion at the microscopic level and has important clinical value in hepatocellular carcinoma (HCC). Therefore, this study aimed to construct a preoperative nomogram for predicting the positive expression of glypican-3 (GPC3) based on gadoxetic acid-enhanced (Gd-EOB-DTPA) MRI hepatobiliary phase (HBP) radiomics, imaging and clinical feature., Methods: We retrospectively included 137 patients with HCC who underwent Gd-EOB-DTPA-enhanced MRI and subsequent liver resection or puncture biopsy at our hospital from January 2017 to December 2021 as training cohort. Subsequently collected from January 2022 to June 2023 as a validation cohort of 49 patients, Radiomic features were extracted from the entire tumor region during the HBP using 3D Slicer software and screened using a t-test and least absolute shrinkage selection operator algorithm (LASSO). Then, these features were used to construct a radiomics score (Radscore) for each patient, which was combined with clinical factors and imaging features of the HBP to construct a logistic regression model and subsequent nomogram model. The clinicoradiologic, radiomics and nomogram models performance was assessed by the area under the curve (AUC), calibration, and decision curve analysis (DCA). In the validation cohort,the nomogram performance was assessed by the area under the curve (AUC)., Results: In the training cohort, a total of 1688 radiomics features were extracted from each patient. Next, radiomics with ICCs<0.75 were excluded, 1587 features were judged as stable using intra- and inter-class correlation coefficients (ICCs), 26 features were subsequently screened using the t-test, and 11 radiomics features were finally screened using LASSO. The nomogram combining Radscore, age, serum alpha-fetoprotein (AFP) >400ng/mL, and non-smooth tumor margin (AUC=0.888, sensitivity 77.7%, specificity 91.2%) was superior to the radiomics (AUC=0.822, sensitivity 81.6%, specificity 70.6%) and clinicoradiologic (AUC=0.746, sensitivity 76.7%, specificity 64.7%) models, with good consistency in calibration curves. DCA also showed that the nomogram had the highest net clinical benefit for predicting GPC3 expression.In the validation cohort, the ROC curve results showed predicted GPC3-positive expression nomogram model AUC, sensitivity, and specificity of 0.800, 58.5%, and 100.0%, respectively., Conclusion: HBP radiomics features are closely associated with GPC3-positive expression, and combined clinicoradiologic factors and radiomics features nomogram may provide an effective way to non-invasively and individually screen patients with GPC3-positive HCC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, Wu, Zhou, Yu, Shi, Wang, Gao, Lv and Zhu.)

In recent years, environmental pollution and public health incidents caused by the recycling of spent lead-acid batteries (LABs) has becoming more frequent, posing potential risk to both the ecological environment and human health. Accurately assessing the environmental risk associated with the recycling of spent LABs is a prerequisite for achieving pollution control. In this study, a spent LABs recycling factory in Chongqing was investigated through on-site investigation, sample analysis. Exposure assessment and health risk assessment were also conducted. The results showed that: firstly, Pb and As concentrations exceeding the standard limit values were found in the environmental air and vegetables near the spent LABs recycling factory. Secondly, exposure assessment results showed that total average daily exposure to hazardous substances for children (3.46 × 10 -2  mg/kg) is higher than for adults (4.80 × 10 -2  mg/kg). The main exposure pathways for Pb, Cr, Ni, Cu, Zn, and Hg are ingestion of vegetables, while those for Cd, As, and Sb are through inhalation. Thirdly, health risk assessment results indicate that environmental exposure poses unacceptable non-carcinogenic and carcinogenic risk to both adults and children near the spent LABs recycling factory, with children facing higher risk than adults. Pb and As are the main contributors to non-carcinogenic risk, and Ni and As are the main contributors to unacceptable carcinogenic risk. In particular, As, has a greater contribution to total carcinogenic risk index through inhalation than vegetable ingestion. Overall, vegetable ingestion and inhalation are the main exposure pathways for non-carcinogenic and carcinogenic risk. Consequently, future risk assessment should focus on the impact of hazardous substances on children, as well as the health risk associated with ingestion of vegetables and inhalation. Our findings will provide basic information for proposing measures of environmental risk prevention during the recycling of spent LABs, for example, controlling of As in exhaust gas emissions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Mitotic catastrophe is distinct from other cell death modes due to unique nuclear alterations characterized as multi and/or micronucleation. Mitotic catastrophe is a common and virtually unavoidable consequence during cancer therapy. However, a comprehensive understanding of mitotic catastrophe remains lacking. Herein, we summarize the anticancer drugs that induce mitotic catastrophe, including microtubule-targeting agents, spindle assembly checkpoint kinase inhibitors, DNA damage agents and DNA damage response inhibitors. Based on the relationships between mitotic catastrophe and other cell death modes, we thoroughly evaluated the roles played by mitotic catastrophe in cancer treatment as well as its advantages and disadvantages. Some strategies for overcoming its shortcomings while fully utilizing its advantages are summarized and proposed in this review. We also review how mitotic catastrophe regulates cancer immunotherapy. These summarized findings suggest that the induction of mitotic catastrophe can serve as a promising new therapeutic approach for overcoming apoptosis resistance and strengthening cancer immunotherapy., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Serum anti-Müllerian hormone (AMH) is a biomarker for predicting antral follicle counts but there is no clear consensus on whether AMH is indicative of primordial follicle counts in humans. Mice were used as a model species in this study to obtain accurate follicle counts across the reproductive phase of life. Serum AMH was measured in 62 female C57Bl6/J mice aged 25 to 401 days. Primordial and primary follicles were determined by stereological counts and all secondary and antral follicles were counted in serial histological sections. Serum AMH was most strongly correlated with small- and medium-sized antral follicles. Immunohistochemistry and stepwise multiple regression confirmed that these follicle development stages are the key determinants of serum AMH, with little contribution from other stages. Primordial follicles were not found to have strong correlations with serum AMH or antral follicle counts, particularly in younger females, but the strength of the association appeared to increase with age. This result is likely attributed to high interindividual variation in primordial follicle activation and preantral follicle survival rates. Recent large studies in human populations have shown similar results but the primary limitation of these studies was that primordial follicle counts were determined from ovarian cortical biopsies, where regional variation in follicle distribution may affect the quality of the data. In the present study, whole ovaries were surveyed, eliminating this limitation. The findings indicate that primordial follicle counts are not closely related with either serum AMH or antral follicle counts in females in the early phase of the reproductive phase of life., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Anxiety is characterized by altered brain networks. Directional information flows among dynamic brain networks concerning neuropathogenesis of anxiety have not yet been investigated. The role of directional influences between networks in gene-environment effects on anxiety remains to be further elucidated. In a large community sample, this resting-state functional MRI study estimated dynamic effective connectivity among large-scale brain networks based on a sliding-window approach and Granger causality analysis, providing dynamic and directional information for signal transmission in networks. We first explored altered effective connectivity among networks related to anxiety in distinct connectivity states. Due to the potential gene-environment effects on brain and anxiety, we further performed mediation and moderated mediation analyses to investigate the role of altered effective connectivity networks in relationships between polygenic risk scores, childhood trauma, and anxiety. State and trait anxiety scores showed correlations with altered effective connectivity among extensive networks in distinct connectivity states (p < .05, uncorrected). Only in a more frequent and strongly connected state, there were significant correlations between altered effective connectivity networks and trait anxiety (P FDR  <0.05). Furthermore, mediation and moderated mediation analyses showed that the effective connectivity networks played a mediating role in the effects of childhood trauma and polygenic risk on trait anxiety. State-dependent effective connectivity changes among brain networks were significantly related to trait anxiety, and mediated gene-environment effects on trait anxiety. Our work sheds novel light on the neurobiological mechanisms underlying anxiety, and provides new insights into early objective diagnosis and intervention evaluation., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Inter-tissue communication (ITC) is critical for maintaining the physiological functions of multiple tissues and is closely related to the onset and development of various complex diseases. Nevertheless, there is no well-organized data resource for known ITC molecules with explicit ITC routes from source tissues to target tissues. To address this issue, in this work, we manually reviewed nearly 190,000 publications and identified 1408 experimentally supported ITC entries in which the ITC molecules, their communication routes, and their functional annotations were included. To facilitate our work, these curated ITC entries were incorporated into a user-friendly database named IntiCom-DB. This database also enables visualization of the expression abundances of ITC proteins and their interaction partners. Finally, bioinformatics analyses on these data revealed common biological characteristics of the ITC molecules. For example, tissue specificity scores of ITC molecules at the protein level are often higher than those at the mRNA level in the target tissues. Moreover, the ITC molecules and their interaction partners are more abundant in both the source tissues and the target tissues. IntiCom-DB is freely available as an online database. As the first comprehensive database of ITC molecules with explicit ITC routes to the best of our knowledge, we hope that IntiCom-DB will benefit future ITC-related studies.

Background: While an association between postoperative acute kidney injury (AKI) and adverse events exists, the incidence and impact of postoperative AKI after pancreaticoduodenectomy for pancreatic ductal adenocarcinoma remain unclear. This study aimed to diagnose AKI and investigate the risk factors for and prognostic value of postoperative AKI., Methods: Clinical characteristics of patients who underwent pancreaticoduodenectomy between 2013 and 2020 at a high-volume centre were collected retrospectively. The Kidney Disease Improving Global Outcomes criteria were used to diagnose AKI. A 1:2 propensity score matching (PSM) was used to minimise bias between the AKI and non-AKI groups. Short-term surgical and long-term survival outcomes were compared between groups. Multivariate logistic regression analysis assessed the independent risk factors for AKI development, major complications, and 30-day mortality., Results: Postoperative AKI occurred in 10.7% of 1312 patients. Total bilirubin level > 250 μmol/L (odds ratio [OR]: 3.24; p < 0.001), estimated glomerular filtration rate < 60 ml/min/1.73 m 2 (OR: 2.30; p = 0.048), and intraoperative estimated blood loss >1000 ml (OR: 2.96; p = 0.001) were independent risk factors for postoperative AKI. After PSM, higher incidences of major complications (p < 0.001) and 30-day mortality (p < 0.001) were observed in the AKI group than in the non-AKI group. There was no difference in long-term overall survival outcomes between both groups (p = 0.535). AKI was an independent predictor of major complications (OR: 3.06; p < 0.001) and 30-day mortality (OR: 2.87; p = 0.034)., Conclusions: Postoperative AKI is common after pancreaticoduodenectomy for pancreatic ductal adenocarcinoma and has a predictive effect on major complications and 30-day mortality. Therefore, prevention and proper management of postoperative AKI are required in clinical practice., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: The short-term outcome and long-term survival of pancreaticoduodenectomy with additional para-aortic dissection (PAD) for patients with resectable pancreatic cancer remain obscure., Patients and Methods: Consecutive patients who underwent radical pancreaticoduodenectomy for resectable pancreatic cancer in a single high-volume center during a 7-year period were included retrospectively. Both short- and long-term effects of PAD were compared between the PAD group and the no PAD group. Then, the PAD group was divided into the non-metastatic para-aortic lymph node (PALN-) group and the metastatic PALN (PALN+) group to further analyze the prognosis of PALN+., Results: Of the 909 included patients, 280 (30.8%) underwent PAD during pancreaticoduodenectomy. The PAD group had a higher rate of intra-abdominal infection compared with the no PAD group (28.6% vs. 20.7%, P = 0.009) but no differences were found in the incidence of other complications. The overall survival (OS) and recurrence-free survival (RFS) were also comparable between the two groups. Subgroup analysis showed that patients with PALN+ had a worse OS than patients in the PALN- group (median of 14 vs. 20 months, P = 0.048). Multivariate Cox regression analysis further revealed that PALN+ was an independent adverse predictor of OS (hazard ratio: 1.70, P = 0.007)., Conclusions: This study suggests that the addition of PAD during pancreaticoduodenectomy does not improve the prognosis of patients with resectable pancreatic cancer and may lead to an increased risk of infection. However, the accurate preoperative assessment and appropriate treatment strategy for patients with PALN+ need further investigation due to the poor prognosis., (© 2022. Society of Surgical Oncology.)

Objective: Collateral circulation could help preserve the blood supply and protect penumbra in ischemic stroke (IS), critical for late-window therapeutic decisions and clinical outcomes. In this study, we aimed to investigate the prognostic value of two collateral indexes measured by arterial spin labeling (ASL) and MR angiography (MRA) in subacute IS patients., Materials and Methods: Fifty-five subacute IS patients with large artery atherosclerosis were retrospectively collected. Arterial transit artifact (ATA) on ASL and good circulation (GC) on MRA were ranked as markers of leptomeningeal collaterals and fast collaterals, respectively. Volume and relative cerebral blood flow (rCBF) of infarct and hypoperfusion area were calculated. Stroke severity was determined by baseline- and discharge- National Institute of Hospital Stroke Scale (NIHSS). Functional independence (FI) was defined as 3-month modified Ranking Scale ≤2. Univariate analyses and multivariable logistic regression analyses were conducted to identify the independent predictors of FI., Results: Thirty-eight patients (69.1 %) presented ATA and 29 (52.7 %) patients presented GC. Univariate analyses showed that baseline-NIHSS, discharge-NIHSS, rCBF of infarct, presence of ATA and GC were associated with FI (P < 0.05). After multivariable adjustment, ATA (adjusted Odds Ratio [OR]: 13.785, 95 % CI: 2.608-72.870, P = 0.002) and GC (adjusted OR: 8.317, 95 % CI: 1.629-42.454, P = 0.011) remained independent predictors of FI. Besides, patients with both ATA and GC had the highest frequencies of FI while patients with neither of them showed the lowest (94.7 % vs 14.3 %, P < 0.001), indicating a positive synergistic effect between ATA and GC., Conclusion: The combination of ASL and MRA simultaneously reflects leptomeningeal collaterals and fast collaterals, providing a useful method to predict functional outcomes of subacute IS patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Heterogeneous MRI manifestations restrict the efficiency and consistency of neuroradiologists in diagnosing hypoxic-ischemic encephalopathy (HIE) due to complex injury patterns. This study aimed to develop and validate an intelligent HIE identification model (termed as DLCRN, deep learning clinical-radiomics nomogram) based on conventional structural MRI and clinical characteristics., Methods: In this retrospective case-control study, full-term neonates with HIE and healthy controls were collected in two different medical centers from January 2015 to December 2020. Multivariable logistic regression analysis was implemented to establish the DLCRN model based on conventional MRI sequences and clinical characteristics. Discrimination, calibration, and clinical applicability were used to evaluate the model in the training and validation cohorts. Grad-class activation map algorithm was implemented to visualize the DLCRN., Results: 186 HIE patients and 219 healthy controls were assigned to the training, internal validation, and independent validation cohorts. Birthweight was incorporated with deep radiomics signatures to create the final DLCRN model. The DLCRN model achieved better discriminatory power than simple radiomics models, with an area under the curve (AUC) of 0.868, 0.813, and 0.798 in the training, internal validation, and independent validation cohorts, respectively. The DLCRN model was well calibrated and has clinical potential. Visualization of the DLCRN highlighted the lesion areas that conformed to radiological identification., Conclusion: Visualized DLCRN may be a useful tool in the objective and quantitative identification of HIE. Scientific application of the optimized DLCRN model may save time for screening early mild HIE, improve the consistency of HIE diagnosis, and guide timely clinical management., (© 2023 S. Karger AG, Basel.)

Female reproductive cycle, also known as menstrual cycle or estrous cycle in primate or non-primate mammals, respectively, dominates the reproductive processes in non-pregnant state. However, in addition to reproductive tissues, reproductive cycle could also perform global regulation because the receptors of two major female hormones fluctuating throughout the cycle, estrogen and progesterone, are widely distributed. Therefore, a multi-tissue gene expression landscape is in continuous demand for better understanding the systemic changes during the reproductive cycle but remains largely undefined. Here we delineated a transcriptomic landscape covering 15 tissues of C57BL/6J female mice in two phases of estrous cycle, estrus and diestrus, by RNA-sequencing. Then, a number of genes, pathways, and transcription factors involved in the estrous cycle were revealed. We found the estrous cycle could widely regulate the neuro-functions, immuno-functions, blood coagulation and so on. And behind the transcriptomic alteration between estrus and diestrus, 13 transcription factors may play important roles. Next, bioinformatics modeling with 1,263 manually curated gene signatures of various physiological and pathophysiological states systematically characterized the beneficial/deleterious effects brought by estrus/diestrus on individual tissues. We revealed that the estrous cycle has a significant effect on cardiovascular system (aorta, heart, vein), in which the anti-hypertensive pattern in aorta induced by estrus is one of the most striking findings. Inspired by this point, we validated that two hypotensive drugs, felodipine and acebutolol, could exhibit significantly enhanced efficacy in estrus than diestrus by mouse and rat experiments. Together, this study provides a valuable data resource for investigating reproductive cycle from a transcriptomic perspective, and presents models and clues for investigating precision medicine associated with reproductive cycle., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhou, Yan, Liu, Hu, Zhou, Sun, Tang, Zheng, Yang and Cui.)

Beyond causing local injury, stroke disrupts structural and functional organization of the brain networks, exposing patients to a high risk of cognitive impairment by affecting the neural network activity. However, the impact of these pathological changes on cognition-related neural circuits is not well understood. In this study, we mainly focused on structures and directed functional connectivity within the Papez circuit in subacute stroke patients. Forty-five stroke patients and thirty-four age-, sex-matched healthy controls were included in our study. The Papez circuit gray matter were measured to explore ischemia-induced structural alterations. And Granger causality analysis with the hippocampus as seed regions was performed to identify alterations of directional functional connectivity within the neural circuit. We also explored the associations between cerebral changes with cognitive status. Compared with healthy controls, stroke patients revealed marked atrophy in gray matter of the Papez circuit, including ipsilateral hippocampus, amygdala, thalamus, and caudal anterior cingulate gyrus. Additionally, there are alterations in the directed functional connections between the bilateral hippocampus and cingulate gyrus within the Papez circuit. These altered effective connectivities were correlated with cognitive function after cerebrovascular event. Taken together, in the early post-stroke period, disruptions of the Papez circuit in both architecture and directed functional connectivity have already occurred and might affect the cognitive function. These findings have prompted researchers to better understand the potential mechanisms underlying vascular cognitive impairment and to investigate new therapeutic targets that could reduce cognitive burden., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Effectively predicting the risk of adverse pregnancy outcome (APO) in women with systemic lupus erythematosus (SLE) during early and mid-pregnancy is a challenge. This study was aimed to identify potential markers for early prediction of APO risk in women with SLE., Methods: The GSE108497 gene expression dataset containing 120 samples (36 patients, 84 controls) was downloaded from the Gene Expression Omnibus database. Weighted gene co-expression network analysis (WGCNA) was performed, and differentially expressed genes (DEGs) were screened to define candidate APO marker genes. Next, three individual machine learning methods, random forest, support vector machine-recursive feature elimination, and least absolute shrinkage and selection operator, were combined to identify feature genes from the APO candidate set. The predictive performance of feature genes for APO risk was assessed using area under the receiver operating characteristic curve (AUC) and calibration curves. The potential functions of these feature genes were finally analyzed by conventional gene set enrichment analysis and CIBERSORT algorithm analysis., Results: We identified 321 significantly up-regulated genes and 307 down-regulated genes between patients and controls, along with 181 potential functionally associated genes in the WGCNA analysis. By integrating these results, we revealed 70 APO candidate genes. Three feature genes, SEZ6 , NRAD1 , and LPAR4 , were identified by machine learning methods. Of these, SEZ6 (AUC = 0.753) showed the highest in-sample predictive performance for APO risk in pregnant women with SLE, followed by NRAD1 (AUC = 0.694) and LPAR4 (AUC = 0.654). After performing leave-one-out cross validation, corresponding AUCs for SEZ6 , NRAD1 , and LPAR4 were 0.731, 0.668, and 0.626, respectively. Moreover, CIBERSORT analysis showed a positive correlation between regulatory T cell levels and SEZ6 expression ( P < 0.01), along with a negative correlation between M2 macrophages levels and LPAR4 expression ( P < 0.01)., Conclusions: Our preliminary findings suggested that SEZ6 , NRAD1 , and LPAR4 might represent the useful genetic biomarkers for predicting APO risk during early and mid-pregnancy in women with SLE, and enhanced our understanding of the origins of pregnancy complications in pregnant women with SLE. However, further validation was required., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Deng, Zhou, Shi, Yang, Huang, Zhang, Wang, Ma, Liu, Li, Yan and Yang.)

Background: Proton exchange rate ( k ex ) magnetic resonance imaging (MRI) has recently been developed, with preliminary results demonstrating its potential for evaluating reactive oxygen species. This prospective cohort study investigated the k ex in different stroke stages and its correlation with stroke severity and prognosis., Methods: In all, 96 ischemic stroke patients were included in the study. Patients were divided into 3 groups based on stroke phase (acute, subacute, and chronic). A spin echo-echo planar imaging sequence with presaturation powers of 1.5, 2.5, and 3.5 µT was implemented to obtain Z-spectra, and k ex maps were constructed from direct saturation-removed omega plots. Relative k ex (r k ex ) and the relative apparent diffusion coefficient (rADC) were calculated as the ratio of k ex or ADC in the infarcts to values in contralateral tissue, respectively. Correlations between both k ex and r k ex and National Institute of Health Stroke Scale (NIHSS) scores were evaluated. Receiver operating characteristic (ROC) analysis was used to evaluate the performance of k ex , r k ex , rADC, and lesion volume for predicting acute stroke outcome., Results: The k ex was significantly higher in ischemic lesions than in contralateral tissue at all stages. In addition, the k ex of acute lesions was higher than that of subacute and chronic lesions [mean (± SD) 935.1±81.5 vs. 881.4±55.7 and 866.9±76.7 s -1 , respectively; P<0.05 and P<0.01, respectively]. The difference in k ex between subacute and chronic lesions was not significant. In acute stroke, there was a limited correlation between a lesion's k ex and NIHSS score (R 2 =0.16; P=0.01) and between r k ex and NIHSS score (R 2 =0.28; P=0.001). Acute stroke patients with poor prognosis had significantly higher lesion k ex and r k ex than did those with good prognosis ( k ex : 991.1±78.2 vs. 893.1±55.1 s -1 , P<0.001; r k ex : 1.28±0.09 vs. 1.15±0.06, P<0.001). In ROC analyses, k ex and r k ex showed favorable predictive performance for acute stroke outcome, with areas under the curve (AUC) of 0.837 and 0.880, respectively, which were slightly but not significantly higher than the AUCs for lesion volume (0.730) and rADC (0.673)., Conclusions: This study indicates that k ex MRI is promising for the diagnosis and management of ischemic stroke because it can reflect the oxidative stress of lesions and predict prognosis., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-22-78/coif). The authors have no other conflicts of interest to declare., (2022 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

As an important predictor of adulthood psychopathology, self-reported childhood abuse appears heritable and is associated with brain abnormalities. However, the specific genetic mechanisms behind these brain alterations remain largely unknown. This study recruited young adults who reported different degrees of childhood abuse from the community. In order to fully understand the influence of genes on brain changes related to self-reported childhood abuse, various experiments were conducted in this study. Firstly, volume changes of gray matter and white matter related to childhood abuse were investigated by using advanced magnetic resonance imaging techniques. After sequencing the whole exons, we further investigated the relationship between polygenic risk score, brain volume alterations, and childhood abuse score. Furthermore, transcription-neuroimaging association analysis was used to identify risk genes whose expressions were associated with brain volume alterations. The gray matter volumes of left caudate and superior parietal lobule, and white matter volumes of left cerebellum and right temporal lobe-basal ganglia region were significantly correlated with the childhood abuse score. More importantly, brain volume changes mediated the influence of polygenic risk on self-reported childhood abuse. Additionally, transcription-neuroimaging association analysis reported 63 risk genes whose expression levels were significantly associated with childhood abuse-related brain volume changes. These genes are involved in multiple biological processes, such as nerve development, synaptic transmission, and cell construction. Combining data from multiple perspectives, our work provides evidence of brain abnormalities associated with childhood abuse, and further indicates that polygene genetic risk and risk gene expression may affect the occurrence of childhood abuse by brain regulation, which provides insights into the molecularpathology and neuromechanism of childhood adversity. Paying attention to the physical and mental health of high-risk children may be a fundamental way to prevent childhood abuse and promote lifelong mental health., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tian, Li, Li, Zhang, Wang, Wan, Fang, Wu, Zhou, Qin, Zhu, Liu and Zhu.)

Background: Anxiety is usually attributed to adverse environmental factors, but it is known as a polygenic inheritance disease. Gene-environment interactions on the occurrence and severity of anxiety are still unclear. The role of brain network connectivity in the gene-environment effects on anxiety has not been explored and may be key to understanding neuropathogenesis and guiding treatment., Methods: This study recruited 177 young adults from the community that completed functional magnetic resonance imaging, Childhood Trauma Questionnaire (CTQ), state-trait anxiety scores, and whole exome sequencing. We calculated polygenic risk score (PRS) for anxiety and the sum score of CTQ, which are genetic and environmental factors that may affect anxiety, respectively. Abnormal brain network connectivity determined by the gene-environment effects and its associations with anxiety scores were then explored., Results: Except for the main effect of PRS or CTQ on intra-network connectivity, significant interactions were found in intra-network connectivity of visual network, default mode network, self-reference network, and sensorimotor network. Moreover, altered network connectivity was related to anxious tendency. In particular, the effect of CTQ on trait anxiety was mediated by the disrupted sensorimotor network, accompanied by a significant direct effect. However, the PRS influence on anxiety was mainly mediated through sensorimotor network paths, which exceeded the direct influence and was moderated by childhood trauma levels., Conclusions: These network-specific functional changes related to individual gene-environment risks advance our understanding of psychiatric pathogenesis of anxiety and provide new insights for clinical intervention., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To develop a model incorporating radiomic features and clinical factors to accurately predict acute ischemic stroke (AIS) outcomes., Materials and Methods: Data from 522 AIS patients (382 male [73.2%]; mean age ± standard deviation, 58.9 ± 11.5 years) were randomly divided into the training (n = 311) and validation cohorts (n = 211). According to the modified Rankin Scale (mRS) at 6 months after hospital discharge, prognosis was dichotomized into good (mRS ≤ 2) and poor (mRS > 2); 1310 radiomics features were extracted from diffusion-weighted imaging and apparent diffusion coefficient maps. The minimum redundancy maximum relevance algorithm and the least absolute shrinkage and selection operator logistic regression method were implemented to select the features and establish a radiomics model. Univariable and multivariable logistic regression analyses were performed to identify the clinical factors and construct a clinical model. Ultimately, a multivariable logistic regression analysis incorporating independent clinical factors and radiomics score was implemented to establish the final combined prediction model using a backward step-down selection procedure, and a clinical-radiomics nomogram was developed. The models were evaluated using calibration, receiver operating characteristic (ROC), and decision curve analyses., Results: Age, sex, stroke history, diabetes, baseline mRS, baseline National Institutes of Health Stroke Scale score, and radiomics score were independent predictors of AIS outcomes. The area under the ROC curve of the clinical-radiomics model was 0.868 (95% confidence interval, 0.825-0.910) in the training cohort and 0.890 (0.844-0.936) in the validation cohort, which was significantly larger than that of the clinical or radiomics models. The clinical radiomics nomogram was well calibrated ( p > 0.05). The decision curve analysis indicated its clinical usefulness., Conclusion: The clinical-radiomics model outperformed individual clinical or radiomics models and achieved satisfactory performance in predicting AIS outcomes., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2022 The Korean Society of Radiology.)

Rationale: Although non-contrast computed tomography (NCCT) is the recommended examination for the suspected acute ischemic stroke (AIS), it cannot detect significant changes in the early infarction. We aimed to develop a deep-learning model to identify early invisible AIS in NCCT and evaluate its diagnostic performance and capacity for assisting radiologists in decision making. Methods : In this multi-center, multi-manufacturer retrospective study, 1136 patients with suspected AIS but invisible lesions in NCCT were collected from two geographically distant institutions between May 2012 to May 2021. The AIS lesions were confirmed based on the follow-up diffusion-weighted imaging and clinical diagnosis. The deep-learning model was comprised of two deep convolutional neural networks to locate and classify. The performance of the model and radiologists was evaluated by the area under the receiver operator characteristic curve (AUC), sensitivity, specificity, and accuracy values with 95% confidence intervals. Delong's test was used to compare the AUC values, and a chi-squared test was used to evaluate the rate differences. Results: 986 patients (728 AIS, median age, 55 years, interquartile range [IQR]: 47-65 years; 664 males) were assigned to the training and internal validation cohorts. 150 patients (74 AIS, median age, 63 years, IQR: 53-75 years; 100 males) were included as an external validation cohort. The AUCs of the model were 83.61% (sensitivity, 68.99%; specificity, 98.22%; and accuracy, 89.87%) and 76.32% (sensitivity, 62.99%; specificity, 89.65%; and accuracy, 88.61%) for the internal and external validation cohorts based on the slices. The AUC of the model was much higher than that of two experienced radiologists (65.52% and 59.48% in the internal validation cohort; 64.01% and 64.39% in external validation cohort; all P < 0.001). The accuracy of two radiologists increased from 62.00% and 58.67% to 92.00% and 84.67% when assisted by the model for patients in the external validation cohort. Conclusions : This deep-learning model represents a breakthrough in solving the challenge that early invisible AIS lesions cannot be detected by NCCT. The model we developed in this study can screen early AIS and save more time. The radiologists assisted with the model can provide more effective guidance in making patients' treatment plan in clinic., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objectives: Pancreatic calcifications (PC) are considered specific for chronic pancreatitis (CP), but PC may also be present in non-CP diseases. The aims are to understand the pattern of calcifications in different diseases and to determine they were related to malignant diseases., Methods: A retrospective study was performed including patients with PC or CP undergoing surgery in the Department of General Surgery of Ruijin Hospital from January 2003 to June 2018., Results: PC were observed in 168 (4.5%) of the 3755 patients with pancreatic lesions treated during the study period. The majority of patients with PC had three kinds of CP (73.2%) while 26.8% had other five kinds of non-CP diseases. In patients with non-CP diseases, the incidence of PC in malignant intraductal papillary mucinous neoplasm (IPMN) was significantly higher than benign IPMN (8.3% vs. 0.7%, p = 0.004). In patients of CP with pancreatic mass (n = 81), PC (Odds ratio = 28.6, p = 0.000), advanced age (> 55 years) and parenchymal atrophy were independent predictors for malignancy. In patients of CP without pancreatic mass (n = 110), there were 82 cases (74.5%) with PC and 5 cases (4.5%) with pancreatic ductal adenocarcinoma. The regression model of risk factors was not successful., Conclusions: The disease spectrum with PC was very diverse. PC may be related to malignant IPMN in non-CP diseases and is related to malignancy in the patients of CP with pancreatic mass and indications for resection., (© 2022. The Author(s).)

Objective: Clinically relevant postoperative pancreatic fistula (CR-POPF) remains the major cause of morbidity following pancreaticoduodenectomy (PD). Several model score systems such as the Fistula Risk Score (FRS) have been developed to predict CR-POPF using preoperative and intraoperative data. Machine learning (ML) algorithms are increasingly applied in the medical field and they could be used to assess the risk of CR-POPF, identify clinically meaningful data and guide drain removal., Methods: Data from consecutive patients who underwent PD between January 1, 2010 and March 31, 2021 at a single high-volume center was collected retrospectively in this study. Demographics, clinical features, intraoperative parameters, and laboratory values were used to conduct the ML model. Four different ML algorithms (CatBoost, lightGBM, XGBoost and Random Forest) were used to train this model with cross-validation., Results: A total of 2421 patients with 62 clinical parameters were enrolled in this ML model. The majority of patients (76.3%) underwent open PD while others underwent robot-assisted PD. CR-POPF occurred in 424 (17.5%) patients. The CatBoost algorithm outperformed other algorithms with a mean area under the receiver operating characteristic curve (AUC) of 0.81 (95% confidence interval: 0.80-0.82) from the 5-fold cross-validation procedure. In the test dataset, the CatBoost algorithm also achieved the best mean-AUC of 0.83. The most important value was mean drain fluid amylase (DFA) in the first seven postoperative days (POD). The performance of models that used only preoperative data and intraoperative data was marginally lower than that of models that used combined data., Conclusion: Our ML algorithms could be applied as early diagnostic tools for CR-POPF in patients who underwent PD. Such real-time clinical decision support tools can identify patients with a high risk of CR-POPF, help in developing the perioperative management plan and guide the optimal timing of drain removal., (Copyright © 2022 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.)

Background: Corticospinal tract (CST) injury has been shown to exert a major influence on functional recovery after ischemic stroke., Purpose: To evaluate the prognostic value of CST injury estimated using a recent developed tractometry-based method., Study Type: Prospective., Population: Forty-eight patients with CST damage induced by stroke lesion who underwent brain magnetic resonance imaging within 7 days from onset., Sequence: Diffusion-weighted imaging (b = 1000 seconds/mm 2 ) and diffusion kurtosis imaging (DKI) spin-echo echo-planar sequence with three b-values (0, 1250, and 2500 seconds/mm 2 ) at 3.0 T., Assessment: A recently developed approach that combines tract segmentation and orientation mapping was used for CST-specific tractography and tractometry. CST injury was estimated using the proposed method with diffusion metrics extracted from DKI sequence and with the first principal component (PC1) of the metrics. We also calculated the weighted lesion load (wLL) for comparison. Clinical evaluation included the National Institutes of Health Stroke Score in the acute phase and the modified Rankin scale at 3 months post-stroke. The correlations between CST injury and initial motor impairment, as well as the prognostic values of CST injury for functional outcomes were evaluated., Statistical Tests: Pearson correlation and logistic regression. Area under the receiver operating characteristic curve. P < 0.05 was considered statistically significant., Results: CST injury calculated with diffusion metrics except fractional anisotropy all showed significant correlations with initial motor impairment. PC1 achieved the largest correlation coefficient (R = 0.65) compared with wLL and other diffusion metrics. In addition to wLL, DKI&#95;AK, AFD&#95;total, and PC1 maximum all showed predictive values for functional outcomes., Data Conclusion: Structural injury to CST is important for the assessment of the extent of injury and the prediction of functional outcome. The method proposed in our study could provide an imaging indicator to quantify the CST injury after ischemic stroke., Level of Evidence: 2 TECHNICAL EFFICACY: Stage 1., (© 2021 International Society for Magnetic Resonance in Medicine.)

Tumor cells use metabolic reprogramming to keep up with the need for bioenergy, biosynthesis, and oxidation balance needed for rapid tumor division. This phenomenon is considered a marker of tumors, including colon cancer (CRC). As an important pathway of cellular energy metabolism, fatty acid metabolism plays an important role in cellular energy supply and oxidation balance, but presently, our understanding of the exact role of fatty acid metabolism in CRC is limited. Currently, no lipid metabolism therapy is available for the treatment of CRC. The establishment of a lipidmetabolism model regulated by oncogenes/tumor suppressor genes and associated with the clinical characteristics of CRC is necessary to further understand the mechanism of fatty acid metabolism in CRC. In this study, through multi-data combined with bioinformatic analysis and basic experiments, we introduced a tumor suppressor gene, EPHX2, which is rarely reported in CRC, and confirmed that its inhibitory effect on CRC is related to fatty acid degradation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhou, Li, Guan, Zhou, Zhu, Wang and Li.)

Female anti-Müllerian hormone (AMH) overexpressing (Thy1.2-AMHTg/0) mice experience fetal resorption (miscarriage) by mid-gestation. This study examined whether the ovary, uterine implantation sites and hypothalamus are potential sites of AMH action, as AMH type-2 receptor (AMHR2) expression is reported in each tissue. Pregnancy in Thy1.2-AMHTg/0 mice was compared to wild-type (WT) mice via histological examination of implantation sites, hormone assays, embryo culture and embryo transfer. Uterine AMH and AMHR2 expression was examined by RT-qPCR and immunohistochemistry. The first signs of fetal resorption in the Thy1.2-AMHTg/0 dams occurred at embryonic day 9.5 (E9.5) with 100% of fetuses resorbing by E13.5. Cultured embryos from Thy1.2-AMHTg/0 dams had largely normal developmental rates but a small proportion experienced a minor developmental delay relative to embryos from WT dams. However, embryos transferred from WT donor females always failed to survive to term when transferred into Thy1.2-AMHTg/0 dams. Amh and Amhr2 mRNA was detected in the gravid uterus but at very low levels relative to expression in the ovaries. Progesterone and estradiol levels were not significantly different between WT and Thy1.2-AMHTg/0 dams during pregnancy but luteinizing hormone (LH) levels were significantly elevated in Thy1.2-AMHTg/0 dams at E9.5 and E13.5 relative to WT dams. Collectively, these experiments suggest that AMH overexpression does not cause fetal resorption through an effect on oocytes or preimplantation embryo development. The Thy1.2-AMHTg/0 fetal resorption phenotype is nearly identical to that of transgenic LH overexpression models, suggesting that neuroendocrine mechanisms may be involved in the cause of the miscarriage.

Rationale and Objectives: The direct damage caused by ischemic stroke is relatively localized, but structural reorganization of cortical regions could occur across the brain. Changes of large-scale, cortical structural brain networks after basal ganglia stroke are less well reported. We, therefore, aim to explore the abnormalities of cortical morphology and structural network topology in patients with unilateral basal ganglia stroke during the subacute period., Materials and Methods: Thirty patients with first-ever basal ganglia stroke and thirty age- and sex-matched healthy controls were recruited for our analysis. Patients underwent structural magnetic resonance imaging examinations and clinical assessment from seven days to three months post-stroke. Alterations in cortical morphology and topological properties of the cortical structural network were measured respectively using the surface-based morphology and graph-theoretical methods., Results: We observed focal cortical atrophy, specifically in areas of frontal and temporal cortices. Moreover, the cortical thickness in the contralesional transverse temporal gyrus and superior temporal gyrus was positively correlated with cognitive function scores. Network analysis revealed that patients with basal ganglia stroke showed increased clustering coefficient, increased mean local efficiency as well as a reorganization of degree-based hubs. In addition, these patients also showed reduced robustness under a random attack compared to healthy controls., Conclusion: These findings indicated a unique pattern of cortical reorganization and the abnormal topological organization of cortical thickness-based structural covariance networks in patients with basal ganglia stroke, which is beneficial to understand the pathophysiological mechanisms of functional disorders at the cortical structural network level and find potential targets for induced neuromodulation., (Copyright © 2021 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

BACKGROUNDAfter the initial surge in COVID-19 cases, large numbers of patients were discharged from a hospital without assessment of recovery. Now, an increasing number of patients report postacute neurological sequelae, known as "long COVID" - even those without specific neurological manifestations in the acute phase.METHODSDynamic brain changes are crucial for a better understanding and early prevention of "long COVID." Here, we explored the cross-sectional and longitudinal consequences of COVID-19 on the brain in 34 discharged patients without neurological manifestations. Gray matter morphology, cerebral blood flow (CBF), and volumes of white matter tracts were investigated using advanced magnetic resonance imaging techniques to explore dynamic brain changes from 3 to 10 months after discharge.RESULTSOverall, the differences of cortical thickness were dynamic and finally returned to the baseline. For cortical CBF, hypoperfusion in severe cases observed at 3 months tended to recover at 10 months. Subcortical nuclei and white matter differences between groups and within subjects showed various trends, including recoverable and long-term unrecovered differences. After a 10-month recovery period, a reduced volume of nuclei in severe cases was still more extensive and profound than that in mild cases.CONCLUSIONOur study provides objective neuroimaging evidence for the coexistence of recoverable and long-term unrecovered changes in 10-month effects of COVID-19 on the brain. The remaining potential abnormalities still deserve public attention, which is critically important for a better understanding of "long COVID" and early clinical guidance toward complete recovery.FUNDINGNational Natural Science Foundation of China.

Ketoprofen (KTF) is a nonsteroidal anti-inflammatory drug frequently detected in natural and engineering waters. Because KTF is particularly photolabile (half-life ∼4 min), knowledge of the fate and ecological risks of KTF photoproducts in the aquatic environment is especially essential. Herein, we systematically investigated the photophysics, photochemistry, and photosensitization of KTF photoproducts in aqueous solution under 365 nm irradiation (UV 365 ). Results show that KTF photolyzed rapidly and formed 3-ethyl-α-hydroxylbenzophenone (EtOH-BP), 3-ethyl-α-hydroperoxylbenzophenone (EtOOH-BP), 3-acetylbenzophenone (AcBP), and 3-ethylbenzophenone (EtBP), as identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and high-resolution mass spectrometry (HRMS). The presence of O 2 significantly affected the evolution of photoproducts during KTF photolysis. The photophysical properties of EtBP and AcBP were characterized by spectroscopic approaches. In particular, transient absorption spectra obtained by nanosecond laser flash photolysis (LFP) indicated that EtBP and AcBP were excited to triplet states with lifetimes of 28 and 2.4 µs, respectively. EtBP underwent further photodegradation, giving rise to EtOH-BP, EtOOH-BP, and AcBP upon UV 365 irradiation. The reaction is proposed to proceed through an excimer precursor ( 3 [EtBP···EtBP]*) followed by intramolecular H-abstraction. In contrast, AcBP was relatively photostable, particularly under aerated condition. Both EtBP and AcBP have strong photosensitizing activity, as evidenced by the triplet probe 4-(N,N-dimethylamino)benzonitrile (DMABN). ECOSAR program suggested that the photoproducts are more ecotoxic and bioaccumulative than the parent KTF. Results of this study underscore the need to scrutinize the formation and fate of KTF photoproducts in sunlit surface waters., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Childhood trauma can alter brain-development trajectories and lead to a greater risk of psychopathology developing in adulthood. For this reason, understanding experience-dependent brain abnormalities associated with different trauma subtypes is crucial for identifying developmental processes disrupted by unfavorable early environments and for proposing early intervention measures to reduce trauma's negative effects., Methods: This study used multimodal magnetic resonance imaging (MRI) to explore the neural correlates of distinct subtypes of childhood trauma. We recruited a large community sample of young adults (mean age, 24.1, SD 1.9 years) who completed a Childhood Trauma Questionnaire, were given behavioral scores, and underwent multimodal MRI. To quantify brain changes, we used functional connectivity density (FCD) mapping based on whole brain analysis, regions of interest (ROI) analysis, and morphological measurements. Experience-dependent brain abnormalities were identified by multivariable linear regression., Results: We found that diverse brain regions in the FCD mapping were significantly related to 4 trauma subtypes and belonged to different cognitive components used for various behaviors. Experience-related influences on functional circuits and brain morphology were observed in extensive regions, including the sensorimotor, cingulum, accumbens, insula, and frontal-parietal areas, as well as in regions within the default mode network., Conclusions: Identifying specific regions or systems may be a valid strategy for understanding the pathogenesis and development process of psychiatric disorders in people with different traumatic experiences and may facilitate better-targeted intervention strategies for maltreated children., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/qims-21-435). The authors have no conflicts of interest to declare., (2022 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Mitotic catastrophe (MC) is a newly identified type of anticancer mechanism for multidrug resistance (MDR) prevention. However, the long cellular death process resulting from MC is not beneficial for anticancer treatment. BZML is a novel colchicine-binding site inhibitor which can overcome MDR by inducing MC; however, BZML-induced MC cells underwent a long cellular death process. Thus, to improve anticancer therapies based on drug-induced MC, BZML-induced MC was served as a model to further study the underlying molecular mechanisms in the process of MC. Here, BZML could induce p53-dependent senescence in A549/Taxol cells, a MDR cell line. This senescence was a secondary effect of MC in overcoming MDR. During MC, BZML-induced destruction of protein-degradation system contributed not only to an increase of p53 protein but also to the accumulation of survivin in nucleus of A549/Taxol cells. Importantly, the nuclear accumulation of survivin was not the inducer but the result of BZML-induced MC, and it promoted the survival of senescent cells. Moreover, it provided additional vulnerability and critical opportunities for sequentially applied therapies. Further, targeting survivin with YM155 accelerated the death of MC cells by timely eliminating therapy-induced senescent cells and strengthening the efficiency of BZML in overcoming MDR in A549/Taxol cells. Collectively, nuclear accumulation of survivin delayed cellular death during MC by promoting the survival of BZML-induced senescent A549/Taxol cells. Moreover, "one-two punch" approach to cancer treatment based on combination therapy with YM155 for survivin suppression might be a new strategy for potentiating MC to overcome MDR., (Copyright © 2021 Elsevier B.V. All rights reserved.)

As one of the most studied resting-state functional networks, default mode network (DMN) is related to pathogenesis in neuropsychiatry. However, it is unclear whether changed DMN connectivity is transformed into vulnerability to psychopathology in adults who experienced childhood trauma, and what is the underlying genetic basis. Exploring the effect of DMN on environment-behavior pathway and the related genetic modulation mechanisms could further a better understanding of psychiatric pathogenesis and early prevention strategy. Two hundred and sixteen young adults with varying levels of early trauma indexed by the Childhood Trauma Questionnaire (CTQ) were recruited from the community. Static and dynamic functional connectivity based on DMN seeds and independent component analysis based on whole-brain voxels were combined to explore DMN alterations related to the CTQ score. Relationships between CTQ score, DMN connectivity, and behavioral scores were confirmed by mediation effect analysis. Imaging-genomic correlations were further used to identify risk genes whose expression was associated with the DMN changes. Dysregulated DMN connectivity was found both in seed-level and voxel-level analyses. Moreover, the functional disruption in the left temporal pole, right parahippocampal gyrus, and frontoparietal connectivity mediated the effects of childhood trauma on emotional behavior. The serotonin transporter gene was identified and might suggest the biological underpinning of the relationship between childhood trauma, DMN, and emotion regulation. Changed DMN may be useful as biomarkers to provide a powerful supplement to psychological evaluation related to childhood trauma. Combined with gene expression profiles, our findings advance a more integrative understanding of DMN alterations induced by childhood trauma, and clarify its implications for psychiatric pathogenesis and early prevention strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tian, Li, Zhang, Wang, Liu, Wan, Fang, Wu, Zhou, Qin and Zhu.)

tRNA-derived fragments (tRFs) constitute a novel class of small non-coding RNA cleaved from tRNAs. In recent years, researches have shown the regulatory roles of a few tRFs in cancers, illuminating a new direction for tRF-centric cancer researches. Nonetheless, more specific screening of tRFs related to oncogenesis pathways, cancer progression stages and cancer prognosis is continuously demanded to reveal the landscape of the cancer-associated tRFs. In this work, by combining the clinical information recorded in The Cancer Genome Atlas (TCGA) and the tRF expression profiles curated by MINTbase v2.0, we systematically screened 1,516 cancer-associated tRFs (ca-tRFs) across seven cancer types. The ca-tRF set collectively combined the differentially expressed tRFs between cancer samples and control samples, the tRFs significantly correlated with tumor stage and the tRFs significantly correlated with patient survival. By incorporating our previous tRF-target dataset, we found the ca-tRFs tend to target cancer-associated genes and onco-pathways like ATF6-mediated unfolded protein response, angiogenesis, cell cycle process regulation, focal adhesion, PI3K-Akt signaling pathway, cellular senescence and FoxO signaling pathway across multiple cancer types. And cell composition analysis implies that the expressions of ca-tRFs are more likely to be correlated with T-cell infiltration. We also found the ca-tRF expression pattern is informative to prognosis, suggesting plausible tRF-based cancer subtypes. Together, our systematic analysis demonstrates the potentially extensive involvements of tRFs in cancers, and provides a reasonable list of cancer-associated tRFs for further investigations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhou, Cui and Zhou.)

Haematopoietic stem/progenitor cell (HSPC) integrates intracellular signal network from growth factors (GFs) and utilizes its proliferation feature to generate high yields of transplantable cells upon ex vivo culture. However, the molecular basis for HSPC activation and proliferation is not completely understood. The goal of this study was to investigate proliferation regulator in the downstream of GFs and develop HSPC expansion strategy. Microarray and Ingenuity Pathway Analysis were performed to evaluate differentially expressed genes in cytokine-induced CD34 + cells after ex vivo culture. We identified that MEK1 was a potential HSPC proliferation regulator, which represented indispensable roles and MEK1 silence attenuated the proliferation of HSPC. Notably, 500 nM MEK1 agonist, PAF C-16, increased the numbers of phenotypic HSPC and induced cell cycling of HSPC. The PAF C-16 expanded HSPC demonstrated comparative clonal formation ability and secondary expansion capacity compared to the vehicle control. Our results provide insights into regulating the balance between proliferation and commitment of HSPC by targeting the HSPC proliferation-controlling network. This study demonstrates that MEK1 critically regulates HSPC proliferation and cell production in the ex vivo condition for transplantation., (© 2021 John Wiley & Sons Ltd.)