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Arsenic exposure model of offspring mice was established and intervened with 6-chlorobenzo[d]isoxazol-3-ol (CBIO), a D-amino acid oxidase (DAAO) inhibitor, to explore the role of DAAO in cognitive impairment of offspring mice induced by arsenic during early developmental stage. Female mice and their pups treated with 0 or 60 mg/L sodium arsenite (NaAsO 2 ) via drinkable water from the first day of gestation till the end of lactation. On the 28th day after birth, the offspring mice in the drinking distilled water group were randomly divided into control and 1 mg/mL CBIO group. The offspring mice in the arsenic group were divided into 60 mg/L NaAsO 2 group and 60 mg/L NaAsO 2  + 1 mg/mL CBIO group, CBIO was administered to the lateral ventricle for one week. Additionally, D-serine and L-serine concentrations were detected by UHPLC-MS/MS, Real-time RT-PCR and Western blot were applied to measure DAAO, serine racemase (SR), N-methyl-D-aspartate receptor (NMDAR), synaptophysin (SYP) and postsynaptic density (PSD95) levels in the hippocampus. Results disclosed that arsenic could reduce the levels of D-serine, L-serine, SR and NMDAR, while upregulate DAAO levels, however, inhibiting DAAO levels could increase D-serine and NR1 levels. These findings indicated that DAAO might be involved in cognitive impairment of offspring mice induced by arsenic during early developmental stage by affecting D-serine metabolism.

Background Identifying new targets in triple negative breast cancer (TNBC) remains critical. REG3A (regenerating islet-derived protein 3 A), a calcium-dependent lectin protein, was thoroughly investigated for its expression and functions in breast cancer. Methods Bioinformatics and local tissue analyses were employed to identify REG3A expression in breast cancer. Genetic techniques were employed to modify REG3A expression, and the resulting effects on the behaviors of breast cancer cells were examined. Subcutaneous xenograft models were established to investigate the involvement of REG3A in the in vivo growth of breast cancer cells. Results Analysis of the TCGA database uncovered increased REG3A levels in human breast cancer tissues. Additionally, REG3A mRNA and protein levels were elevated in TNBC tissues of locally treated patients, contrasting with low expression in adjacent normal tissues. In primary human TNBC cells REG3A shRNA notably hindered cell proliferation, migration, and invasion while triggering caspase-mediated apoptosis. Similarly, employing CRISPR-sgRNA for REG3A knockout showed significant anti-TNBC cell activity. Conversely, REG3A overexpression bolstered cell proliferation and migration. REG3A proved crucial for activating the Akt-mTOR cascade, as evidenced by decreased Akt-S6K1 phosphorylation upon REG3A silencing or knockout, which was reversed by REG3A overexpression. A constitutively active mutant S473D Akt1 (caAkt1) restored Akt-mTOR activation and counteracted the proliferation inhibition and apoptosis induced by REG3A knockdown in breast cancer cells. Crucially, REG3A played a key role in maintaining mTOR complex integrity. Bioinformatics identified zinc finger protein 680 (ZNF680) as a potential REG3A transcription factor. Knocking down or knocking out ZNF680 reduced REG3A expression, while its overexpression increased it in primary breast cancer cells. Additionally, enhanced binding between ZNF680 protein and the REG3A promoter was observed in breast cancer tissues and cells. In vivo, REG3A shRNA significantly inhibited primary TNBC cell xenograft growth. In REG3A-silenced xenograft tissues, reduced REG3A levels, Akt-mTOR inhibition, and activated apoptosis were evident. Conclusion ZNF680-caused REG3A overexpression drives tumorigenesis in breast cancer possibly by stimulating Akt-mTOR activation, emerging as a promising and innovative cancer target.

The June‐July Yangtze flooding in 1998 and 2020 drew incredible attention owing to the extreme precipitation events and devastating societal/economic damages. However, the quantitative estimation of the moisture transport mechanism is intensely discussed but still unresolved. Here we investigated two events from a unique perspective of Eulerian atmospheric water tracers that tries to explain the two events from model physics. The results showed that the moisture supplies from the Northwest Pacific decreased despite of different inducements, whereas the southwest summer monsoon (SWSM)‐related moisture supplies exhibited conspicuous enhancements in both events, suggesting that the SWSM‐related moisture supplies controlled the occurrence of Yangtze flooding. The physical processes of the two events were further compared. The 2020 flooding was more severe than the 1998 event, which was related to the stronger advective convergences and in‐stratus condensations of the SWSM‐related moisture. Plain Language Summary In 1998 and 2020, the Yangtze River valley experienced extreme rainfalls during June–July. The associated atmospheric river was detected to be significantly enhanced by the moisture from the southwest summer monsoon‐related source regions (such as the Bay of Bengal, Arabian Sea, Tropical Indian Ocean, Indo‐China Peninsula, and India) in both events. On the contrary, the moisture supplies from the Northwest Pacific declined. These results suggested that the southwest summer monsoon‐related moisture supplies played vital roles in the formations of extreme rainfalls over the Yangtze River valley. Additionally, our study investigated the differences in the physical mechanisms of the two extreme rainfall events. The stronger advective transport and cloud processes forced more southwest summer monsoon‐related moisture to be converted into precipitation around the Yangtze River, ultimately leading to more severe flooding in 2020 than in 1998. Key Points The southwest summer monsoon (SWSM)‐related moisture supplies regulate the emergence of the Yangtze flooding during June–July Along with the flooding appearances, the moisture supplies from the Northwest Pacific to the Yangtze River valley decrease Stronger advective transport and in‐stratus condensations of the SWSM‐related moisture avail the larger flooding in 2020 than in 1998

Patients with gastric cancer often exhibit poor responses to immunotherapy and experience unfavorable outcomes. This study aims to investigate the relationship between NKAIN1 levels in the tumor microenvironment and gastric carcinoma patients characteristics. Gene expression analysis, multiplex immunohistochemistry using tissue microarrays, and Quantitative Pathology Imaging System were conducted for determining the expression of NKAIN1 in gastric carcinoma tissues and association with patient outcomes. Additionally, we used the Spearman correlation method to assess the relationship between NKAIN1 protein expression in the tumor immune microenvironment and immune checkpoint markers of gastric carcinoma. Lastly, we evaluated the predictive significance of NKAIN1 presence using Cox regression models. The study findings indicated a significant increase in NKAIN1 expression in gastric carcinoma tissues compared to non-tumor stomach tissues. Moreover, a clear association between NKAIN1 expression and CTLA-4, as well as PD-L1, was identified. Importantly, the increased NKAIN1 protein expression was identified as an independent prognostic factor for adverse clinical outcomes in gastric cancer. In conclusion, this study supports NKAIN1 as a prognostic marker and promising target for immune therapy in stomach carcinoma.

Breast cancer is one of the leading fatal diseases for women worldwide who cannot have surgery typically have to rely on systemic chemotherapy to extend their survival. Doxorubicin (DOX) is one of the most commonly used chemotherapeutic agents against breast cancer, but acquired resistance to DOX can seriously impede the efficacy of chemotherapy, leading to poor prognosis and recurrences of cancer. Resveratrol (RES) is a phytoalexin with pharmacological antitumor properties, but its underlying mechanisms are not clearly understood in the treatment of DOX‐resistant breast cancer. We used cell viability assays, cell scratch tests, and transwell assays combined with Western blotting and immunofluorescent staining to evaluate the effects of RES on chemoresistance and the epithelial‐mesenchymal transitions (EMTs) in adriamycin‐resistant MCF7/ADR breast cancer cells, and to investigate its underlying mechanisms. The results showed that a treatment of RES combining with DOX effectively inhibited cell growth, suppressed cell migration, and promoted cell apoptosis. RES reversed EMT properties of MCF7/ADR cells by modulating the connection between SIRT1 and β‐catenin, which provides a hopeful therapeutic avenue to conquer DOX‐resistance and thereby prolong survival rates in breast cancer patients. Resveratrol alleviates DOX‐resistance in breast cancer cells. Resveratrol reverses EMT properties. Resveratrol modulates SIRT1/β‐catenin signaling pathway.

To date, only 34 cases of primary pulmonary rhabdomyosarcoma (PPRMS) in the middle-aged and elderly population have been published. However, analyses of the clinicopathological characteristics and prognosis of PPRMS in this population have not been performed. A 75-year-old man visited our hospital because of abdominal pain and discomfort. His serum lactate dehydrogenase, neuron specific enolase, and progastrin-releasing peptide levels were elevated. Positron emission tomography–computed tomography revealed a lobulated mass of 7.6 × 5.5 cm2 in the lower lobe of the left lung with abnormally high fluoro-2-deoxy-d-glucose metabolism. Histologically, the tumor cells were small with little cytoplasm, deep nuclear staining, and heavily stained nuclear chromatin. Immunohistochemically, the tumor cells were positive for desmin, MyoD1 myogenin, synaptophysin, and CD56. Cytogenetic analysis for FOXO1A translocation was negative. Finally, the patient was diagnosed with PPRMS. He received combined chemotherapy with vincristine 1 mg, actinomycin 0.4 mg, cyclophosphamide 0.8 mg; however, only one course of chemotherapy was completed, and the patient died 2 months after diagnosis. PPRMS in middle-aged and elderly people is a highly malignant soft tissue tumor with significant clinicopathological characteristics.

1,2-Dichloroethane (1,2-DCE) is a widespread environmental contaminant as well as a frequent occupational hazard. Given that inflammation and oxidative stress are key mechanisms in 1,2-DCE-induced cerebral edema, we investigated the efficacy of caffeic acid phenethyl ester (CAPE), a natural anti-inflammatory and antioxidant agent known to protect blood-brain barrier (BBB) integrity, against this intoxication and explored its underlying mechanisms. Static inhalation exposure was used to establish a mouse model of 1,2-DCE-induced toxic cerebral edema. Cerebral edema was evaluated based on brain water content, histopathological changes, and tight junction proteins (TJPs) expression. The related anti-inflammatory and antioxidant mechanisms were analyzed by examining the p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways, respectively. Additionally, the levels of specific cytokines and oxidative stress markers were quantified in both brain tissue and serum. CAPE alleviated the body weight loss and reduced the brain water content in 1,2-DCE-intoxicated mice. Hematoxylin and eosin (HE) staining revealed that CAPE effectively ameliorated the characteristic pathological manifestations of brain edema. CAPE mediated its protective effects through the downregulation of both the p38 MAPK and Nrf2 signaling pathways, resulting in suppressed expression of the cytokines tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and matrix metalloproteinase-9 (MMP-9), normalized levels of glutathione (GSH) and malondialdehyde (MDA), and attenuated loss of the TJPs Occludin and ZO-1. Furthermore, CAPE reversed the 1,2-DCE-induced alterations in pro-inflammatory cytokines and oxidative stress markers in peripheral serum, while inhibiting the expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) in brain tissue. This study provides the first evidence that CAPE effectively alleviates cerebral edema through mitigating both peripheral and central inflammatory responses and oxidative stress induced by 1,2-DCE.

We have previously reported that the activation of astrocytes and microglia may lead to the overproduction of proinflammatory mediators, which could induce neuroinflammation and cause brain edema in 1,2-dichloroethane (1,2-DCE)-intoxicated mice. In this research, we further hypothesized that astrocyte–microglia crosstalk might trigger neuroinflammation and contribute to brain edema in 1,2-DCE-intoxicated mice. The present research revealed, for the first time, that subacute intoxication with 1,2-DCE might provoke the proinflammatory polarization of microglia, and pretreatment with minocycline, a specific inhibitor of microglial activation, may attenuate the enhanced protein levels of ionized calcium-binding adapter molecule1 (Iba-1), cluster of differentiation 11b (CD11b), glial fibrillary acidic protein (GFAP), soluble calcium-binding protein 100B (S100B), tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), inducible nitric oxide synthase (iNOS), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), matrix metalloproteinase-9 (MMP-9), Toll-like receptor 4 (TLR4), MyD88, and p-p65, and ameliorate the suppressed protein expression levels of occludin and claudin 5; we also observed changes in water content and made pathological observations on edema in the brains of 1,2-DCE-intoxicated mice. Moreover, pretreatment with fluorocitrate, an inhibitor of reactive astrocytes, could also reverse the alteration in protein expression levels of GFAP, S100B, Iba-1, CD11b, TNF-α, IL-6, iNOS, VCAM-1, ICAM-1, MMP-9, occludin, and claudin 5 in the brain of 1,2-DCE intoxicated mice. Furthermore, pretreatment with melatonin, a well-known anti-inflammatory drug, could also attenuate the above-mentioned changes in the brains of 1,2-DCE-intoxicated mice. Altogether, the findings from this research indicated that microglial activation might play an important role in triggering neuroinflammation, and hence may contribute to brain edema formation; additionally, the findings suggested that molecular crosstalk between reactive astrocytes and activated microglia may amplify the neuroinflammatory reaction, which could induce secondary brain injury in 1,2-DCE-intoxicated mice.

This study aims to investigate the impact of cerebral white matter lesions (CWMLs) on auditory, speech, and non-verbal cognitive (NVC) outcomes following cochlear implantation (CI) in children with prelingually sensorineural deafness (PLSND) and to identify prognostic factors for these domains. This province-wide retrospective cohort study included PLSND patients with CWMLs undergoing CI, employing propensity score matching for control. Participants were categorized into four groups based on CWMLs severity for auditory, speech, and NVC assessments at various post-CI intervals. Mixed models were used to analyze prognostic factors. In a cohort of 1163 children with PLSND, 15% exhibited CWMLs. CWMLs patients exhibited poorer pre-CI auditory and reduced post-implantation outcomes, correlated with lesion severity. Recovery patterns varied (auditory: rapid-slow; speech: slow-rapid-slow; NVC: rapid-stable), with speech recovery trailing auditory recovery. Greater severity of CWMLs and elevated pre-CI hearing thresholds are risk factors for poorer post-CI auditory and speech outcomes. Conversely, higher income, enhanced pre-CI auditory and NVC capabilities, prolonged rehabilitation, and cesarean delivery are protective factors for these outcomes. Greater severity of CWMLs served as an independent risk factor for post-CI NVC, while cesarean delivery, strong pre-CI speech capabilities, and Advanced Bionics CI device emerged as independent protective factors. This study highlights the importance of incorporating CWMLs severity, perinatal history, and clinical characteristics into preoperative assessments to refine CI candidacy criteria. The identified recovery patterns further guide personalized rehabilitation strategies, contributing to improved long-term outcomes in children with PLSND.

Apoptosis plays an important role in neural development and neurological disorders. In this study, we found that O-GlcNAcylation, a unique protein posttranslational modification with O-linked β-N-acetylglucosamine (GlcNAc), promoted apoptosis through attenuating phosphorylation/activation of AKT and Bad. By using co-immunoprecipitation and mutagenesis techniques, we identified O-GlcNAc modification at both Thr308 and Ser473 of AKT. O-GlcNAcylation-induced apoptosis was attenuated by over-expression of AKT. We also found a dynamic elevation of protein O-GlcNAcylation during the first four hours of cerebral ischemia, followed by continuous decline after middle cerebral artery occlusion (MCAO) in the mouse brain. The elevation of O-GlcNAcylation coincided with activation of cell apoptosis. Finally, we found a negative correlation between AKT phosphorylation and O-GlcNAcylation in ischemic brain tissue. These results indicate that cerebral ischemia induces a rapid increase of O-GlcNAcylation that promotes apoptosis through down-regulation of AKT activity. These findings provide a novel mechanism through which O-GlcNAcylation regulates ischemia-induced neuronal apoptosis through AKT signaling.