Time-resolved NMR detection of prolyl-hydroxylation in intrinsically disordered region of HIF-1α.

Prolyl-hydroxylation is an oxygen-dependent posttranslational modification (PTM) that is known to regulate fibril formation of collagenous proteins and modulate cellular expression of hypoxia-inducible factor (HIF) α subunits. However, our understanding of this important but relatively rare PTM has remained incomplete due to the lack of biophysical methodologies that can directly measure multiple prolyl-hydroxylation events within intrinsically disordered proteins. Here, we describe a real-time 13C-direct detection NMR-based assay for studying the hydroxylation of two evolutionarily conserved prolines (P402 and P564) simultaneously in the intrinsically disordered oxygen-dependent degradation domain of hypoxic-inducible factor 1α by exploiting the "proton-less" nature of prolines. We show unambiguously that P564 is rapidly hydroxylated in a time-resolved manner while P402 hydroxylation lags significantly behind that of P564. The differential hydroxylation rate was negligibly influenced by the binding affinity to prolyl-hydroxylase enzyme, but rather by the surrounding amino acid composition, particularly the conserved tyrosine residue at the +1 position to P564. These findings support the unanticipated notion that the evolutionarily conserved P402 seemingly has a minimal impact in normal oxygen-sensing pathway.

USP1-mediated deubiquitination of KDM1A promotes the malignant progression of triple-negative breast cancer.

Previous research has indicated the highly expressed lysine-specific histone demethylase 1A (KDM1A) in several human malignancies, including triple-negative breast cancer (TNBC). However, its detailed mechanisms in TNBC development remain poorly understood. The mRNA levels of KDM1A and Yin Yang 1 (YY1) were determined by RT-qPCR analysis. Western blot was performed to measure KDM1A and ubiquitin-specific protease 1 (USP1) protein expression. Cell proliferation, apoptosis, invasion, migration and stemness were evaluated by MTT assay, EdU assay, flow cytometry, transwell invasion assay, wound-healing assay and sphere-formation assay, respectively. ChIP and dual-luciferase reporter assays were conducted to determine the relationship between YY1 and KDM1A. Xenograft tumor experiment and IHC were carried out to investigate the roles of USP1 and KDM1A in TNBC development in vivo. The highly expressed KDM1A was demonstrated in TNBC tissues and cells, and KDM1A knockdown significantly promoted cell apoptosis, and hampered cell proliferation, invasion, migration, and stemness in TNBC cells. USP1 could increase the stability of KDM1A via deubiquitination, and USP1 depletion restrained the progression of TNBC cells through decreasing KDM1A expression. Moreover, YY1 transcriptionally activated KDM1A expression by directly binding to its promoter in TNBC cells. Additionally, USP1 inhibition reduced KDM1A expression to suppress tumor growth in TNBC mice in vivo. In conclusion, YY1 upregulation increased KDM1A expression via transcriptional activation. USP1 stabilized KDM1A through deubiquitination to promote TNBC progression.

Soluble PD-L1: a potential dynamic predictive biomarker for immunotherapy in patients with proficient mismatch repair colorectal cancer.

BACKGROUND: Circulating soluble programmed death ligand 1 (sPD-L1) can negatively regulate T-cell function and serve as a prognostic or predictive marker in a variety of cancers. However, rare studies have evaluated the potential roles of sPD-L1, and no study has estimated its predictive value for the efficacy of immune treatment in colorectal cancer (CRC). METHODS: Plasma samples from 192 CRC patients were used to estimate correlations between clinicopathological features and sPD-L1, secreted PD-L1 (secPD-L1) and exosomal PD-L1 (exoPD-L1). Baseline and posttreatment sPD-L1 levels were also investigated in 55 patients with metastatic CRC (mCRC) treated with chemotherapy ± targeted therapy and 40 patients with proficient mismatch repair (pMMR) mCRC treated with combination immunotherapy. Both sPD-L1 and secPD-L1 were quantified by enzyme-linked immunosorbent assay, while exoPD-L1 was analyzed using flow cytometry. RESULTS: secPD-L1 was the major component and positively correlated with sPD-L1 in CRC, while exoPD-L1 was almost undetectable. Higher levels of sPD-L1 were detected in patients with distant metastasis, especially those with distant lymph node metastasis and tissue combined positive score (CPS) instead of tumor proportion score (TPS). Chemotherapy or targeted therapy did not significantly impact sPD-L1 concentration. Progressive disease on combination immunotherapy was associated with an increase in sPD-L1 level, whereas no significant change was observed in patients with durable clinical benefit. CONCLUSION: sPD-L1 mainly consisted of secPD-L1, and its level was higher in patients with distant metastasis, especially distant lymph node metastasis and positive CPS. sPD-L1 is a potential dynamic marker to identify rapid progression on combination immunotherapy and avoid ineffective treatment for pMMR CRC.

Potent and selective inhibition of pathogenic viruses by engineered ubiquitin variants.

The recent Middle East respiratory syndrome coronavirus (MERS-CoV), Ebola and Zika virus outbreaks exemplify the continued threat of (re-)emerging viruses to human health, and our inability to rapidly develop effective therapeutic countermeasures. Many viruses, including MERS-CoV and the Crimean-Congo hemorrhagic fever virus (CCHFV) encode deubiquitinating (DUB) enzymes that are critical for viral replication and pathogenicity. They bind and remove ubiquitin (Ub) and interferon stimulated gene 15 (ISG15) from cellular proteins to suppress host antiviral innate immune responses. A variety of viral DUBs (vDUBs), including the MERS-CoV papain-like protease, are responsible for cleaving the viral replicase polyproteins during replication, and are thereby critical components of the viral replication cycle. Together, this makes vDUBs highly attractive antiviral drug targets. However, structural similarity between the catalytic cores of vDUBs and human DUBs complicates the development of selective small molecule vDUB inhibitors. We have thus developed an alternative strategy to target the vDUB activity through a rational protein design approach. Here, we report the use of phage-displayed ubiquitin variant (UbV) libraries to rapidly identify potent and highly selective protein-based inhibitors targeting the DUB domains of MERS-CoV and CCHFV. UbVs bound the vDUBs with high affinity and specificity to inhibit deubiquitination, deISGylation and in the case of MERS-CoV also viral replicative polyprotein processing. Co-crystallization studies further revealed critical molecular interactions between UbVs and MERS-CoV or CCHFV vDUBs, accounting for the observed binding specificity and high affinity. Finally, expression of UbVs during MERS-CoV infection reduced infectious progeny titers by more than four orders of magnitude, demonstrating the remarkable potency of UbVs as antiviral agents. Our results thereby establish a strategy to produce protein-based inhibitors that could protect against a diverse range of viruses by providing UbVs via mRNA or protein delivery technologies or through transgenic techniques.

Long non-coding RNA cox-2 prevents immune evasion and metastasis of hepatocellular carcinoma by altering M1/M2 macrophage polarization.

Macrophages have been shown to demonstrate a high level of plasticity, with the ability to undergo dynamic transition between M1 and M2 polarized phenotypes. We investigate long non-coding RNA (lncRNA) cox-2 in macrophage polarization and the regulatory mechanism functions in hepatocellular carcinoma (HCC). Lipopolysaccharide (LPS) was used to induce RAW264.7 macrophages into M1 type, and IL-4 was to induce RAW264.7 macrophages into M2 type. We selected mouse hepatic cell line Hepal-6 and hepatoma cell line HepG2 for co-incubation with M1 or M2 macrophages. Quantitative real-time PCR was used to detect the expressions of lncRNA cox-2 and mRNAs. ELISA was conducted for testing IL-12 and IL-10 expressions; Western blotting for epithelial mesenchymal transition related factors (E-cadherin and Vimentin). An MTT, colony formation assay, flow cytometry, transwell assay, and stretch test were conducted to test cell abilities. The M1 macrophages had higher lncRNA cox-2 expression than that in the non-polarized macrophages and M2 macrophages. The lncRNA cox-2 siRNA decreased the expression levels of IL-12, iNOS, and TNF-α in M1 macrophages, increased the expression levels of IL-10, Arg-1, and Fizz-1 in M2 macrophages (all P < 0.05). The lncRNA cox-2 siRNA reduces the ability of M1 macrophages to inhibit HCC cell proliferation, invasion, migration, EMT, angiogenesis and facilitate apoptosis while strengthening the ability of M2 macrophages to promote proliferation HCC cell growth and inhibit apoptosis. These findings indicate that lncRNA cox-2 inhibits HCC immune evasion and tumor growth by inhibiting the polarization of M2 macrophages.

Long Non-Coding RNA PVT1/miR-150/ HIG2 Axis Regulates the Proliferation, Invasion and the Balance of Iron Metabolism of Hepatocellular Carcinoma.

BACKGROUND/AIMS: To investigate the biological roles and underlying molecular mechanisms of long non-coding RNA (lncRNA) PVT1 in Hepatocellular carcinoma (HCC). METHODS: qRT-PCR was performed to measure the expression of miRNA and mRNA. Western blot was performed to measure the protein expression. CCK-8 assay was performed to determine cell proliferation. Flow cytometry was performed to detect cell apoptosis. Wounding-healing assay and Transwell assay was performed to detect cell migration and invasion. Dual luciferase reporter assay was performed to verify the target relationship. Quantichrom iron assay was performed to check uptake level of cellular iron. RESULTS: PVT1 expression was up-regulated in HCC tissues and cell lines. Function studies revealed that PVT1 knockdown significantly suppressed cell proliferation, migration and invasion, and induced cell apoptosis in vitro. Furthermore, PVT1 could directly bind to microRNA (miR)-150 and down-regulate miR-150 expression. Hypoxia-inducible protein 2 (HIG2) was found to be one target gene of miR-150, and PVT1 knockdown could inhibit the expression of HIG2 through up-regulating miR-150 expression. In addition, the expression of miR-150 was down-regulated, while the expression of HIG2 was up-regulated in HCC tissues and cell lines. Moreover, inhibition of miR-150 could partly reverse the biological effects of PVT1 knockdown on proliferation, motility, apoptosis and iron metabolism in vitro, which might be associated with dysregulation of HIG2. In vivo results showed that PVT1 knockdown suppressed tumorigenesis and iron metabolism disorder by regulating the expression of miR-150 and HIG2. CONCLUSION: Taken together, the present study demonstrates that PVT1/miR-150/HIG2 axis may lead to a better understanding of HCC pathogenesis and provide potential therapeutic targets for HCC.

Effects of Age and Location in Chinese Relative Clauses Processing.

Three experiments investigated Chinese relative clause processing with children, youths and elders using sentence-picture matching and self-paced reading methods. In Experiment 1, we found that object-extracted clause were easier to comprehend than subject-extracted clause , and object-modified relative clause (i.e., object-modified subject-extracted clause[Formula: see text]object-modified object-extracted clause) were difficult to comprehend than subject modified relative clause (subject-modified subject-extracted clause[Formula: see text]subject-modified object-extracted clause). Importantly, this paper also found 5-6.5 ages may be critical for children to comprehend RCs in Chinese. Experiment 2 also showed that S-ORCs were easier to comprehend than S-SRCs for youths and elders. Further, elders have more difficulty comprehending RCs than youths. Experiment 3 indicated that there were no significant differences in difficulty between O-SRCs and O-ORCs, and no differences were found between youths and elders. In general, our findings gave support to predictions of working memory-based theory, and also indicated that RCs processing has an intricate course. Many factors such as syntactic, language specificity, experience, personality, must all be considered in sentence processing.

LIM protein JUB promotes epithelial-mesenchymal transition in colorectal cancer.

Metastasis is the leading cause of cancer-related death in almost all types of cancers, including colorectal cancer (CRC). Metastasis is a complex, multistep, dynamic biological event, and epithelial-mesenchymal transition (EMT) is a critical process during the cascade. Ajuba family proteins are LIM domain-containing proteins and are reported to be transcription repressors regulating different kinds of physiological processes. However, the expression and pathological roles of Ajuba family proteins in tumors, especial in tumor metastasis, remain poorly studied. Here, we found that JUB, but not the other Ajuba family proteins, was highly upregulated in clinical specimens and CRC cell lines. Ectopic expression of JUB induced EMT and enhanced motility and invasiveness in CRC, and vice versa. Mechanistic study revealed that JUB induces EMT via Snail and JUB is also required for Snail-induced EMT. The expression of JUB shows an inverse correlation with E-cadherin expression in clinical specimens. Taken together, these findings revealed that the LIM protein JUB serves as a tumor-promoting gene in CRC by promoting EMT, a critical process of metastasis. Thus, the LIM protein JUB may provide a novel target for therapy of metastatic CRC.

Paeonol alleviates ox-LDL-induced endothelial cell injury by targeting the heme oxygenase-1/phosphoinositide 3-kinase/protein kinase B pathway.

Atherosclerosis is a leading cause of vascular disease worldwide. Paeonol has been reported to have therapeutical potential in atherosclerosis. The aim of this study is to explore the effect of paeonol on oxidized low-density lipoprotein (ox-LDL)-induced endothelial cells injury and the underlying mechanism. Human umbilical vein endothelial cells (HUVECs) were treated with ox-LDL (100 µg/ml) to mimic atherosclerosis in vitro. The cell viability, proliferation, and apoptosis were assessed by cell counting kit-8 (CCK8), 5-ethynyl-2'-deoxyuridine (EdU), and flow cytometry, respectively. The angiogenesis was detected by tube formation assay. The levels of inflammatory factor were measured by enzyme-linked immunosorbent assay (ELISA). In addition, the levels of Fe2+, reactive oxygen species (ROS), and glutathione (GSH) were detected to assess ferroptosis. The western blot was used to detect the protein expression. Ox-LDL inhibited cell viability, proliferation, and angiogenesis, but induced apoptosis and inflammation in HUVECs, and paeonol (75 µM) relieves ox-LDL-induced HUVEC injury. Also, paeonol inhibited ox-LDL-induced ferroptosis of HUVECs. Interestingly, heme oxygenase-1 (HMOX1) knockdown alleviated ox-LDL-induced HUVECs injury and ferroptosis. Paeonol affected ox-LDL-induced HUVECs via regulating HMOX1. In addition, paeonol regulated PI3K/AKT pathway via HMOX1, and the inhibitor of phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway reversed the effects of HMOX1 knockdown on ox-LDL-induced HUVECs. Paeonol alleviated ox-LDL-induced HUVEC injury by regulating the PI3K/AKT pathway via targeting HMOX1.

TMEM97 knockdown inhibits 5-fluorouracil resistance by regulating epithelial-mesenchymal transition and ABC transporter expression via inactivating the Akt/mTOR pathway in 5-fluorouracil-resistant colorectal cancer cells.

Resistance to 5-fluorouracil (5-FU) is still a primary setback to the success of colorectal cancer (CRC) chemotherapy. Transmembrane protein 97 (TMEM97) functions as an oncogene in CRC. However, the role and mechanism of TMEM97 in regulating 5-FU resistance in CRC cells remains unclear. TMEM97 expression in CRC samples was analyzed by GEPIA and human protein atlas (HPA) databases. TMEM97, E-cadherin, Vimentin, N-cadherin, P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1)/ABCC1, ABCC2, and the changes of protein kinase B/mammalian target of rapamycin (mTOR) pathway were explored by western blot analysis. IC50 value for 5-FU and cell viability was examined by MTT assay. Apoptosis was evaluated by flow cytometry. TMEM97 was highly expressed in colon adenocarcinoma (COAD) and rectum adenocarcinoma (READ) based on GEPIA and HPA databases. TMEM97 knockdown attenuated 5-FU resistance in HCT116/R and SW480/R cells, as evidenced by the reduced IC50 value for 5-FU and the increased apoptosis. TMEM97 knockdown suppressed epithelial-mesenchymal transition (EMT), expression of ATP-binding cassette (ABC) transporters, and the Akt/mTOR pathway. Mechanistically, activation of Akt/mTOR pathway abolished the inhibitory effects of TMEM97 knockdown on 5-FU resistance, EMT, and ABC transporter expression. In conclusion, TMEM97 knockdown inhibited 5-FU resistance in CRC by regulating EMT and ABC transporter expression via inactivating the Akt/mTOR pathway.

Case report: Robust response to sintilimab in advanced distal cholangiocarcinoma with PD-L1 expression and DNA damage repair.

Cholangiocarcinoma (CCA) is a highly heterogeneous tumor that occurs in the bile duct epithelium; adenosquamous carcinoma is a rare pathological subtype of CCA. The clinical treatment of patients with metastatic distal CCA poses significant challenges. We report a 53-year-old female diagnosed with a stage III adenosquamous carcinomas of distal CCA. Metastasis occurred 4 months postoperatively and she was diagnosed with stage IV disease. The patient was treated with Gemcitabine + Oxaliplatin (GEMOX) and Capecitabine + Oxaliplatin (CAPEOX), followed by sintilimab monotherapy. After two cycles of treatment, the patient achieved partial response (PR) and the lesion continued to shrink. After 37 months of follow-up, the patient's liver metastasis had almost completely disappeared, and complete response (CR) was achieved. Moreover, she had more than 46 months of disease progression-free survival (PFS). Immunohistochemical testing showed high expression of PD-L1, and next-generation sequencing revealed the presence of mutations in DNA damage repair (DDR) pathway genes. To the best of our knowledge, this is the first reported case of the successful treatment of metastatic distal adenosquamous CCA with sintilimab alone. Remarkably, patients of CCA with high PD-L1 expression and DDR pathway gene mutations may benefit from sintilimab treatment.

Multicenter Evaluation of a Weakly Supervised Deep Learning Model for Lymph Node Diagnosis in Rectal Cancer at MRI.

Purpose To develop a Weakly supervISed model DevelOpment fraMework (WISDOM) model to construct a lymph node (LN) diagnosis model for patients with rectal cancer (RC) that uses preoperative MRI data coupled with postoperative patient-level pathologic information. Materials and Methods In this retrospective study, the WISDOM model was built using MRI (T2-weighted and diffusion-weighted imaging) and patient-level pathologic information (the number of postoperatively confirmed metastatic LNs and resected LNs) based on the data of patients with RC between January 2016 and November 2017. The incremental value of the model in assisting radiologists was investigated. The performances in binary and ternary N staging were evaluated using area under the receiver operating characteristic curve (AUC) and the concordance index (C index), respectively. Results A total of 1014 patients (median age, 62 years; IQR, 54-68 years; 590 male) were analyzed, including the training cohort (n = 589) and internal test cohort (n = 146) from center 1 and two external test cohorts (cohort 1: 117; cohort 2: 162) from centers 2 and 3. The WISDOM model yielded an overall AUC of 0.81 and C index of 0.765, significantly outperforming junior radiologists (AUC = 0.69, P < .001; C index = 0.689, P < .001) and performing comparably with senior radiologists (AUC = 0.79, P = .21; C index = 0.788, P = .22). Moreover, the model significantly improved the performance of junior radiologists (AUC = 0.80, P < .001; C index = 0.798, P < .001) and senior radiologists (AUC = 0.88, P < .001; C index = 0.869, P < .001). Conclusion This study demonstrates the potential of WISDOM as a useful LN diagnosis method using routine rectal MRI data. The improved radiologist performance observed with model assistance highlights the potential clinical utility of WISDOM in practice. Keywords: MR Imaging, Abdomen/GI, Rectum, Computer Applications-Detection/Diagnosis Supplemental material is available for this article. Published under a CC BY 4.0 license.

Multiparametric magnetic resonance imaging (MRI)-based radiomics model explained by the Shapley Additive exPlanations (SHAP) method for predicting complete response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer: a multicenter retrospective study.

Background: Predicting the response to neoadjuvant chemoradiotherapy (nCRT) before initiating treatment is essential for tailoring therapeutic strategies and monitoring prognosis in locally advanced rectal cancer (LARC). In this study, we aimed to develop and validate radiomic-based models to predict clinical and pathological complete responses (cCR and pCR, respectively) by incorporating the Shapley Additive exPlanations (SHAP) method for model interpretation. Methods: A total of 285 patients with complete pretreatment clinical characteristics and T1-weighted (T1W) and T2-weighted (T2W) magnetic resonance imaging (MRI) at 3 centers were retrospectively recruited. The features of tumor lesions were extracted by PyRadiomics and selected using least absolute shrinkage and selection operator (LASSO) algorithm. The selected features were used to build multilayer perceptron (MLP) models alone or combined with clinical features. Area under the receiver operating characteristic curve (AUC), decision curve, and calibration curve were applied to evaluate performance of models. The SHAP method was adopted to explain the prediction models. Results: The radiomic-based models all showed better performances than clinical models. The clinical-radiomic models showed the best differentiation on cCR and pCR with mean AUCs of 0.718 and 0.810 in the validation set, respectively. The decision curves of the clinical-radiomic models showed its values in clinical application. The SHAP method powerfully interpreted the prediction models both at a holistic and individual levels. Conclusions: Our study highlights that the radiomic-based prediction models have more excellent abilities than clinical models and can effectively predict treatment response and optimize therapeutic strategies for patients with LARCs.

Reclassification of RAS/BRAF allele mutations predicts the survival benefit of triplet chemotherapy in metastatic colorectal cancer.

Background: Different RAS/BRAF allele mutations imply distinct biological properties in various solid tumors. Recently, several studies have focused on the predictive and prognostic roles of various RAS/BRAF allele mutations in colorectal cancer (CRC) but the results remain controversial. Methods: Between March 2017 and September 2022, the patients diagnosed as stages I-IV CRC with detailed medical records including next-generation sequencing (NGS) data and clinicopathological follow-up information available at our center were enrolled. Survival data were estimated using the Kaplan-Meier method, and the difference was tested in a log-rank test. Multivariate tests were carried out using Cox models. Results: A total of 1029 CRC patients were included, and the incidence of RAS/BRAF mutation was 58.4%. The hypermutated cohort was defined as patients with microsatellite instability-H or POLE/D mutation. In the non-hypermutational cohort, only KRAS G13D mutation was associated with a higher incidence and inferior disease-free survival in patients with stage I-III CRC. In the cohort of patients with non-hypermutated metastatic colorectal cancer (mCRC), we assessed the risk of various RAS/BRAF allele mutations and subsequently reclassified patients into four groups based on first-line median progression-free survival: wild type (group 1), low-risk RAS/BRAF mutation (group 2, RAS/BRAF mutations other than KRAS G13D/G12V/G12C or BRAF V600E), high-risk RAS mutation (group 3, KRAS G13D/G12V/G12C), and BRAF V600E mutation (group 4). mCRC patients with high-risk RAS mutation could significantly benefit from intensive triplet chemotherapy (hazard ratio, 2.54; 95% confidence interval, 1.36-5.12; p = 0.0091). Conclusion: In the non-hypermutated CRC cohort, the prognostic risk of various RAS/BRAF allele mutations varied between local and metastatic CRC. KRAS G13D mutation tended to be the only prognostic marker for stages I-III CRC; however, KRAS G13D/G12V/G12C mutations collectively defined a high-risk subgroup of mCRC patients with poor prognosis, who would benefit from intensive triplet chemotherapy.

Upregulation of CPE promotes cell proliferation and tumorigenicity in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers worldwide and a leading cause of cancer related death. Although the mortality rate of CRC is decreasing, finding novel targets for its therapy remains urgent. Carboxypeptidase E (CPE), a member of the pro-protein convertases, which are involved in the maturation of protein precursors, has recently been reported as elevated in many types of cancer. However, its role and mechanisms in tumor progression are poorly understood. METHODS: In the present study, we investigated expression of CPE in CRC cell lines and tumor tissues using Western blot and real-time qRT-PCR. Plasmids for overexpression and depletion of CPE were constructed and analyzed by Western blot, MTT and colony formation assays and bromodeoxyuridine incorporation assays. The relative expression of p21, p27, and cyclin D1 were analyzed by Real-time qRT-PCR in the indicated cells. RESULTS: Our study showed that CPE was significantly upregulated in CRC cell lines and tumor tissues. MTT and colony formation assays indicated that overexpression of CPE enhanced cell growth rates. BrdU incorporation and flow-cytometry assays showed that ectopic expression of CPE increased the S-phase fraction cells. Soft agar assay proved enhanced tumorigenicity activity in CPE over-expressing CRC cells. Further studies of the molecular mechanisms of CPE indicated that is promoted cell proliferation and tumorigenicity through downregulation of p21 and p27, and upregulation of cyclin D1. CONCLUSIONS: Taken together, these data suggest that CPE plays an important role in cell cycle regulation and tumorigenicity, and may serve as a potential target for CRC therapeutics.

Alpha ERS-ERD Pattern during Divergent and Convergent Thinking Depends on Individual Differences on Metacontrol.

The role of metacontrol in creativity is theoretically assumed, but experimental evidence is still lacking. In this study, we investigated how metacontrol affects creativity from the perspective of individual differences. Sixty participants completed the metacontrol task, which was used to divide participants into a high-metacontrol group (HMC) versus a low (LMC) group. Then, these participants performed the alternate uses task (AUT; divergent thinking) and the remote associates test (RAT; convergent thinking), while their EEG results were recorded continuously. Regarding their behavior, the HMC group showed superior creative performance in the AUT and RAT, compared with the LMC group. For the electrophysiology, the HMC group showed larger stimulus-locked P1 and P3 amplitudes than the LMC group. Furthermore, the HMC group exhibited smaller alpha desynchronization (ERD) than the LMC group at the initial stages of the AUT task, followed by a flexible switching between alpha synchronization and desynchronization (ERS-ERD) during the process of selective retention in the AUT. In addition, the HMC group evoked smaller alpha ERD during the initial retrieval and the backtracking process in the RAT, associated with cognitive control adaptability. The aforementioned results indicate that metacontrol reliably contributes to the idea generation process, and HMC individuals could flexibly adjust their cognitive control strategies according to the demand for creative idea generation.

Peer victimization and children's internet addiction in China: a moderated mediation model.

Background: Peer victimization used to be considered as a crucial risk factor for children addicted to the internet. Whereas some victimized ones are function better than would be expected. Variability across individuals indicates that it is necessary to understand how children cope with being bullied and why they do not exhibit maladaptive outcomes. Objective: We explored the underlying mechanisms by testing whether subjective well-being was a mediator between peer victimization and Internet addiction and whether the mediation effects conditioned on the levels of parent-child relationship (PCR). Methods: Data were collected from 65, 868 elementary school students in China (Mage = 9.56 years, SD = 0.62, 54.0% male) using four questionnaires. Results: We found that: (1) subjective well-being can partially mediate the relationship of the two variables; and (2) PCR can moderate direct path and second half of the intermediary process. These moderating effects were stronger for children with higher PCR vs. lower PCR, as a strong PCR can help children to deal with intense emotions and to access effective resources to obtain support. Conclusion: This study deepens our understanding of how peer victimization leads to internet addiction, identifies a supportive PCR as a crucial factor that strengthens the resilience of child victims, and highlights the value of focusing on improving the relationship between parents and children in intervening internet addiction related to peer victimization.

Metastatic sites and lesion numbers cooperated to predict efficacy of PD-1 inhibitor-based combination therapy for patients with metastatic colorectal cancer.

BACKGROUND: Limited data have been used to evaluate the efficacy of immunotherapy in metastatic colorectal cancer (mCRC). Furthermore, potential markers that can be used to identify responding patients and to further improve efficacy have not been fully explored. METHODS AND RESULTS: In our study, we included a total of 97 patients with mCRC, who each received programmed death-1 (PD-1) inhibitor-based combination therapy at our center. All 12 hypermutated patients benefited from immunotherapy, with median progression-free survival (mPFS) reaching 28.3 months, regardless of liver metastasis. The objective response rate (ORR) of non-hypermutated patients was 16.5% (14/85), with an mPFS of 4.0 months. For non-hypermutated patients, multivariate analysis revealed that the combination of liver metastasis and baseline lesion number significantly stratified response and survival. The lesion-based analysis indicated that the lymph node was the most responsive, followed by the peritoneum and lung, with liver metastasis being the least responsive. None of the patients (0/7) with negative programmed ligand-1 (PD-L1) expression responded, and positive PD-L1 expression may serve as a biomarker (mPFS 5.7 vs. 2.2 months, p = 0.002) that can be used to further guide treatment in non-hypermutated mCRC with liver metastasis (CRLMs). CONCLUSION: Patients with hypermutated mCRC benefited significantly from immunotherapy, whereas the non-hypermutated cohort with liver metastasis and numerous lesions showed less benefit. The lesion sites reflected varying levels of efficacy, among which PD-L1 potentially cooperated to guide the immunotherapy of CRLMs.

Involvement of the sensorimotor system in less advanced L2 processing: Evidence from a semantic category decision task.

There is increasing evidence indicating that the sensorimotor system is involved in advanced L2 processing, which raises the question of what role sensorimotor information plays in the course of less advanced L2 comprehension. In the current study, two experiments were conducted using a lexical decision task (LDT) and semantic category task (SCT). The results showed that, in the LDT, a task more likely to result in participants making judgments based on the physical properties of words (e.g., familiarity, orthography), "up" words (e.g., sun, plane) did not result in faster upward than downward responses, and "down" words (e.g., tunnel, cave) also did not result in faster downward than upward responses. In the SCT, compatibility effects were found; specifically, searching for the up target after "up" words was faster than after "down" words and searching for the bottom target after "down" words was faster than after "upward-pointing" words. Hence, we concluded that L2 sensorimotor association, at least for L2 with low proficiency, not automatic in nature and is dependent upon deeper semantic task demands.

Is Mate Preference Recognizable Based on Electroencephalogram Signals? Machine Learning Applied to Initial Romantic Attraction.

Initial romantic attraction (IRA) refers to a series of positive reactions toward potential ideal partners based on individual preferences; its evolutionary value lies in facilitating mate selection. Although the EEG activities associated with IRA have been preliminarily understood; however, it remains unclear whether IRA can be recognized based on EEG activity. To clarify this, we simulated a dating platform similar to Tinder. Participants were asked to imagine that they were using the simulated dating platform to choose the ideal potential partner. Their brain electrical signals were recorded as they viewed photos of each potential partner and simultaneously assessed their initial romantic attraction in that potential partner through self-reported scale responses. Thereafter, the preprocessed EEG signals were decomposed into power-related features of different frequency bands using a wavelet transform approach. In addition to the power spectral features, feature extraction also accounted for the physiological parameters related to hemispheric asymmetries. Classification was performed by employing a random forest classifier, and the signals were divided into two categories: IRA engendered and IRA un-engendered. Based on the results of the 10-fold cross-validation, the best classification accuracy 85.2% (SD = 0.02) was achieved using feature vectors, mainly including the asymmetry features in alpha (8-13 Hz), beta (13-30 Hz), and theta (4-8 Hz) rhythms. The results of this study provide early evidence for EEG-based mate preference recognition and pave the way for the development of EEG-based romantic-matching systems.