The Kv4 potassium channel modulator NS5806 attenuates cardiac hypertrophy in vivo and in vitro.

The compound NS5806 is a Kv4 channel modulator. This study investigated the chronic effects of NS5806 on cardiac hypertrophy induced by transverse aortic constriction (TAC) in mice in vivo and on neonatal rat ventricular cardiomyocyte hypertrophy induced by endothelin-1 (ET-1) in vitro. Four weeks after TAC, NS5806 was administered by gavage for 4 weeks. Echocardiograms revealed pronounced left ventricular (LV) hypertrophy in TAC-treated mice compared with sham mice. NS5806 attenuated LV hypertrophy, as manifested by the restoration of LV wall thickness and weight and the reversal of contractile dysfunction in TAC-treated mice. NS5806 also blunted the TAC-induced increases in the expression of cardiac hypertrophic and fibrotic genes, including ANP, BNP and TGF-ß. Electrophysiological recordings revealed a significant prolongation of action potential duration and QT intervals, accompanied by an increase in susceptibility to ventricular arrhythmias in mice with cardiac hypertrophy. However, NS5806 restored these alterations in electrical parameters and thus reduced the incidence of mouse sudden death. Furthermore, NS5806 abrogated the downregulation of the Kv4 protein in the hypertrophic myocardium but did not influence the reduction in Kv4 mRNA expression. In addition, NS5806 suppressed in vitro cardiomyocyte hypertrophy. The results provide novel insight for further ion channel modulator development as a potential treatment option for cardiac hypertrophy.

Trends and factors influencing the mental health of college students in the post-pandemic: four consecutive cross-sectional surveys.

Background: The long-term impact of COVID-19 on the mental health and well-being of college students, specifically trends over time after full removal of COVID-19 restrictions, has not been well-studied. Methods: Four consecutive cross-sectional surveys were conducted in December 2022 (N = 689), March 2023 (N = 456), June 2023 (N = 300), and November 2023 (N = 601) at a university in Sichuan Province, China. Results: The proportion of students with COVID-19 panic decreased from 95.1 to 77.3% (p < 0.001). The prevalence of moderate anxiety and above decreased from 18 to 13.6% (p < 0.001), and the prevalence of moderate and above depression decreased from 33.1 to 28.1% (p < 0.001), while the prevalence of post-traumatic stress disorder (PTSD) increased from 21.5 to 29.6% (p < 0.005). Further, the proportion of suicidal thoughts increased from 7.7 to 14.8% (p < 0.001). Suicidal thoughts and self-injuries were significantly associated with COVID-19 panic, depression, anxiety, and PTSD. Students who reported being in close contact with COVID-19 patients in the past were more likely to develop PTSD. Further, COVID-19-induced panic was a risk factor for self-injury. Conclusion: One year after the COVID-19 pandemic, the overall mental health of college students was not optimal. Hence, we can conclude that the long-term impacts of COVID-19 on the mental health of college students may have already occurred. To mitigate this impact and prepare for the next major public health event, strengthening college students' mental health curricula and promoting healthy behaviors among college students should be a priority for universities and education authorities.

Loss of clear cell characteristics in aggressive clear cell odontogenic carcinoma: a case report.

BACKGROUND: Clear cell odontogenic carcinoma (CCOC) is an odontogenic carcinoma characterized by sheets and islands of vacuolated and clear cells. The diagnosis of atypical CCOC can pose a challenge when tumor cells deviate from their characteristic clear morphology, even with the aid of genetic profiling for CCOC identification. CASE PRESENTATION: In this manuscript, we detailed the inaugural instance of a recurrently recurring clear cell odontogenic carcinoma (CCOC) with pronounced squamous differentiation in a 64-year-old male. The primary tumor in this individual initially displayed a biphasic clear cell phenotype. However, subsequent to the third recurrence, the clear tumor cells were entirely supplanted by epidermoid cells characterized by eosinophilic cytoplasm, vesicular chromatin, and prominent nucleoli. Notable aggressive attributes such as necrosis, conspicuous cytological malignancy, perineural dissemination, and vascular invasion were noted. Additionally, the tumor progressed to manifest lung metastases. The tumor cells exhibited positive immunoreactivity for AE1/AE3, KRT19, Pan-CK, EMA, P40, P63, CK34ßE12, and P53, while they tested negative for CK35ßH11, KRT7, S-100, and neuroendocrine markers. The Ki-67 proliferation index was calculated at an average of 15%. Furthermore, FISH analysis unveiled the presence of the EWSR1::ATF1 gene fusion. CONCLUSIONS: This case illustrated a rare and aggressive case of CCOC characterized by significant squamous differentiation upon recurrence of the tumor.

TAX1BP1 and FIP200 orchestrate non-canonical autophagy of p62 aggregates for mouse neural stem cell maintenance.

Autophagy plays a pivotal role in diverse biological processes, including the maintenance and differentiation of neural stem cells (NSCs). Interestingly, while complete deletion of Fip200 severely impairs NSC maintenance and differentiation, inhibiting canonical autophagy via deletion of core genes, such as Atg5, Atg16l1, and Atg7, or blockade of canonical interactions between FIP200 and ATG13 (designated as FIP200-4A mutant or FIP200 KI) does not produce comparable detrimental effects. This highlights the likely critical involvement of the non-canonical functions of FIP200, the mechanisms of which have remained elusive. Here, utilizing genetic mouse models, we demonstrated that FIP200 mediates non-canonical autophagic degradation of p62/sequestome1, primarily via TAX1BP1 in NSCs. Conditional deletion of Tax1bp1 in fip200 hGFAP conditional knock-in (cKI) mice led to NSC deficiency, resembling the fip200 hGFAP conditional knockout (cKO) mouse phenotype. Notably, reintroducing wild-type TAX1BP1 not only restored the maintenance of NSCs derived from tax1bp1-knockout fip200 hGFAP cKI mice but also led to a marked reduction in p62 aggregate accumulation. Conversely, a TAX1BP1 mutant incapable of binding to FIP200 or NBR1/p62 failed to achieve this restoration. Furthermore, conditional deletion of Tax1bp1 in fip200 hGFAP cKO mice exacerbated NSC deficiency and p62 aggregate accumulation compared to fip200 hGFAP cKO mice. Collectively, these findings illustrate the essential role of the FIP200-TAX1BP1 axis in mediating the non-canonical autophagic degradation of p62 aggregates towards NSC maintenance and function, presenting novel therapeutic targets for neurodegenerative diseases.

ATF3 is involved in rSjP40-mediated inhibition of HSCs activation in Schistosoma japonicum-infected mice.

Schistosomiasis is a parasitic disease characterized by liver fibrosis, a process driven by the activation of hepatic stellate cells (HSCs) and subsequent collagen production. Previous studies from our laboratory have demonstrated the ability of Schistosoma japonicum protein P40 (SjP40) to inhibit HSCs activation and exert an antifibrotic effect. In this study, we aimed to elucidate the molecular mechanism underlying the inhibitory effect of recombinant SjP40 (rSjP40) on HSCs activation. Using a cell model in which rSjP40 inhibited LX-2 cell activation, we performed RNA-seq analyses and identified ATF3 as the most significantly altered gene. Further investigation revealed that rSjP40 inhibited HSCs activation partly by suppressing ATF3 activation. Knockdown of ATF3 in mouse liver significantly alleviated S. japonicum-induced liver fibrosis. Moreover, our results indicate that ATF3 is a direct target of microRNA-494-3p, a microRNA associated with anti-liver fibrosis effects. rSjP40 was found to downregulate ATF3 expression by upregulating microRNA-494-3p in LX-2 cells. This downregulation led to the inhibition of the expression of liver fibrosis proteins α-SMA and COL1A1, ultimately alleviating liver fibrosis caused by S. japonicum.

Dual Inhibition of Factor XIIa and Factor XIa Produces a Synergistic Anticoagulant Effect.

ABSTRACT: Clinical practice shows that a critical unmet need in the field of thrombosis prevention is the availability of anticoagulant therapy without bleeding risk. Inhibitors against FXIa or FXIIa have been extensively studied because of their low bleeding risk. However, whether these compounds produce synergistic effects has not yet been explored. In this study, analyses of activated partial thromboplastin time in combination with the FXIa inhibitor PN2KPI and the FXIIa inhibitor Infestin4 at different proportions were performed using the SynergyFinder tool identifying synergistic anticoagulation effects. Both an FeCl 3 -induced carotid artery thrombosis mouse model and a transient occlusion of the middle cerebral artery mouse model showed that the combination of PN2KPI and Infestin4, which are 28.57% and 6.25% of the effective dose, respectively, significantly prevents coagulation, and furthermore, dual inhibition does not cause bleeding risk.

The Influence of Perinatal Psychological Changes on Infant Neurodevelopment in Shanghai, China: A Longitudinal Group-based Trajectory Analysis.

OBJECTIVE: This prospective cohort study, conducted at the Fenglin Community Health Service Center (FCHC) in Xuhui District, Shanghai, aimed to investigate the impact of maternal psychological status on offspring neurodevelopment. METHODS: A total of 430 mother-child pairs were included, with pregnant women enrolled between February 18, 2020, and April 19, 2021. Face-to-face interviews and electronic data collection on demographic characteristics, health conditions and medical history were employed at various stages of pregnancy and postpartum. Maternal depression and anxiety were assessed using the PHQ-9 and GAD-7 scales, while offspring neurodevelopment was measured at six months using the Ages and Stages Questionnaire 3rd Edition (ASQ-3). In statistical analyses, group-based trajectory modeling (GBTM) was employed to identify the latent groups for maternal psychological trajectories, including depression and anxiety, and logistic regression was used to explore associations between maternal psychological trajectories and offspring neurodevelopment, adjusting for potential confounders. RESULTS: Five latent trajectory groups were identified for both depression and anxiety, exhibiting distinct patterns over time. Results indicated that maternal psychological trajectories were associated with various domains of offspring neurodevelopment, including communication, problem-solving, personal-social, and gross motor skills. Specifically, mothers in trajectory groups characterized by the highest level of depression or anxiety showed increased odds of offspring neurodevelopmental delays compared to reference groups. CONCLUSION: Our findings underscore the importance of maternal mental health during the perinatal period and highlight the potential implications for offspring neurodevelopment. Further research is warranted to elucidate underlying mechanisms and inform targeted interventions to support maternal mental well-being and optimize offspring outcomes.

Construction of an Artificial Sequential Light-Harvesting System and White-Light Material Utilizing Supramolecular Gels.

The molecular (pyren-1-yloxy)-acetic acid (Py) with excellent fluorescence properties was synthesized from 1-hydroxypyrene (Hp) and formed a supramolecular gel with an acid-base stimulus response in dimethylformamide and water. On the basis of gel, the fluorescent dye perylene 3, 9-dicarbxylic acid, and rhodamine 6g were added successively to construct a step-by-step artificial light-harvesting system, so that the fluorescence color changed from blue-purple to green to red, and white light emission was realized by adjusting the ratio of donors and acceptors.

Feasibility study of use of desflurane combined with dexmedetomidine in inhibiting postoperative neurocognitive disorders in elderly patients under general anesthesia: A perspective study.

This study aimed to explore whether the combined application of desflurane and dexmedetomidine (Dex) reduces the occurrence of postoperative neurocognitive disorders (PND) in patients. We selected patients in our hospital who underwent surgery under general anesthesia, and divided them into two groups: Dex and desflurane (Dex + Des) and desflurane (Des) groups. The data of patients were collected and the Mini-Mental State Examination (MMSE) score was used to assess cognitive status. The blood cell counts were determined preoperatively and on postoperative days 1, 3, and 6, and the percentage of neutrophils and lymphocytes were also recorded. The statistical methods used were the independent-samples t-test and the χ 2 test. Pearson's correlation was used to analyze the correlation between PND and inflammation. The incidence of PND in the Dex + Des group was lower than that in the Des group. The postoperative MMSE scores in the Dex + Des group were higher than those in the Des group (p = 0.032). The percentage of neutrophils in the Dex + Des group was significantly lower than that in the Des group on the first and third days after surgery (p = 0.007; p = 0.028). The MMSE scores on the first day after surgery were negatively correlated with the multiple changes in white blood counts and the percentage of neutrophils (r = -0.3038 and -0.3330). Dex combined with Des reduced the incidence of PND and reduced the postoperative inflammatory cell counts.

A novel score for predicting falls in community-dwelling older people: a derivation and validation study.

BACKGROUND: Early detection of patients at risk of falling is crucial. This study was designed to develop and internally validate a novel risk score to classify patients at risk of falls. METHODS: A total of 334 older people from a fall clinic in a medical center were selected. Least absolute shrinkage and selection operator (LASSO) regression was used to minimize the potential concatenation of variables measured from the same patient and the overfitting of variables. A logistic regression model for 1-year fall prediction was developed for the entire dataset using newly identified relevant variables. Model performance was evaluated using the bootstrap method, which included measures of overall predictive performance, discrimination, and calibration. To streamline the assessment process, a scoring system for predicting 1-year fall risk was created. RESULTS: We developed a new model for predicting 1-year falls, which included the FRQ-Q1, FRQ-Q3, and single-leg standing time (left foot). After internal validation, the model showed good discrimination (C statistic, 0.803 [95% CI 0.749-0.857]) and overall accuracy (Brier score, 0.146). Compared to another model that used the total FRQ score instead, the new model showed better continuous net reclassification improvement (NRI) [0.468 (0.314-0.622), P < 0.01], categorical NRI [0.507 (0.291-0.724), P < 0.01; cutoff: 0.200-0.800], and integrated discrimination [0.205 (0.147-0.262), P < 0.01]. The variables in the new model were subsequently incorporated into a risk score. The discriminatory ability of the scoring system was similar (C statistic, 0.809; 95% CI, 0.756-0.861; optimism-corrected C statistic, 0.808) to that of the logistic regression model at internal bootstrap validation. CONCLUSIONS: This study resulted in the development and internal verification of a scoring system to classify 334 patients at risk for falls. The newly developed score demonstrated greater accuracy in predicting falls in elderly people than did the Timed Up and Go test and the 30-Second Chair Sit-Stand test. Additionally, the scale demonstrated superior clinical validity for identifying fall risk.

Discovery of Aurovertin B as a Potent Metastasis Inhibitor against Triple-Negative Breast Cancer: Elucidating the Complex Role of the ATF3-DUSP1 Axis.

Triple-negative breast cancer (TNBC) is characterized by high mortality rates primarily due to its propensity for metastasis. Addressing this challenge necessitates the development of effective antimetastatic therapies. This study aimed to identify natural compounds with potential antimetastatic properties mainly based on the high-throughput phenotypic screening system. This system, utilizing luciferase reporter gene assays combined with scratch wound assays, evaluates compounds based on their influence on the epithelial-mesenchymal transition (EMT) marker E-cadherin. Through this approach, aurovertin B (AVB) was revealed to have significant antimetastatic capability. Notably, AVB exhibited substantial metastasis suppression in many TNBC cell lines, including MDA-MB-231, HCC1937 and 4T1. Also, its remarkable antimetastatic activity was demonstrated in vivo via the orthotopic breast cancer mouse model. Further exploration revealed a pronounced association between AVB-induced upregulation of DUSP1 (dual-specificity phosphatase 1) and its inhibitory effect on TNBC metastasis. Additionally, microarray analysis conducted to elucidate the underlying mechanism of the AVB-DUSP1 interaction identified ATF3 (activating transcription factor 3) as a critical transcription factor instrumental in DUSP1 transcriptional activation. This discovery, coupled with observations of enhanced ATF3-DUSP1 expression and consequent reduction in TNBC metastatic foci in response to AVB, provides novel insights into the molecular mechanisms driving metastasis in TNBC. Significance Statement We construct a high-throughput phenotypic screening system utilizing EMT marker E-cadherin promoter luciferase reporter gene combined with scratch wound assays. Aurovertin B was revealed to possess significant antimetastatic activity through this approach, which was further demonstrated via in vivo and in vitro experiments. The discovery of the regulatory role of the ATF3-DUSP1 pathway enriches our understanding of TNBC metastasis mechanism and suggests the potential of ATF3 and DUSP1 as biomarkers for diagnosing TNBC metastasis.

Application of convolutional neural networks in medical images: a bibliometric analysis.

Background: In the field of medical imaging, the rapid rise of convolutional neural networks (CNNs) has presented significant opportunities for conserving healthcare resources. However, with the wide spread application of CNNs, several challenges have emerged, such as enormous data annotation costs, difficulties in ensuring user privacy and security, weak model interpretability, and the consumption of substantial computational resources. The fundamental challenge lies in optimizing and seamlessly integrating CNN technology to enhance the precision and efficiency of medical diagnosis. Methods: This study sought to provide a comprehensive bibliometric overview of current research on the application of CNNs in medical imaging. Initially, bibliometric methods were used to calculate the frequency statistics, and perform the cluster analysis and the co-citation analysis of countries, institutions, authors, keywords, and references. Subsequently, the latent Dirichlet allocation (LDA) method was employed for the topic modeling of the literature. Next, an in-depth analysis of the topics was conducted, and the topics in the medical field, technical aspects, and trends in topic evolution were summarized. Finally, by integrating the bibliometrics and LDA results, the developmental trajectory, milestones, and future directions in this field were outlined. Results: A data set containing 6,310 articles in this field published from January 2013 to December 2023 was complied. With a total of 55,538 articles, the United States led in terms of the citation count, while in terms of the publication volume, China led with 2,385 articles. Harvard University emerged as the most influential institution, boasting an average of 69.92 citations per article. Within the realm of CNNs, residual neural network (ResNet) and U-Net stood out, receiving 1,602 and 1,419 citations, respectively, which highlights the significant attention these models have received. The impact of coronavirus disease 2019 (COVID-19) was unmistakable, as reflected by the publication of 597 articles, making it a focal point of research. Additionally, among various disease topics, with 290 articles, brain-related research was the most prevalent. Computed tomography (CT) imaging dominated the research landscape, representing 73% of the 30 different topics. Conclusions: Over the past 11 years, CNN-related research in medical imaging has grown exponentially. The findings of the present study provide insights into the field's status and research hotspots. In addition, this article meticulously chronicled the development of CNNs and highlighted key milestones, starting with LeNet in 1989, followed by a challenging 20-year exploration period, and culminating in the breakthrough moment with AlexNet in 2012. Finally, this article explored recent advancements in CNN technology, including semi-supervised learning, efficient learning, trustworthy artificial intelligence (AI), and federated learning methods, and also addressed challenges related to data annotation costs, diagnostic efficiency, model performance, and data privacy.

Restoring BARX2 in OSCC reverses partial EMT and suppresses metastasis through miR-186-5p/miR-378a-3p-dependent SERPINE2 inhibition.

Tumor cells undergoing partial epithelial-mesenchymal transition (pEMT) are pivotal in local invasion and lymphatic metastasis of oral squamous cell carcinoma (OSCC), yet the mechanisms behind pEMT reversal remain poorly understood. In this study, the loss of BARX2 expression was revealed during the process of oral epithelial carcinogenesis and identified to activate the pEMT program, facilitate metastasis, and be associated with poor prognosis. Restoring BARX2 expression in OSCC cell lines effectively reversed tumor pEMT, evident in E/N-Cadherin switching, reduced cell invasion, proliferation, and stemness, and inhibited murine lung metastasis. BARX2 re-expression negatively correlated with several pEMT markers, notably SERPINE2, which was enriched in the invasive OSCC front, enhancing stemness and promoting metastasis, particularly in cervical lymph nodes. Furthermore, rescuing SERPINE2 impaired the inhibitory effect of BARX2 on the pEMT programs and reconstructed ECM through re-expression of MMP1. Mechanistically, we identified that BARX2 inhibited SERPINE2 through activating miR-186-5p and miR-378a-3p. These miRNAs, upregulated by BARX2, post-transcriptionally degraded SERPINE2 mRNA via targeting specific sequences. Blocking miR-186-5p and miR-378a-3p effectively abolished the negative regulatory effect of BARX2 on SERPINE2. Overall, our findings highlight BARX2 as a partial EMT-reverser in OSCC, providing fresh therapeutic prospects for restoring BARX2 signaling to inhibit invasion and metastasis.

Thermosensitive gel-nano system against esophageal cancer via restoring p53 activity and boosting T-cell immunity.

In esophageal cancer (EC), clinical specimen testing has uncovered a significant increase in BTB and CNC homolog 1 (BACH1) expression and a shift towards an immunosuppressive environment, alongside a notable decrease in p53 protein expression. Therefore, therapeutic strategies focusing on BACH1 inhibition and p53 upregulation appear promising. Traditional oral treatments for EC lack precision and efficacy. Here, we propose a novel approach employing tumor-targeted nanoparticles (NPs) for drug delivery. However, the formation of a drug reservoir at the esophageal site, crucial for the sustained release of therapeutics, presents significant challenges in nano-delivery systems for EC treatment. To address this, we developed a thermosensitive hydrogel composed of F127 and tannic acid, serving as a vehicle for NP loading. These NPs, synthesized through the emulsion/volatization methods of mPEG-PLGA-PLL-cRGD, facilitate in situ drug delivery. Upon contacting esophageal tissue, the hydrogel transitions to a gel, adhering to the lining and enabling sustained release of encapsulated therapeutics. The formulation encompasses NPs laden with small interfering RNA targeting BACH1 (siBACH1) and the p53 activator PRIMA-1, creating a cohesive gel-nano system. Preliminary biological assessments demonstrate that this injectable, thermosensitive gel-nano system adheres effectively to esophageal tissue and targets EC cells. For better modeling clinical outcomes, a patient-derived organoid xenograft (PDOX) model was innovated, involving transplantation of EC-derived organoids into humanized mice, reconstructed with peripheral blood mononuclear cells (PBMCs). Post-treatment analysis showed substantial EC growth inhibition (89.51% tumor inhibition rate), significant BACH1 level reduction, restored anti-tumor immune responses, and pronounced tumor apoptosis. In summary, our study introduces a thermosensitive gel-nano system for EC treatment via restoring p53 activity and boosting T-cell immunity, with potential for clinical application.

Revealing prognostic insights of programmed cell death (PCD)-associated genes in advanced non-small cell lung cancer.

The management of patients with advanced non-small cell lung cancer (NSCLC) presents significant challenges due to cancer cells' intricate and heterogeneous nature. Programmed cell death (PCD) pathways are crucial in diverse biological processes. Nevertheless, the prognostic significance of cell death in NSCLC remains incompletely understood. Our study aims to investigate the prognostic importance of PCD genes and their ability to precisely stratify and evaluate the survival outcomes of patients with advanced NSCLC. We employed Weighted Gene Co-expression Network Analysis (WGCNA), Least Absolute Shrinkage and Selection Operator (LASSO), univariate and multivariate Cox regression analyses for prognostic gene screening. Ultimately, we identified seven PCD-related genes to establish the PCD-related risk score for the advanced NSCLC model (PRAN), effectively stratifying overall survival (OS) in patients with advanced NSCLC. Multivariate Cox regression analysis revealed that the PRAN was the independent prognostic factor than clinical baseline factors. It was positively related to specific metabolic pathways, including hexosamine biosynthesis pathways, which play crucial roles in reprogramming cancer cell metabolism. Furthermore, drug prediction for different PRAN risk groups identified several sensitive drugs explicitly targeting the cell death pathway. Molecular docking analysis suggested the potential therapeutic efficacy of navitoclax in NSCLC, as it demonstrated strong binding with the amino acid residues of C-C motif chemokine ligand 14 (CCL14), carboxypeptidase A3 (CPA3), and C-X3-C motif chemokine receptor 1 (CX3CR1) proteins. The PRAN provides a robust personalized treatment and survival assessment tool in advanced NSCLC patients. Furthermore, identifying sensitive drugs for distinct PRAN risk groups holds promise for advancing targeted therapies in NSCLC.

Phosphoproteomics reveals a novel mechanism underlying the proarrhythmic effects of nilotinib, vandetanib, and mobocertinib.

The use of tyrosine kinase inhibitors (TKIs) has resulted in significant occurrence of arrhythmias. However, the precise mechanism of the proarrhythmic effect is not fully understood. In this study, we found that nilotinib (NIL), vandetanib (VAN), and mobocertinib (MOB) induced the development of "cellrhythmia" (arrhythmia-like events) in a concentration-dependent manner in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Continuous administration of NIL, VAN, or MOB in animals significantly prolonged the action potential durations (APD) and increased susceptibility to arrhythmias. Using phosphoproteomic analysis, we identified proteins with altered phosphorylation levels after treatment with 3 µM NIL, VAN, and MOB for 1.5 h. Using these identified proteins as substrates, we performed kinase-substrate enrichment analysis to identify the kinases driving the changes in phosphorylation levels of these proteins. MAPK and WNK were both inhibited by NIL, VAN, and MOB. A selective inhibitor of WNK1, WNK-IN-11, induced concentration- and time-dependent cellrhythmias and prolonged field potential duration (FPD) in hiPSC-CMs in vitro; furthermore, administration in guinea pigs confirmed that WNK-IN-11 prolonged ventricular repolarization and increased susceptibility to arrhythmias. Fingding indicated that WNK1 inhibition had an in vivo and in vitro arrhythmogenic phenotype similar to TKIs. Additionally,three of TKIs reduced hERG and KCNQ1 expression at protein level, not at transcription level. Similarly, the knockdown of WNK1 decreased hERG and KCNQ1 protein expression in hiPSC-CMs. Collectively, our data suggest that the proarrhythmic effects of NIL, VAN, and MOB occur through a kinase inhibition mechanism. NIL, VAN, and MOB inhibit WNK1 kinase, leading to a decrease in hERG and KCNQ1 protein expression, thereby prolonging action potential repolarization and consequently cause arrhythmias.

The Role of Natural Killer Cells in the Tumor Immune Microenvironment of EBV-Associated Nasopharyngeal Carcinoma.

Endemic nasopharyngeal carcinoma (NPC) is closely associated with the Epstein-Barr virus (EBV), which contributes to tumor development and influences the tumor immune microenvironment (TIME) in NPC. Natural killer (NK) cells, as part of the innate immune system, play a crucial role in responding to viral infections and malignant cell transformations. Notably, NK cells possess a unique ability to target tumor cells independent of major histocompatibility complex class I (MHC I) expression. This means that MHC I-deficient tumor cells, which can escape from effective T cell attack, are susceptible to NK-cell-mediated killing. The activation of NK cells is determined by the signals generated through inhibitory and activating receptors expressed on their surface. Understanding the role of NK cells in the complex TIME of EBV+ NPC is of utmost importance. In this review, we provide a comprehensive summary of the current understanding of NK cells in NPC, focusing on their subpopulations, interactions, and cytotoxicity within the TIME. Moreover, we discuss the potential translational therapeutic applications of NK cells in NPC. This review aims to enhance our knowledge of the role of NK cells in NPC and provide valuable insights for future investigations.

Differential Impact of 0.01% and 0.05% Atropine Eyedrops on Ocular Surface in Young Adults.

Purpose: To evaluate the effect of low-concentration (0.01% and 0.05%) atropine eyedrops on ocular surface characteristics in young adults. Methods: Twenty-six myopic students aged 18 to 30 years were randomly assigned to receive either 0.01% or 0.05% atropine once nightly for 14 days, followed by cessation, with a ≥14-day interval between each administration. Assessments were conducted one, two, seven, and 14 days after using atropine with corresponding timepoints after atropine cessation. Tear meniscus height and first and average noninvasive keratograph tear film breakup time (NIKBUT-first, NIKBUT-average) were measured using Keratograph 5M, whereas the objective scatter index (OSI) was measured by OQAS II devices; the ocular surface disease index (OSDI) score was also obtained. Results: The mean OSI peaked after two days of administration of 0.05% atropine (ß = 0.51, P = 0.001), accompanied by significant decreases in NIKBUT-first (ß = -7.73, P < 0.001) and NIKBUT-average (ß = -8.10, P < 0.001); the OSDI peaked after 14 days (ß = 15.41, P < 0.001). The above parameters returned to baseline one week after atropine discontinuation (all P > 0.05). NIKBUT-first and NIKBUT-average reached their lowest points after 14 days of 0.01% atropine administration (NIKBUT-first: ß = -4.46, P = 0.005; NIKBUT-average: ß = -4.42, P = 0.001), but those significant changes were diminished once atropine treatment stopped. Conclusions: Young adult myopes experienced a significant but temporary impact on the ocular surface with 0.05% atropine administration, whereas 0.01% atropine had a minimal effect. Translational Relevance: The investigation of the ocular surface effects of different concentrations of atropine may inform evidence-based clinical decisions regarding myopia control in young adults.

Large-Scale Synthesis of Highly Porous CuO/Cu2O/Cu/Carbon Derived from Aerogels for Lithium-Ion Battery Anodes.

In this work, an effective strategy for the large-scale fabrication of highly porous CuO/Cu2O/Cu/carbon (P-Cu-C) has been established. Cu-cross-linked aerogels were first continuously prepared using a continuous flow mode to form uniform beads, which were transformed into P-Cu-C with a subsequent pyrolysis process. Various pyrolysis temperatures were used to form a series of P-Cu-C including P-Cu-C-250, P-Cu-C-200, P-Cu-C-350, and P-Cu-C-450 to investigate suitable pyrolysis conversion processes. The obtained P-Cu-C series were utilized as anodes of lithium-ion batteries, in which P-Cu-C-250 exhibited a higher reversible gravimetric capacity, excellent rate capability, and superior cycle stability. The enhanced behavior of P-Cu-C-250 was benefitted from the synergistic interaction between uniformly dispersed CuO, Cu2O, Cu nanoparticles, and highly graphitized carbon with a large surface area and highly porous structure. More importantly, the preparation of P-Cu-C-250 could be scaled up by taking advantage of the continuous flow synthesis mode, which may provide pilot- or industrial-scale applications. The large-scale fabrication proposed here may give a universal method to fabricate highly porous metal oxide-carbon anode materials for electrochemical energy conversion and storage applications. Porous CuO/Cu2O/Cu/carbon derived from Cu-crosslinked aerogels was used as Li-ion battery anode materials, exhibiting a high reversible areal capacity, large gravimetric capacity, superior cycling performance, and excellent rate capacity. A continuous preparation method is established to ensure the product scaled up.

Effect of spectacle lenses with aspherical lenslets on choroidal thickness in myopic children: a 3-year follow-up study.

BACKGROUND: To investigate the impact of wearing spectacle lenses with highly aspherical lenslets (HAL) for 3 years and the impact of switching from single-vision lenses (SVL) to HAL on choroidal thickness (ChT). METHODS: Fifty-one participants who had already worn HAL for 2 years continued wearing them for an additional year (HAL group). Further, 50 and 41 participants who had worn spectacle lenses with slightly aspherical lenslets (SAL) and SVL for 2 years, respectively, switched to wearing HAL for another year (SAL-HAL and SVL-HAL groups). Additionally, 48 new participants aged 10-15 years were enrolled to wear SVL at the third year (new-SVL group). ChT was measured every 6 months throughout the study. RESULTS: Significant differences were observed in the changes in ChT among the four groups at the third year (all P < 0.05 except for the outer nasal region: P = 0.09), with the new-SVL group showing larger reductions compared with the other three groups. However, none of the three HAL-wearing groups showed significant changes in ChT at the third year (all P > 0.05). When comparing the changes in ChT for 3 years among the HAL, SAL-HAL, and SVL-HAL groups, significant differences were found before switching to HAL, but these differences were abolished after all participants switched to HAL. CONCLUSIONS: Compared to those in the SVL group, choroid thinning was significantly inhibited in all the HAL groups. Wearing HAL for 3 years no longer had a choroidal thickening effect but could still inhibit choroidal thinning compared to wearing SVL. TRIAL REGISTRATION: The study was registered at the Chinese Clinical Trial Registry (ChiCTR1800017683), http://www.chictr.org.cn/showproj.aspx?proj=29789 .