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Mutant epidermal growth factor receptor (EGFR) is a common driver of non-small cell lung cancer (NSCLC). While mutant EGFR has been reported to limit the efficacy of immunotherapy, a subset of EGFR mutant NSCLC patients benefit from treatment with immune checkpoint inhibitors. A better understanding of how co-occurring genomic alterations in oncogenic driver genes impact immunotherapy efficacy may provide a more complete understanding of cancer heterogeneity and identify biomarkers of response. Here, we investigated the effects of frequent EGFR co-mutations in EGFR mutant lung cancer models and identified loss-of-function mutation of CDKN2A as a potential sensitizer to anti-PD-1 treatment in vitro and in vivo. Mechanistically, CDKN2A loss impacted the composition of the tumor immune microenvironment (TIME) by promoting the expression of PD-L2 through reduced ubiquitination of c-Myc, and mutant EGFR cooperated to upregulate c-Myc and PD-L2 by activating the MAPK pathway. Blocking PD-L2 induced anti-tumor immune responses mediated by CD8+ T cells in EGFR/CDKN2A co-mutated lung cancer. Importantly, a small-molecule PD-L2 inhibitor, zinc undecylenate, remodeled the TIME of EGFR/CDKN2A co-mutant tumors and enhanced the anti-tumor efficacy of EGFR-tyrosine kinase inhibitors. Collectively, these results identify EGFR/CDKN2A co-mutation as a distinct subtype of NSCLC that shows superior sensitivity to immune checkpoint blockade and reveals a potential combined therapeutic strategy for treating this NSCLC subtype.

Existing studies mainly focused on the inhibition of the task-interfering response to understand the inhibitory deficits of obsessive-compulsive disorder (OCD). However, recent studies suggested that inhibitory function is broadly involved in response preparation and implementation. It is yet unknown if the inhibition dysfunction in OCD extends beyond the task-interfering response to the general inhibitory function. Here we address this issue based on the multidimensional eye-movement measurements, which can better capture the inhibitory deficits than manual responses. Thirty-one OCD patients and 32 healthy controls (HCs) completed the anti-saccade task where multidimensional eye-movement features were developed. Confirmatory factor analysis (CFA) suggested two components of inhibitory function that negatively correlated with each other: one component of oculomotor hyperactivity in generating oculomotor output which is characterized with early premature saccades, early cross rates and saccade number; the other component of task-specific oculomotor efficiency which is characterized with task accuracy, saccade latency, correction rate, and amplitude gain. Importantly, OCD showed both stronger oculomotor hyperactivity and deficient oculomotor efficiency than HCs, and the machine-learning-based classifications showed that the features of oculomotor hyperactivity had higher prediction accuracy than the features of oculomotor efficiency in distinguishing OCD from HCs. Our results suggested that OCD has concurrent deficits in oculomotor hyperactivity and oculomotor efficiency, which may originate from a common inhibitory dysfunction., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Identifying epitopes and their corresponding T-cell receptor (TCR) sequences is crucial in the face of rapidly mutating viruses. Peptide synthesis is often required to confirm the exact epitope sequences, which is time-consuming and expensive. In this study, we introduce a scalable workflow to identify the exact sequences of virus epitopes and reactive TCRs targeting the epitopes from memory T cells. Following the narrowing down of epitopes to specific regions via the tandem minigene (TMG) system, our workflow incorporates the utilization of peptide-major histocompatibility complex-displaying yeasts (pMHC-displaying yeasts) to rapidly screen immunogenic epitopes' precise sequences, obviating the necessity for the chemical synthesis of peptides. Focusing on SARS-CoV-2, we identify the precise sequences of reactive TCRs, targeting conserved epitopes across the Coronaviridae family, from the blood of COVID-19-recovered individuals over 8 months. Notably, we reveal that at least 75% (6/8) of the tested donors harbor T cells targeting a shared epitope, KTFPPTEPK, derived from the N protein. Furthermore, several identified TCRs exhibit cross-reactivity to mutant epitopes, suggesting a potential mechanism for sustained T-cell responses against emerging SARS-CoV-2 variants., (© 2024. The Author(s).)

Background: The primary goal of the intensive care unit is to the anxiety of conscious patients is often ignored in the care unit., Aim: The purpose of this study was to assess the efficacy of various non-pharmacological therapies for anxiety disorders in adult patients in the intensive care unit, in order to enhance humanistic care in the intensive care unit and to promote the patients' physical and mental recovery together., Study Design: We conducted a systematic and comprehensive search of the literature in five databases (including the Cochrane Library, PubMed, EBSCO, Web of Science, and Embase) covering nearly a decade for randomized controlled trials of non-pharmacological therapies to reduce anxiety in adult intensive care unit patients. Two researchers independently assessed the quality of the literature, collected and condensed the data, and used STATA software to perform a network meta-analysis. The ranking probabilities for each intervention were calculated using the Surface under the Cumulative Ranking (SUCRA) method. The study protocol was registered with PROSPERO., Results: This study ultimately included 26 randomized controlled trials involving 2791 adult ICU patients. Non-pharmacological interventions for anxiety in adult ICU patients included music therapy, aromatherapy, ICU diary, virtual reality, massage therapy, monitoring room diary, and health education. when compared to the control group (usual care), aromatherapy + music therapy [MD = -2.65, 95% CI (-4.76, -0.54)] (P = 0.0137) and music therapy [MD = -1.77, 95% CI (-3.40, -0.13)] (P = 0.0338) were superior in reducing anxiety in adult ICU patients. The results of the network meta-analysis showed that aromatherapy combined with music therapy significantly alleviated anxiety in adult ICU patients (SUCRA: 99.8%)., Conclusions: Music therapy combined with aromatherapy has demonstrated superior effectiveness compared to other non-pharmacological interventions for reducing anxiety in awake adults in the ICU. However, the underlying mechanisms of this combined therapy require further exploration., Relevance to Clinical Practice: Future research on the use of music therapy combined with aromatherapy in the care unit may help reduce anxiety in patients while fostering their physical and mental healing; however, individual variances and unique clinical circumstances must be considered., (© 2024 The Author(s). Nursing in Critical Care published by John Wiley & Sons Ltd on behalf of British Association of Critical Care Nurses.)

Background: Given the prevalent utilization of integrated traditional Chinese and western medicine (ITCWM) in the management of acute pancreatitis, the majority of studies have concentrated on severe cases, lacking robust evidence-based medical research. Real-world investigations can provide an objective assessment of the clinical effectiveness of combining traditional Chinese medicine with western medicine. Consequently, relying on real-world research, we intend to evaluate the clinical efficacy and safety of the combined approach in treating mild to moderate acute pancreatitis., Methods: A total of 563 AP patients from Henan Provincial Hospital of Traditional Chinese Medicine were collected from January 2019 to October 2023. A propensity score matching (PSM) analysis was conducted to evaluate the clinical efficacy of traditional Chinese medicine (TCM) in treating mild to moderate acute pancreatitis. Patients were divided into a control group (61 cases) and an integrated traditional Chinese and Western medicine (ITCWM) group (120 cases). To further assess the clinical efficacy of TCM enema in the treatment of mild to moderate acute pancreatitis, PSM analysis was conducted across three groups. The patients were categorized into a control group ( n = 49), an oral TCM treatment group (OCM group, n = 274), and an oral TCM plus enema treatment group (OCM+E group, n = 131). Logistic regression was used to analyze factors after treatment in each group, and the Kaplan-Meier method compared symptom duration in each group., Results: Compared with the control group, the ITCWM group significantly decreased C-reactive protein (CRP, mg/L) (17.8 [1.2-59.5] vs. 8.0 [3.3-33.5], P = 0.022), shortened the duration of abdominal distension, abdominal pain, nausea and bitter taste symptoms ( P < 0.05), and shortened the length of hospital stay (median 19.0 and 11.5 days, respectively, P = 0.001); Compared with the other two groups, the neutrophil percentage (NEUT%) was lower (74.1 vs. 61.9 vs. 59.5, P < 0.05) and serum prealbumin (PA, mg/L) was higher (116.0 vs. 184.4 vs. 220.0, P < 0.05), the length of hospitalization (days) was shortened (19.0 vs.12.0 vs.10.0, P < 0.05) in the OCM+E group., Conclusion: The combination of traditional Chinese medicine and modern medicine has been shown to effectively decrease inflammatory indicators in patients with mild to moderate acute pancreatitis, leading to a reduction in symptom duration and hospitalization period, as well as promoting disease recovery. Notably, the use of traditional Chinese medicine in conjunction with enema therapy yields more pronounced benefits., 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 © 2024 Jia, Chen, Liu, Li, Wang, Li and Hu.)

Cognitive dysfunction has been accepted as a possible complication of type 2 diabetes (T2D), but few studies revealed the potential roles of Long non‑coding RNAs (lncRNAs) in cognitive dysfunction in T2D. The current research aims to demonstrate the specific expression patterns of lncRNA-mRNA in the hippocampi of T2D db/db mice exhibiting cognitive impairment. In this study, the results from behavioral tests showed that T2D db/db mice displayed short-term and spatial working memory deficits compared to db/m mice. Furthermore, western blot analysis demonstrated that compared with db/m mice, p-GSK3β (ser9) protein levels were markedly elevated in T2D db/db mice (P < 0.01). In addition, though not statistically significant, the ratio of p-Tau (Ser396) to Tau 46, α-Synuclein expression, and p-GSK3α (ser21) expression were also relatively higher in T2D db/db mice than in db/m mice. The microarray profiling revealed that 75 lncRNAs and 26 mRNAs were dysregulated in T2D db/db mice (> 2.0 fold change, P < 0.05). GO analysis demonstrated that the differentially expressed mRNAs participated in immune response, extracellular membrane-bounded organelle, and extracellular region. KEGG analysis revealed that the differentially expressed mRNAs were mainly involved in one carbon pool by folate, glyoxylate and dicarboxylate metabolism, autophagy, glycine, serine and threonine metabolism, and B cell receptor signaling pathway. A lncRNA‑mRNA coexpression network containing 71 lncRNAs and 26 mRNAs was built to investigate the interaction between lncRNA and mRNA. Collectively, these results revealed the differential hippocampal expression profiles of lncRNAs in T2D mice with cognitive dysfunction, and the findings from this study provide new clues for exploring the potential roles of lncRNAs in the pathogenesis of cognitive dysfunction in T2D., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In the field of oil drilling, accurately predicting the Rate of Penetration (ROP) is crucial for improving drilling efficiency and reducing costs. Traditional prediction methods and existing machine learning approaches often lack accuracy and generalization capabilities, leading to suboptimal results in practical applications. This study proposes an end-to-end ROP prediction model based on BiLSTM-SA-IDBO, which integrates Bidirectional Long Short-Term Memory (BiLSTM), a Self-Attention mechanism (SA), and an Improved Dung Beetle Optimization algorithm (IDBO), incorporating the Bingham physical equation.We enhanced the DBO algorithm by using Sobol sequences for population initialization and integrating the Golden Sine algorithm and dynamic subtraction factors to develop a more robust IDBO. This optimized the BiLSTM-SA model, resulting in a BiLSTM-SA-IDBO model with an RMSE of 0.065, an R² of 0.963, and an MAE of 0.05 on the test set. Compared to the original BiLSTM-SA model, these metrics improved by 78%, 21%, and 83%, respectively. Additionally, we compared this model with BP Neural Network, Random Forest, XGBoost, and LSTM models, and found that our proposed model significantly outperformed these traditional models. Finally, through practical testing, the model's excellent predictive ability and generalization were verified, demonstrating its great potential for practical applications., (© 2024. The Author(s).)

Background: Pituitary tumor-transforming gene 1 (PTTG1) is an important gene in tumour development. However, the relevance of PTTG1 in tumour prognosis, immunotherapy response, and medication sensitivity in human pan-cancer has to be determined., Methods: TIMER, GEPIA, the human protein atlas, GEPIA, TISCH2, and cBioportal examined the gene expression, protein expression, prognostic value, and genetic modification landscape of PTTG1 in 33 malignancies based on the TCGA cohort. The association between PTTG1 and tumour immunity, tumour microenvironment, immunotherapy response, and anticancer drug sensitivity was investigated using GSCA, TIDE, and CellMiner CDB. Molecular docking was used to validate the possible chemotherapeutic medicines for PTTG1. Additionally, siRNA-mediated knockdown was employed to confirm the probable role of PTTG1 in paclitaxel-resistant cells., Results: PTTG1 is overexpressed and associated with poor survival in most tumors. Functional enrichment study revealed that PTTG1 is involved in the cell cycle and DNA replication. A substantial connection between PTTG1 expression and immune cell infiltration points to PTTG1's possible role in the tumour microenvironment. High PTTG1 expression is associated with tumour immunotherapy resistance. The process could be connected to PTTG1, which mediates T cell exhaustion and promotes cytotoxic T lymphocyte malfunction. Furthermore, PTTG1 was found to be substantially linked with sensitivity to several anticancer medications. Suppressing PTTG1 with siRNA reduced clone formation and migration, implying that PTTG1 may play a role in paclitaxel resistance., Conclusion: PTTG1 shows potential as a cancer diagnostic, prognostic, and chemosensitivity marker. Increased PTTG1 expression is linked to resistance to cancer treatment. The mechanism could be linked to PTTG1's role in promoting cytotoxic T lymphocyte dysfunction and mediating T cell exhaustion. It is feasible to consider PTTG1, which is expressed on Treg and Tprolif cells, as a new therapeutic target for overcoming immunotherapy resistance., (© 2024. The Author(s).)

Linguistic communication is often considered as an action serving the function of conveying the speaker's goal to the addressee. Although neuroimaging studies have suggested a role of the motor system in comprehending communicative functions, the underlying mechanism is yet to be specified. Here, by two EEG experiments and a tACS experiment, we demonstrate that the frontocentral beta oscillation, which represents action states, plays a crucial part in linguistic communication understanding. Participants read scripts involving two interlocutors and rated the interlocutors' attitudes. Each script included a critical sentence said by the speaker expressing a context-dependent function of either promise, request, or reply to the addressee's query. These functions were behaviorally discriminated, with higher addressee's will rating for the promise than for the reply and higher speaker's will rating for the request than for the reply. EEG multivariate analyses showed that different communicative functions were represented by different patterns of the frontocentral beta activity but not by patterns of alpha activity. Further tACS results showed that, relative to alpha tACS and sham stimulation, beta tACS improved the predictability of communicative functions of request or reply, as measured by the speaker's will rating. These results convergently suggest a causal role of the frontocentral beta activities in comprehending linguistic communications., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

A unary system is the most conceptually concise design for conducting self-assembly. However, in most DNA-guided self-assembly schemes, a unary system has rarely been adopted because of the inherent challenge of strictly decoupling the monomer synthesis process from the assembly process, which may directly lead to the inaccurate control over assembly. Herein, we provide a multi-stimulus-triggered assembly strategy based on the DNA origami structure, which allows the unary system to realize controllable crystallization and phase transition by exerting allosteric stimuli. We intentionally introduced a specific DNA stimulus to convert the self-aggregation of functionalized groups into the connection of nearby monomers, thus producing multidimensional high-quality crystals. Furthermore, this unary system can undergo a phase transition from simple cubic to face-centered cubic with the introduction of more cation stimuli. We believe that this dynamic stimulation strategy can offer a novel solution for fabricating materials with on-demand modulation.

Background: The pathophysiological mechanisms underlying migraine without aura (MwoA) in females remain incompletely elucidated. Currently, the association between headache laterality and iron deposition (ID), and functional connectivity (FC) in female MwoA patients has not been fully studied., Methods: We prospectively recruited 63 female patients with MwoA and 31 matched healthy controls (HC) from the hospital. ID and FC among the four groups were analyzed using two-sample t-tests (with cluster-wise family-wise error [FWE] correction). Pearson correlation analysis was used to evaluate the relationships between clinical variables and both ID and FC values. Significance level: p < 0.05., Results: Compared to HC, left-sided MwoA exhibited differences in ID in various brain regions, including the cerebellum, left orbital inferior frontal gyrus, left calcarine gyrus, right putamen, and left caudate nucleus, as well as exhibited enhanced FC between the left lobule III of the cerebellum and the right superior temporal gyrus. Compared to bilateral MwoA, left-sided MwoA showed significantly enhanced in FC values in the left calcarine gyrus, the right precentral gyrus, the right postcentral gyrus, and the right lingual gyrus. Additionally, significant differences were observed in the Pearson correlations between clinical variables and both ID and FC in the female MwoA subgroups., Conclusion: Our study provided preliminary evidence indicating significant differences in ID, FC, and correlations among subgroups of female MwoA. This provides neuroimaging references for further subclassifying MwoA patients. This offers valuable insights into potential pathophysiological mechanisms linked to the brain functional impairment in female MwoA., (© 2024 The Author(s). Brain and Behavior published by Wiley Periodicals LLC.)

Given the considerable potential of DOT1L R231Q inhibitors in lung cancer therapy and the problematic pharmacokinetics of nucleoside inhibitors, our group launched a development program of non-nucleoside DOT1L R231Q inhibitors to improve the pharmacokinetic properties. Herein, two series of non-nucleoside compounds bearing piperidine or 3-(aminomethyl)pyrrolidin-3-ol as "ribose mimics" were designed and evaluated through antiproliferation assay and western blot analysis. The optimal TB22 inhibited the proliferation of H460 R231Q cells with an IC 50 value of 2.85 μM, about 13-fold more potent than SGC0946. Notably, TB22 demonstrated significant in vivo efficacy (TGI = 60.57%) in H460 R231Q cell-derived xenograft models and improved pharmacokinetic properties ( t 1/2 = 6.06 ± 2.94 h and CL = 55.18 ± 8.56 mL/kg/min). Moreover, a mechanism study validated that TB22 suppressed malignant phenotypes of lung cancer cells harboring R231Q mutation via the MAPK/ERK signaling pathway. This work provides a promising molecule for lung cancer therapy in favor of clinical patients.

Background: Deformable image registration is an essential technique of medical image analysis, which plays important roles in several clinical applications. Existing deep learning-based registration methods have already achieved promising performance for the registrations with small deformations, while it is still challenging to deal with the large deformation registration due to the limits of the image intensity-similarity-based objective function., Purpose: To achieve the image registration with large-scale deformations, we proposed a multilevel network architecture FCNet to gradually refine the registration results based on semantic feature consistency constraint and flow normalization (FN) strategy., Methods: At each level of FCNet, the architecture is mainly composed to a FeaExtractor, a FN module, and a spatial transformation module. FeaExtractor consists of three parallel streams which are used to extract the individual features of fixed and moving images, as well as their joint features, respectively. Using these features, the initial deformation field is estimated, which passes through a FN module to refine the deformation field based on the difference map of deformation filed between two adjacent levels. This allows the FCNet to progressively improve the registration performance. Finally, a spatial transformation module is used to get the warped image based on the deformation field. Moreover, in addition to the image intensity-similarity-based objective function, a semantic-feature consistency constraint is also introduced, which can further promote the alignments by imposing the similarity between the fixed and warped image features. To validate the effectiveness of the proposed method, we compared our method with the state-of-the-art methods on three different datasets. In EMPIRE10 dataset, 20, 3, and 7 fixed and moving 3D computer tomography (CT) image pairs were used for training, validation, and testing respectively; in IXI dataset, atlas to individual image registration task was performed, with 3D MR images of 408, 58, and 115 individuals were used for training, validation, and testing respectively; in the in-house dataset, patient to atlas registration task was implemented, with the 3D MR images of 94, 3, and 15 individuals being training, validation, and testing sets, respectively., Results: The qualitative and quantitative comparison results demonstrated that the proposed method is beneficial for handling large deformation image registration problems, with the DSC and ASSD improved by at least 1.0% and 25.9% on EMPIRE10 dataset. The ablation experiments also verified the effectiveness of the proposed feature combination strategy, feature consistency constraint, and FN module., Conclusions: Our proposed FCNet enables multiscale registration from coarse to fine, surpassing existing SOTA registration methods and effectively handling long-range spatial relationships., (© 2024 American Association of Physicists in Medicine.)

Metastasis is the major cause of treatment failure in patients with prostate adenocarcinoma (PRAD). Diverse programmed cell death (PCD) patterns play an important role in tumor metastasis and hold promise as predictive indicators for PRAD metastasis. Using the LASSO Cox regression method, we developed PCD score (PCDS) based on differentially expressed genes (DEGs) associated with PCD. Clinical correlation, external validation, functional enrichment analysis, mutation landscape analysis, tumor immune environment analysis, and immunotherapy analysis were conducted. The role of Prostaglandin D2 Synthase (PTGDS) in PRAD was examined through in vitro experiments, single-cell, and Mendelian randomization (MR) analysis. PCDS is elevated in patients with higher Gleason scores, higher T stage, biochemical recurrence (BCR), and higher prostate-specific antigen (PSA) levels. Individuals with higher PCDS are prone to metastasis, metastasis after BCR, BCR, and castration resistance. Moreover, PRAD patients with low PCDS responded positively to immunotherapy. Random forest analysis and Mendelian randomization analysis identified PTGDS as the top gene associated with PRAD metastasis and in vitro experiments revealed that PTGDS was considerably downregulated in PRAD cells against normal prostate cells. Furthermore, the overexpression of PTGDS was found to suppress the migration, invasion, proliferationof DU145 and LNCaP cells. To sum up, PCDS may be a useful biomarker for forecasting the possibility of metastasis, recurrence, castration resistance, and the efficacy of immunotherapy in PRAD patients. Additionally, PTGDS was identified as a viable therapeutic target for the management of PRAD., (© 2024. The Author(s).)

Objective. Respiratory motion, cardiac motion and inherently low signal-to-noise ratio (SNR) are major limitations of in vivo cardiac diffusion tensor imaging (DTI). We propose a novel enhancement method that uses unsupervised learning based invertible wavelet scattering (IWS) to improve the quality of in vivo cardiac DTI. Approach. Our method starts by extracting nearly transformation-invariant features from multiple cardiac diffusion-weighted (DW) image acquisitions using multi-scale wavelet scattering (WS). Then, the relationship between the WS coefficients and DW images is learned through a multi-scale encoder and a decoder network. Using the trained encoder, the deep features of WS coefficients of multiple DW image acquisitions are further extracted and then fused using an average rule. Finally, using the fused WS features and trained decoder, the enhanced DW images are derived. Main result. We evaluate the performance of the proposed method by comparing it with several methods on three in vivo cardiac DTI datasets in terms of SNR, contrast to noise ratio (CNR), fractional anisotropy (FA), mean diffusivity (MD) and helix angle (HA). Comparing against the best comparison method, SNR/CNR of diastolic, gastric peristalsis influenced, and end-systolic DW images were improved by 1%/16%, 5%/6%, and 56%/30%, respectively. The approach also yielded consistent FA and MD values and more coherent helical fiber structures than the comparison methods used in this work. Significance. The ablation results verify that using the transformation-invariant and noise-robust wavelet scattering features enables us to effectively explore the useful information from the limited data, providing a potential mean to alleviate the dependence of the fusion results on the number of repeated acquisitions, which is beneficial for dealing with the issues of noise and residual motion simultaneously and therefore improving the quality ofinvivocardiac DTI. Code can be found inhttps://github.com/strawberry1996/WS-MCNN., (© 2024 Institute of Physics and Engineering in Medicine. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

Background: Hepatocellular carcinoma (HCC) is an aggressive malignancy and a growing global health problem. Reserpine (Res), a plant-derived hypertension drug, has been reported to possess anti-tumor efficacy. However, the role and function of Res in N6-methyladenosine (m6A) regulation and Lenvatinib (Len) resistance in HCC have not been clarified., Purpose: To verify whether Res can be used as a natural small-molecule regulator of m6A to reverse Len resistance in HCC., Methods: Dot blotting, Western blotting and m6A quantification were used to compare and analyze the differential expression of m6A and its methyltransferase METTL3. Western blotting, Real-Time PCR (RT-PCR), cellular thermal shift assay (CETSA) and molecular docking were used to explore the mechanism of interaction between Res and m6A. The effects of Res on the biological characteristics of Lenvatinib-resistant HCC cells were investigated through CCK-8, clone formation, and Transwell assays. Cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models were used to assess the ability of Res to reverse Len resistance in vivo. MeRIP m6A sequencing, PATHWAY analysis and Western blotting were used to analyze the downstream signaling pathways and genes involved in Res-mediated reversal of Len resistance., Results: Len resistance in HCC is related to the increased m6A level and the high expression of METTL3. Res affects the activity of METTL3 protein by binding to it, thereby downregulating the level of m6A. In vitro study showed that Res can sensitize HCC cells to the anti-tumor effects of Len treatment, including blocking proliferation, inhibiting migration, and inducing apoptosis. Len-resistant CDX and PDX models revealed that Res can reverse the resistant phenotype, with the tumor inhibition rates of 77.46 % and 62.1 %, respectively, when combined with Len treatment. Analysis of xenograft tissues showed that the combination of Res and Len down-regulates the m6A level, reduces proliferation biomarkers, and induces apoptosis, which is consistent with the in vitro data. Mechanistically, our preliminary results indicate that Res can up-regulate the SMAD3 level by down-regulating m6A in Len-resistant cells., Conclusions: Reserpine, a small-molecule regulator of m6A, reverses Lenvatinib-resistant phenotypes, including proliferation, migration and anti-apoptosis, in vitro and in vivo by targeting SMAD3 and down-regulating the m6A level in HCC., Competing Interests: Declaration of competing interest All authors disclose no relevant relationships., (Copyright © 2024. Published by Elsevier GmbH.)

There is a lack of effective treatments to overcome resistance to EGFR-TKIs in EGFR mutant tumors. A deeper understanding of resistance mechanisms can provide insights into reducing or eliminating resistance, and can potentially deliver targeted treatment measures to overcome resistance. Here, we identified that the dynamic changes of the tumor immune environment were important extrinsic factors driving tumor resistance to EGFR-TKIs in EGFR mutant cell lines and syngeneic tumor-bearing mice. Our results demonstrate that the acquired resistance to EGFR-TKIs is accompanied by aberrant expression of PD-L2, leading a dynamic shift from an initially favorable tumor immune environment to an immunosuppressive phenotype. PD-L2 expression significantly affected EGFR mutant cell apoptosis that depended on the proportion and function of CD8 + T cells in the tumor immune environment. Combined with single-cell sequencing and experimental results, we demonstrated that PD-L2 specifically inhibited the proliferation of CD8 + T cells and the secretion of granzyme B and perforin, leading to reduced apoptosis mediated by CD8 + T cells and enhanced immune escape of tumor cells, which drives EGFR-TKIs resistance. Importantly, we have identified a potent natural small-molecule inhibitor of PD-L2, zinc undecylenate. In vitro, it selectively and potently blocks the PD-L2/PD-1 interaction. In vivo, it abolishes the suppressive effect of the PD-L2-overexpressing tumor immune microenvironment by blocking PD-L2/PD-1 signaling. Moreover, the combination of zinc undecylenate and EGFR-TKIs can synergistically reverse tumor resistance, which is dependent on CD8 + T cells mediating apoptosis. Our study uncovers the PD-L2/PD-1 signaling pathway as a driving factor to mediate EGFR-TKIs resistance, and identifies a new naturally-derived agent to reverse EGFR-TKIs resistance., (© 2024. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)

To promote the generalization ability of breast tumor segmentation models, as well as to improve the segmentation performance for breast tumors with smaller size, low-contrast and irregular shape, we propose a progressive dual priori network (PDPNet) to segment breast tumors from dynamic enhanced magnetic resonance images (DCE-MRI) acquired at different centers. The PDPNet first cropped tumor regions with a coarse-segmentation based localization module, then the breast tumor mask was progressively refined by using the weak semantic priori and cross-scale correlation prior knowledge. To validate the effectiveness of PDPNet, we compared it with several state-of-the-art methods on multi-center datasets. The results showed that, comparing against the suboptimal method, the DSC and HD95 of PDPNet were improved at least by 5.13% and 7.58% respectively on multi-center test sets. In addition, through ablations, we demonstrated that the proposed localization module can decrease the influence of normal tissues and therefore improve the generalization ability of the model. The weak semantic priors allow focusing on tumor regions to avoid missing small tumors and low-contrast tumors. The cross-scale correlation priors are beneficial for promoting the shape-aware ability for irregular tumors. Thus integrating them in a unified framework improved the multi-center breast tumor segmentation performance.

Purpose: This study aimed to develop a double antigen sandwich ELISA (DAgS-ELISA) method for more efficient, accurate, and quantitative detection of total antibodies against Candida albicans enolase1 (CaEno1) for diagnosing invasive candidiasis (IC)., Methods: DAgS-ELISA was developed using recombinant CaEno1 and a monoclonal antibody as the standard. Performance evaluation included limit of detection, accuracy, and repeatability. Dynamic changes in antibody levels against CaEno1 in serum from systemic candidiasis mice were analyzed using DAgS-ELISA. Patient serum samples from IC, Candida colonization, bacterial infections, and healthy controls were analyzed with DAgS-ELISA and indirect ELISA., Results: DAgS-ELISA outperformed indirect ELISA in terms of linear range and test background. In systemic candidiasis mice, a distinctive 'double-peak' pattern in dynamic antibody levels was observed. Additionally, there was a high level of consistency in the positive rates of CaEno1 antibodies detected by both DAgS-ELISA and indirect ELISA. While the positivity rates differed among patient groups, no significant variations in antibody levels were detected among the various positive patient groups., Conclusions: DAgS-ELISA offers a reliable novel approach for IC diagnosis, enabling rapid, accurate, and quantitative detection of CaEno1 antibodies. Further validation and optimization are needed for its clinical application and effectiveness., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: DNMT3A is a crucial epigenetic regulation enzyme. However, due to its heterogeneous nature and frequent mutation in various cancers, the role of DNMT3A remains controversial. Here, we determine the role of DNMT3A in non-small cell lung cancer (NSCLC) to identify potential treatment strategies., Methods: To investigate the role of loss-of-function mutations of DNMT3A in NSCLC, CRISPR/Cas9 was used to induce DNMT3A-inactivating mutations. Epigenetic inhibitor library was screened to find the synthetic lethal partner of DNMT3A. Both pharmacological inhibitors and gene manipulation were used to evaluate the synthetic lethal efficacy of DNMT3A/KDM1A in vitro and in vivo. Lastly, MS-PCR, ChIP-qPCR, dual luciferase reporter gene assay and clinical sample analysis were applied to elucidate the regulation mechanism of synthetic lethal interaction., Results: We identified DNMT3A is a tumour suppressor gene in NSCLC and KDM1A as a synthetic lethal partner of DNMT3A deletion. Both chemical KDM1A inhibitors and gene manipulation can selectively reduce the viability of DNMT3A-KO cells through inducing cell apoptosis in vitro and in vivo. We clarified that the synthetic lethality is not only limited to the death mode, but also involved into tumour metastasis. Mechanistically, DNMT3A deficiency induces KDM1A upregulation through reducing the methylation status of the KDM1A promoter and analysis of clinical samples indicated that DNMT3A expression was negatively correlated with KDM1A level., Conclusion: Our results provide new insight into the role of DNMT3A in NSCLC and elucidate the mechanism of synthetic lethal interaction between KDM1A and DNMT3A, which might represent a promising approach for treating patients with DNMT3A-deficient tumours., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Ribosome stalling during co-translational translocation at the endoplasmic reticulum (ER) causes translocon clogging and impairs ER protein biogenesis. Mammalian cells resolve translocon clogging vial a poorly characterized translocation-associated quality control (TAQC) process. Here, we combine genome-wide CRISPR screen with live cell imaging to dissect the molecular linchpin of TAQC. We show that substrates translated from mRNAs bearing a ribosome stalling poly(A) sequence are degraded by lysosomes and the proteasome, while substrates encoded by non-stop mRNAs are degraded by an unconventional ER-associated degradation (ERAD) mechanism involving ER-to-Golgi trafficking and KDEL-dependent substrate retrieval. The triaging diversity appears to result from the heterogeneity of NEMF-mediated CATylation, because a systematic characterization of representative CAT-tail mimetics establishes an AT-rich tail as a "degron" for ERAD, whereas an AG-rich tail can direct a secretory protein to the lysosome. Our study reveals an unexpected protein sorting function for CAT-tailing that safeguards ER protein biogenesis., Competing Interests: Competing interests The authors declare no competing financial interest.

Hepatocellular carcinoma (HCC) is an aggressive cancer that has an effect on human health. As a first-line drug for HCC, despite its excellent efficacy, lenvatinib (Len) is prone to developing drug resistance in HCC patients. The N6-methyladenosine (m6A) modification is not only related to the development of HCC but also shows great potential in overcoming HCC resistance. Using Dot Blot, our group first screened a small molecule m6A regulator, lobeline (Lob), from a library of 390 compounds (mostly natural products). In vitro experiments demonstrated that Lob could significantly enhance the sensitivity to Len of Len-resistant HCC (HCC/Len) and inhibit migration of resistant cells. In Len-resistant cell-derived and patient-derived xenograft models, Lob could reverse the resistant phenotype, with reductions in tumor volume of 68% and 60%, respectively. Furthermore, MeRIP-m6A sequencing results indicated that the underlying molecular mechanism of Lob reversal of HCC drug resistance was related to UBE3B. Taken together, this study highlighted that Lob, a plant derived natural product, could reverse the resistance of HCC to Len by regulating the m6A levels. It is hoped that this will provide a pharmacological research basis for the clinical treatment of HCC patients.

Objective: The objective of the study is to investigate the changes in the composition of intestinal microecology in severe acute pancreatitis (SAP) patients with or without intra-abdominal infection and also to analyze the expression of antibiotic resistance genes to provide evidence for early warning of infectious diseases and the rational use of antibiotics., Methods: Twenty patients with SAP were enrolled in the study. According to whether the enrolled patients had a secondary intra-abdominal infection, they were divided into two groups, each consisting of 10 patients. Stool specimens were collected when the patients were admitted to the emergency intensive care unit (EICU), and nucleic acid extraction was performed. Next-generation gene sequencing was used to compare the differences in intestinal microflora diversity and drug resistance gene expression between the two groups., Results: The gut microbiota of patients in the infection group exhibited distribution on multiple clustered branches with some intra-group heterogeneity, and their flora diversity was compromised. The infected group showed an enrichment of various opportunistic bacteria in the gut microbiota, along with a high number of metabolic functions, stress functions to external signals, and genes associated with pathogenesis. Drug resistance genes were expressed in the gut microbiota of both groups, but their abundance was significantly lower in the non-infected group., Conclusion: The intestinal microbiota of patients in the infection group exhibited distribution on multiple clustered branches with some intra-group heterogeneity, and their flora diversity was compromised. Additionally, drug resistance genes were expressed in the gut microbiota of both groups, although their abundance was significantly lower in the non-infected group., 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 © 2024 Wang, Zhang, Dai, Gao, Zhu and Yu.)

Single-cell-derived tumor organoids (STOs) possess a distinct genetic background, making them valuable tools for demonstrating tumor heterogeneity. In order to fulfill the high throughput demands of STO assays, we have developed a microfluidic chip containing 30 000 microwells, which is dedicated to a single cell culture approach for selective expansion and differential induction of cancer stem cells. The microwells are coated with a hydrophilic copolymer to eliminate cell adhesion, and the cell culture is supported by poly(ethylene glycol) (PEG) to establish a nonadhesive culture environment. By utilizing an input cell density of 7 × 10 3 ·mL -1 , it is possible to construct a 4000 single cell culture system through stochastic cell occupation. We demonstrate that the addition of 15% PEG10000 in the cell culture medium effectively prevents cell loss while facilitating tumor stem cell expansion. As were demonstrated by HCT116, HT29, and SW480 colon cancer cells, the microfluidic approach achieved a STO formation rate of ∼20%, resulting in over 800 STOs generated from a single culture. Comprehensive analysis through histomorphology, immunohistochemistry, drug response evaluation, assessment of cell invasion, and biomarker detection reveals the heterogeneity among individual STOs. Specifically, the smaller STOs exhibited higher invasion and drug resistance capabilities compared with the larger ones. The developed microfluidic approach effectively facilitates STO formation and offers promising prospects for investigating tumor heterogeneity, as well as conducting personalized therapy-focused drug screening.

Objective: To explore the genetic basis and clinical phenotype of a Chinese pedigree affected with Focal segmental glomerulosclerosis (FSGS)., Methods: A male patient who was admitted to the First Affiliated Hospital of Zhengzhou University on July 26, 2018 was selected as the study subject. Clinical data of the patient was collected. Next generation sequencing and Sanger sequencing were carried out to detect the variant sites. Bioinformatic software was used to simulate the effect of candidate variant on the protein functions., Results: Ultrasound exam of the patient showed enhanced echo for the renal parenchyma. Kidney biopsy had confirmed the pathological diagnosis of FSGS (non-specific). Electronic microscopy displayed segmental sclerosis of the glomeruli, mild hyperplasia of mesangial cells and matrix. The proband was found to harbor two novel variants of the PLCE1 gene, namely c.3199delA (p.N1067Mfs*15) and c.4441&#95;4443delATC (p.1481&#95;1481del), which were respectively inherited from his mother and father. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were rated as pathogenic (PVS1+PM2&#95;Supporting+PP3; PM2&#95;Supporting+PM3+PP3). Bioinformatic simulation suggested that both variants could significantly affect the tertiary structure of the PLCE1 protein., Conclusion: The c.4441&#95;4443delATC and c.3199delA variants of the PLCE1 gene probably underlay the pathogenesis of the FSGS in this pedigree.

Visual perception is enacted and constrained by the constantly moving eyes. Although it is well known that the first two fixations are crucial for face recognition, the function of each fixation remains unspecified. Here we demonstrate a central-to-divergent pattern of the two fixations and specify their functions: Fix I clustered along the nose bridge to cover the broad facial information; Fix II diverged to eyes, nostrils, and lips to get the local information. Fix II correlated more than Fix I with the differentiating information between faces and contributed more to recognition responses. While face categories can be significantly discriminated by Fix II's but not Fix I's patterns alone, the combined patterns of the two yield better discrimination. Our results suggest a functional division and collaboration of the two fixations in sampling the general-to-specific facial information and add to understanding visual perception as an active process undertaken by structural motor programs., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Recent research certified that DOT1L and its mutations represented by R231Q were potential targets for the treatment of lung cancer. Herein, a series of adenosine-containing derivatives were identified with DOT1L R231Q inhibition through antiproliferation assay and Western blot analysis in the H460 R231Q cell. The most promising compound 37 significantly reduced DOT1L R231Q mediated H3K79 methylation and effectively inhibited the proliferation, self-renewal, migration, and invasion of lung cancer cell lines at low micromolar concentrations. The cell permeability and cellular target engagement of 37 were verified by both CETSA and DARTS assays. In the H460 R231Q OE cell-derived xenograft (CDX) model, 37 displayed pronounced tumor growth inhibition after intraperitoneal administration at 20 mg/kg dose for 3 weeks (TGI = 54.38%), without obvious toxicities. A pharmacokinetic study revealed that 37 possessed tolerable properties ( t 1/2  = 1.93 ± 0.91 h, F  = 97.2%) after intraperitoneal administration in rats. Mechanism study confirmed that 37 suppressed malignant phenotypes of lung cancer carrying R231Q gain-of-function mutation via the MAPK/ERK signaling pathway. Moreover, analysis of the binding modes between molecules and DOT1L WT/R231Q proteins put forward the "Induced-fit" allosteric model in favor to the discovery of potent DOT1L candidates., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 The Authors.)

Young women undergoing anticancer treatment are at risk of premature ovarian failure (POF). Endometrial-derived stem cells (EnSCs) have demonstrated significant therapeutic potential for treating ovarian insufficiency, although the underlying mechanisms remain to be fully understood. This study aims to further investigate the therapeutic effects of EnSCs, particularly through the paracrine action of fibroblast growth factor 2 (FGF2), on POF. The findings show that exogenous FGF2 enhances the survival of ovarian granulosa cells damaged by cisplatin. FGF2 stimulates the proliferation of these damaged cells by suppressing the Hippo signaling pathway and activating YAP expression. In vivo experiments also revealed that FGF2 treatment significantly improves ovarian reserve and endocrine function in mice with POF. These results suggest that FGF2 can boost the proliferative capacity of damaged ovarian granulosa cells through the Hippo-YAP signaling pathway, providing a theoretical foundation for using EnSCs and FGF2 in clinical treatments for POF., 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 © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Although photocatalytic hydrogen production from water holds great potential as a renewable and sustainable energy alternative, the practical application of the technology demands cost-effective, simple photocatalytic systems with high efficiency in hydrogen evolution reaction (HER). Herein, the synthesis and characterization of Cu 31 S 16 /Zn x Cd 1-x S heterostructured nanoplates (Cu 31 S 16 /ZnCdS HNPs) as a high photocatalytic system are reported. The cost-effective, hierarchical structures are easily prepared using the Cu 31 S 16 NPs as the seed by the epitaxial growth of the ZnCdS nanocrystals (NCs). The Cu 31 S 16 /ZnCdS without the noble metal cocatalyst exhibits a high HER rate of 61.7 mmol g -1  h -1 , which is 8,014 and 17 times higher than that of Cu 31 S 16 and ZnCdS, respectively, under visible light irradiation. The apparent quantum yield (AQY) of Cu 31 S 16 /ZnCdS reaches 67.9% at 400 nm with the highest value so far in the reported ZnCdS-based photocatalysts. The excellent activity and stability of the Cu 31 S 16 /ZnCdS are attributed to the formation of a strong internal electric field (IEF) and the Z-scheme pathway. The comprehensive experiments and theoretical calculations provide the direct evidences of the Z-scheme route. This work may offer a way for the design and development of efficient photocatalysts to achieve solar-to-chemical energy conversion at a practically useful level., (© 2024 Wiley‐VCH GmbH.)

Acidic bacterial biofilms-associated enamel white spot lesions (WSLs) are one of the hallmarks of early caries, causing demineralization and decomposition of dental hard tissues. Therefore, to effectively prevent and treat WSLs, it is important to inhibit the activity of cariogenic bacteria while promoting the remineralization of demineralized enamel. Amorphous calcium phosphate (ACP) favors hard tissue remineralization due to its biological activity and ability to release large amounts of Ca 2+ and PO 4 3- . However, ACP-based biomineralization technology is not effective due to its lack of antimicrobial properties. Here, carboxymethyl chitosan (CMCS) was employed as a reducing agent and stabilizer, and dual-functional nanohybrids CMCS/AuNPs/ACP with biofilm resistance and mineralization properties were successfully synthesized. The addition of AuNPs enhances the antimicrobial activity and participates in regulating the formation of hydroxyapatite (HAp). The nanohybrids exhibited significant destructive effects against cariogenic bacteria and their biofilms and showed bactericidal activity under bacteria-induced acidic conditions. More importantly, this nanohybrids showed superior results in promoting the remineralization of demineralized enamel, compared to fluoride and CMCS/ACP in vitro . The CMCS/AuNPs/ACP nanohybrids not only reverse the cariogenic microenvironment at the microbial level, but also promote self-repairing of enamel WSLs regarding the microstructure. The present work offers a theoretical and experimental basis for using the CMCS/AuNPs/ACP nanohybrids as a potential dual-functional agent for the clinical treatment of enamel WSLs., 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 © 2024 Chen, Liu, Zhang, Chen, Wang, Yu and Hao.)

Cultivated peanut ( Arachis hypogaea L.) is a key oil- and protein-providing legume crop of the world. It is full of nutrients, and its nutrient profile is comparable to that of other nuts. Peanut is a unique plant as it showcases a pegging phenomenon, producing flowers above ground, and after fertilization, the developing peg enters the soil and produces seeds underground. This geocarpic nature of peanut exposes its seeds to soil pathogens. Peanut seeds are protected by an inedible pericarp and testa. The pericarp- and testa-specific promoters can be effectively used to improve the seed defense. We identified a pericarp- and testa-abundant expression gene ( AhN8DT-2 ) from available transcriptome expression data, whose tissue-specific expression was further confirmed by the qRT-PCR. The 1827bp promoter sequence was used to construct the expression vector using the pMDC164 vector for further analysis. Quantitative expression of the GUS gene in transgenic Arabidopsis plants showed its high expression in the pericarp. GUS staining showed a deep blue color in the pericarp and testa. Cryostat sectioning of stained Arabidopsis seeds showed that expression is only limited to seed coat (testa), and staining was not present in cotyledons and embryos. GUS staining was not detected in any other tissues, including seedlings, leaves, stems, and roots, except for some staining in flowers. Under different phytohormones, this promoter did not show an increase in expression level. These results indicated that the AhN8DT-2 promoter drives GUS gene expression in a pericarp- and testa-specific manner. The identified promoter can be utilized to drive disease resistance genes, specifically in the pericarp and testa, enhancing peanut seed defense against soil-borne pathogens. This approach has broader implications for improving the resilience of peanut crops and other legumes, contributing to sustainable agricultural practices and food security.

Pancreatic fat is associated with obesity and type 2 diabetes mellitus (T2DM); however, the relationship between different types of pancreatic fat and diabetes status remains unclear. Therefore, we aimed to determine the potential of different types of pancreatic fat accumulation as a risk factor for T2DM in overweight or obese patients. In total, 104 overweight or obese patients were recruited from January 2020 to December 2022. The patients were divided into three groups: normal glucose tolerance (NGT), impaired fasting glucose or glucose tolerance (IFG/IGT), and T2DM. mDixon magnetic resonance imaging (MRI) was used to detect pancreatic fat in all three groups of patients. The pancreatic head fat (PHF), body fat (PBF), and tail fat (PTF) in the IFG/IGT group were 21, 20, and 31% more than those in the NGT group, respectively. PHF, PBF, and PTF were positively associated with glucose metabolic dysfunction markers in the NGT group, and inter-lobular fat volume (IFV) was positively associated with these markers in the IFG/IGT group. The areas under the receiver operating characteristic curves for PHF, PBF, and PTF (used to evaluate their diagnostic potential for glucose metabolic dysfunction) were 0.73, 0.73, and 0.78, respectively, while those for total pancreatic volume (TPV), pancreatic parenchymal volume, IFV, and IFV/TPV were 0.67, 0.67, 0.66, and 0.66, respectively. These results indicate that intra-lobular pancreatic fat, including PHF, PTF, and PBF, may be a potential independent risk factor for the development of T2DM. Additionally, IFV exacerbates glucose metabolic dysfunction. Intra-lobular pancreatic fat indices were better than IFV for the diagnosis of glucose metabolic dysfunction., 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 © 2024 Wang, Li, Li, Luan, Cao, Liu, Hu, Chen, Bu, Liu, Wang and Lu.)

Glioma is a highly vascularized tumor of the central nervous system. Angiogenesis plays a predominant role in glioma progression and is considered an important therapeutic target. Our previous study showed that vasorin (VASN), a transmembrane protein, is overexpressed in glioma and promotes angiogenesis; however, the potential mechanism remains unclear. In this study, we found that human vascular endothelial cells (hEC) co-cultured with VASN-overexpressing glioma cells exhibited accelerated migration ability and increased expression of VASN originated from glioma cells. VASN was found in exosomes secreted by glioma cells and could be taken up by hECs. hECs showed more edge filopodia and significantly upregulated expression of endothelial tip cell marker gene and protein levels after co-culture with VASN-overexpressing glioma cells. In clinical glioma tissue and orthotopic transplantation glioma tissue, the vascular density and the number of vascular endothelial cells with a tip cell phenotype in VASN-overexpressed tissues were significantly higher than in tissues with low expression. At the molecular level, VASN interacted with VEGFR2 and caused internalization and autophosphorylation of VEGFR2 protein, and then activated the AKT signaling pathway. Our study collectively reveals the function and mechanism of VASN in facilitating angiogenesis in glioma, providing a new therapeutic target for glioma., Implications: These findings demonstrate that VASN exocytosed from glioma cells enhanced the migration of vascular endothelial cells by VEGFR2/AKT signaling pathway., (©2024 American Association for Cancer Research.)

Introduction: Obstructive sleep apnea hypopnea syndrome (OSAHS) is associated with cognitive impairment and physiological complications, necessitating further understanding of its mechanisms. This study investigates the relationship between glymphatic system function, brain network efficiency, and cognitive impairment in OSAHS patients using diffusion tensor image analysis along the perivascular space (DTI-ALPS) and resting-state fMRI., Materials and Methods: This study included 31 OSAHS patients and 34 age- and gender-matched healthy controls (HC). All participants underwent GE 3.0T magnetic resonance imaging (MRI) with diffusion tensor image (DTI) and resting-state fMRI scans. The DTI-ALPS index and brain functional networks were assessed. Differences between groups and correlations with clinical characteristics were analyzed. Additionally, the mediating role of brain network efficiency was explored. Finally, receiver operating characteristics (ROC) analysis assessed diagnostic performance., Results: OSAHS patients had significantly lower ALPS-index (1.268 vs. 1.431, p < 0.0001) and moderate negative correlation with Apnea Hypopnea Index (AHI) (r = -0.389, p = 0.031), as well as moderate positive correlation with Montreal Cognitive Assessment (MoCA) (r = 0.525, p = 0.002). Moreover, global efficiency (Eg) of the brain network was positively correlated with the ALPS-index and MoCA scores in OSAHS patients (r = 0.405, p = 0.024; r = 0.56, p = 0.001, respectively). Furthermore, mediation analysis showed that global efficiency partially mediated the impact of glymphatic system dysfunction on cognitive impairment in OSAHS patients (indirect effect = 4.58, mediation effect = 26.9 %). The AUROC for identifying OSAHS and HC was 0.80 (95 % CI 0.69 to 0.91) using an ALPS-index cut-off of 1.35., Conclusions: OSAHS patients exhibit decreased ALPS-index, indicating impaired glymphatic system function. Dysfunction of the glymphatic system can affect cognitive function in OSAHS by disrupting brain functional network, suggesting a potential underlying pathological mechanism. Additionally, preliminary findings suggest that the ALPS-index may offer promise as a potential indicator for OSAHS., Competing Interests: Declaration of competing interest No conflicts of interest exist in the submission of this manuscript, and the manuscript has been approved by all authors for publication., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Lung cancer is a major global health concern with a low survival rate, often due to late-stage diagnosis. Liquid biopsy offers a non-invasive approach to cancer detection and monitoring, utilizing various features of circulating cell-free DNA (cfDNA). In this study, we established two models based on cfDNA coverage patterns at the transcription start sites (TSSs) from 6X whole-genome sequencing: an Early Cancer Screening Model and an EGFR mutation status prediction model. The Early Cancer Screening Model showed encouraging prediction ability, especially for early-stage lung cancer. The EGFR mutation status prediction model exhibited high accuracy in distinguishing between EGFR -positive and wild-type cases. Additionally, cfDNA coverage patterns at TSSs also reflect gene expression patterns at the pathway level in lung cancer patients. These findings demonstrate the potential applications of cfDNA coverage patterns at TSSs in early cancer screening and in cancer subtyping.

Periodontitis is an inflammatory disease characterized by the destruction of periodontal tissues, and the promotion of bone tissue regeneration is the key to curing periodontitis. Psoralen is the main component of Psoralea corylifolia Linn, and has multiple biological effects, including anti-osteoporosis and osteogenesis. We constructed a novel hydrogel loaded with psoralen (PSO) and stromal cell-derived factor-1 (SDF-1) for direct endogenous cell homing. This study aimed to evaluate the synergistic effects of PSO/SDF-1 on periodontal bone regeneration in patients with periodontitis. The results of CCK8, alkaline phosphatase (ALP) activity assay, and Alizarin Red staining showed that PSO/SDF-1 combination treatment promoted cell proliferation, chemotaxis ability, and ALP activity of PDLSCs. qRT-PCR and western blotting showed that the expression levels of alkaline phosphatase (ALP), dwarf-associated transcription factor 2 (RUNX2), and osteocalcin (OCN) gene were upregulated. Rat periodontal models were established to observe the effect of local application of the composite hydrogel on bone regeneration. These results proved that the PSO/SDF-1 combination treatment significantly promoted new bone formation. The immunohistochemical (IHC) results confirmed the elevated expression of ALP, RUNX2, and OCN osteogenic genes. PSO/SDF-1 composite hydrogel can synergistically regulate the biological function and promote periodontal bone formation. Thus, this study provides a novel strategy for periodontal bone regeneration., Competing Interests: 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., (© 2024 The Authors. Published by Elsevier Ltd.)

The transformation of lung adenocarcinoma to small cell lung cancer (SCLC) is a recognized resistance mechanism and a hindrance to therapies using epidermal growth factor receptor tyrosine kinase inhibitors (TKIs). The paucity of pretranslational/posttranslational clinical samples limits the deeper understanding of resistance mechanisms and the exploration of effective therapeutic strategies. Here, we developed preclinical neuroendocrine (NE) transformation models. Next, we identified a transcriptional reprogramming mechanism that drives resistance to erlotinib in NE transformation cell lines and cell-derived xenograft mice. We observed the enhanced expression of genes involved in the EHMT2 and WNT/β-catenin pathways. In addition, we demonstrated that EHMT2 increases methylation of the SFRP1 promoter region to reduce SFRP1 expression, followed by activation of the WNT/β-catenin pathway and TKI-mediated NE transformation. Notably, the similar expression alterations of EHMT2 and SFRP1 were observed in transformed SCLC samples obtained from clinical patients. Importantly, suppression of EHMT2 with selective inhibitors restored the sensitivity of NE transformation cell lines to erlotinib and delayed resistance in cell-derived xenograft mice. We identify a transcriptional reprogramming process in NE transformation and provide a potential therapeutic target for overcoming resistance to erlotinib., Competing Interests: Competing interests statement:The authors declare no competing interest.

It is a challenge for conventional monocular-camera single-light source eye-tracking methods to achieve high-speed eye tracking. In this work, a dual-ring infrared lighting source was designed to achieve bright and dark pupils in high speed. The eye-tracking method used a dual-ring infrared lighting source and synchronized triggers for the even and odd camera frames to capture bright and dark pupils. A pupillary corneal reflex was calculated by the center coordinates of the Purkinje spot and the pupil. A map function was established to map the relationship between the pupillary corneal reflex and gaze spots. The gaze coordinate was calculated based on the mapping function. The average detection time of each gaze spot was 3.76 ms.

We formerly reported that EZH2 inhibitors sensitized HIF-1 inhibitor-resistant cells and inhibited HIF-1α to promote SUZ12 transcription, leading to enhanced EZH2 enzyme activity and elevated H3K27me3 levels, and conversely, inhibition of EZH2 promoted HIF-1α transcription. HIF-1α and EZH2 interacted to form a negative feedback loop that reinforced each other's activity. In this paper, a series of 2,2- dimethylbenzopyran derivatives containing pyridone structural fragments were designed and synthesized with DYB-03, a HIF-1α inhibitor previously reported by our group, and Tazemetostat, an EZH2 inhibitor approved by FDA, as lead compounds. Among these compounds, D-01 had significant inhibitory activities on HIF-1α and EZH2. In vitro experiments showed that D-01 significantly inhibited the migration of A549 cells, clone, invasion and angiogenesis. Moreover, D-01 had good pharmacokinetic profiles. All the results about compound D-01 could lay a foundation for the research and development of HIF-1α and EZH2 dual-targeting compounds., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Guoliang Chen reports financial support was provided by Key Research Project of Department of Education of Liaoning Province. If there are other authors, they 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 © 2024 Elsevier Inc. All rights reserved.)

Objective: To integrate an enhanced molecular diagnostic technique to develop and validate a machine-learning model for diagnosing sepsis., Methods: We prospectively enrolled patients suspected of sepsis from August 2021 to August 2023. Various feature selection algorithms and machine learning models were used to develop the model. The best classifier was selected using 5-fold cross validation set and then was applied to assess the performance of the model in the testing set. Additionally, we employed the Shapley Additive exPlanations (SHAP) method to illustrate the effects of the features., Results: We established an optimized mNGS assay and proposed using the copies of microbe-specific cell-free DNA per milliliter of plasma (CPM) as the detection signal to evaluate the real burden, with strong precision and high accuracy. In total, 237 patients were eligible for participation, which were randomly assigned to either the training set (70 %, n = 165) or the testing set (30 %, n = 72). The random forest classifier achieved accuracy, AUC and F1 scores of 0.830, 0.918 and 0.856, respectively, outperforming other machine learning models in the training set. Our model demonstrated clinical interpretability and achieved good prediction performance in differentiating between bacterial sepsis and non-sepsis, with an AUC value of 0.85 and an average precision of 0.91 in the testing set. Based on the SHAP value, the top nine features of the model were PCT, CPM, CRP, ALB, SBP min , RR max , CREA, PLT and HR max ., Conclusion: We demonstrated the potential of machine-learning approaches for predicting bacterial sepsis based on optimized mcfDNA sequencing assay accurately., (Copyright © 2024. Published by Elsevier B.V.)

Chicken coccidiosis causes disastrous losses to the poultry industry all over the world. Eimeria tenella is the most prevalent of these disease-causing species. Our former RNA-seq indicated that E. tenella ankyrin repeat-containing protein (EtANK) was expressed differently between drug-sensitive (DS) and drug-resistant strains. In this study, we cloned EtANK and analyzed its translational and transcriptional levels using quantitative real-time PCR (qPCR) and western blotting. The data showed that EtANK was significantly upregulated in diclazuril-resistant (DZR) strain and maduramicin-resistant (MRR) strain compared with the drug-sensitive (DS) strain. In addition, the transcription levels in the DZR strains isolated from the field were higher than in the DS strain. The translation levels of EtANK were higher in unsporulated oocysts (UO) than in sporozoites (SZ), sporulated oocysts (SO), or second-generation merozoites (SM), and the protein levels in SM were significantly higher than in UO, SO, and SZ. The results of the indirect immunofluorescence localization showed that the protein was distributed mainly at the anterior region of SZ and on the surface and in the cytoplasm of SM. The fluorescence intensity increased further with its development in vitro. An anti-rEtANK polyclonal antibody inhibited the invasive ability of E. tenella in DF-1 cells. These results showed that EtANK may be related to host cell invasion, required for the parasite's growth in the host, and may be involved in the development of E. tenella resistance to some drugs., 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 © 2024 Elsevier GmbH. All rights reserved.)

Alternative splicing (AS), an important post-transcriptional regulation mechanism in eukaryotes, can significantly increase transcript diversity and contribute to gene expression regulation and many other complicated developmental processes. While plant gene AS events are well described, few studies have investigated the comprehensive regulation machinery of plant AS. Here, we use multi-omics to analyse peanut AS events. Using long-read isoform sequencing, 146 464 full-length non-chimeric transcripts were obtained, resulting in annotation corrections for 1782 genes and the identification of 4653 new loci. Using Iso-Seq RNA sequences, 271 776 unique splice junctions were identified, 82.49% of which were supported by transcriptome data. We characterized 50 977 polyadenylation sites for 23 262 genes, 12 369 of which had alternative polyadenylation sites. AS allows differential regulation of the same gene by miRNAs at the isoform level coupled with polyadenylation. In addition, we identified many long non-coding RNAs and fusion transcripts. There is a suppressed effect of 6mA on AS and gene expression. By analysis of chromatin structures, the genes located in the boundaries of topologically associated domains, proximal chromosomal telomere regions, inter- or intra-chromosomal loops were found to have more unique splice isoforms, higher expression, lower 6mA and more transposable elements (TEs) in their gene bodies than the other genes, indicating that chromatin interaction, 6mA and TEs play important roles in AS and gene expression. These results greatly refine the peanut genome annotation and contribute to the study of gene expression and regulation in peanuts. This work also showed AS is associated with multiple strategies for gene regulation., (© 2024 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.)

Gliomas are highly vascularized malignancies, but current anti-angiogenic treatments have not demonstrated practical improvements in patient survival. Studies have suggested that glioma-derived endothelial cell (GdEC) formed by glioma stem cell (GSC) differentiation may contribute to the failure of this treatment. However, the molecular mechanisms involved in GSC endothelial differentiation remain poorly understood. We previously reported that vasorin (VASN) is highly expressed in glioma and promotes angiogenesis. Here, we show that VASN expression positively correlates with GdEC signatures in glioma patients. VASN promotes the endothelial differentiation capacity of GSC in vitro and participates in the formation of GSC-derived vessels in vivo. Mechanistically, vascular endothelial growth factor receptor 2 (VEGFR2) is a critical factor that mediates the regulation of VASN on GSC endothelial differentiation. Separation of cell chromatin fractionation and chromatin immunoprecipitation-sequencing analysis show that VASN interacts with Notch1 and co-translocates into the cell nuclei, where VASN binds to the VEGFR2 gene promoter to stimulate its transcription during the progression of GSC differentiation into GdEC. Together, these findings elucidate the role and mechanisms of VASN in promoting the endothelial differentiation of GSC and suggest VASN as a potential target for anti-angiogenic therapy based on intervention in GdEC formation in gliomas., (© 2024 Federation of American Societies for Experimental Biology.)

Stem cells have been documented as a new therapeutic method for ovarian injuries such as premature ovarian failure (POF). However, effects of exosomes (Exos) derived from human endometrial stem cells (EnSCs) on diminished ovarian failure remain to be carefully elucidated. Our study aims to investigate the mechanisms of EnSC-Exos in the recovery of the cisplatin-induced granulosa cell injury model in vitro or POF mouses model in vivo and whether the Hippo signaling pathway is involved in the regulation. In this study, we established successful construction of the cisplatin-induced granulosa cell injury model and evaluated Hippo signaling pathway activation in cisplatin-damaged granulosa cells (GCs). Furthermore, laser scanning confocal microscope and immunofluorescence demonstrated that EnSC-Exos can be transferred to cisplatin-damaged GCs to decrease apoptosis. In addition, the enhanced expression of YAP at the protein level as well as YAP/TEAD target genes, such as CTGF, ANKRD1, and the increase of YAP into the nucleus in immunofluorescence staining after the addition of EnSC-Exos to cisplatin-damaged GCs confirmed the suppression of Hippo signaling pathway. While in vivo , EnSC-Exos successfully remedied POF in a mouse model. Collectively, our findings suggest that chemotherapy-induced POF was associated with the activating of Hippo signaling pathway. Human EnSC-Exos significantly elevated the proliferation of ovarian GCs and the ovarian function by regulating Hippo signaling pathway. These findings provide new insights for further understanding of EnSC-Exos in the recovery of ovary function., Competing Interests: 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., (© 2024 The Authors.)

The distance from the virtual image to the human eye is an important factor in measuring the comfort of a head-mounted display (HMD). However, accurately measuring their distance is challenging due to the dynamic changes in virtual presence and distance. In this paper, we proposed a virtual image distance measurement prototype based on a variable-focus liquid lens and derived a virtual image distance calculation model. We built a variable-focus liquid lens experimental platform to verify the method's correctness. In addition, we proposed an improved optimization algorithm that can efficiently and accurately search for the optimal focal length corresponding to the maximum sharpness moment of the virtual image within the focal length value space. Verified in an experimental scene of 0.5 m to 3.5 m, we observed that the error between the object image distance and the virtual image distance at the same focal length is about 5 cm. The proposed virtual image distance measurement method can accurately measure the distance value of the virtual image in the HMD. This method can be widely used in virtual and augmented reality, especially in the task of constructing realistic scenes.

Enamel white spot lesions (WSLs) are usually caused by the dissolution of minerals (mainly calcium and phosphate) on the tooth surface due to the acidic environment in the oral cavity. Without timely intervention, WSLs may lead to white spots or a sense of transparency on the tooth surface, and even the formation of dental caries (tooth decay) in severe cases. The key to preventing and treating WSLs is inhibiting the activity of acid-producing bacteria and promoting the remineralization of demineralized enamel. In this study, the network structure formed by sodium tripolyphosphate (TPP) cross-linked chitosan was used to stabilize calcium phosphate, and the multifunctional nanocomposite was constructed by integrating antibacterial components of traditional Chinese medicine, honokiol nanoparticles (HK-NPs) and sodium fluoride to achieve the purpose of resisting cariogenic bacteria and remineralizing with sustained release of calcium and phosphate ions. Notably, we enhanced the remineralization effect of nanocomposites with the help of functional nanocoatings inspired by the mussel biomimetic coating. The experimental results show that the synergistic remineralization effect of nanocomposite and nanocoating is better than that of a single strategy. This multi-prong treatment strategy provides the theoretical and experimental basis for the clinical prevention and treatment of WSLs., Competing Interests: The authors declare no conflicts of interest., (This journal is © The Royal Society of Chemistry.)

Smart manufacturing has been transforming toward industrial digitalization integrated with various advanced technologies. Metaverse has been evolving as a next-generation paradigm of a digital space extended and augmented by reality. In the metaverse, users are interconnected for various virtual activities. In consideration of advanced possibilities that may be brought by the metaverse, it is envisioned that industrial metaverse should be integrated into smart manufacturing to upgrade industry for more visible, intelligent and efficient production in the future. Therefore, a conceptual model, named IMverse Model, and novel characteristics of the industrial metaverse for smart manufacturing are proposed in this article. Besides, an industrial metaverse architecture, named IMverse Architecture, is proposed involving several key enabling technologies. Typical innovative applications of the industrial metaverse throughout the whole product life cycle for smart manufacturing are presented with insights. Nonetheless, in prospect of future, the industrial metaverse still faces limitations and is far from implementation. Thus, challenges and open issues of the industrial metaverse for smart manufacturing are discussed, then outlook is provided for further research and application.

Ulcerative colitis (UC) is a complex inflammatory disease of colorectum that induces abnormal immune responses and severely affects the quality of life of the patients. Grape seed proanthocyanidin extract (GSPE) exerts anti-inflammatory and antioxidant functions in many inflammatory diseases. The objective of this study was to investigate the potential therapeutic effects and underlying mechanisms of GSPE in UC using a dextran sodium sulfate (DSS)-induced mouse UC model and a lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage model. In this study, we found that the GSPE markedly prevented DSS-induced weight loss and colon length shortening in UC mice. Further investigations showed that GSPE significantly attenuated the expression of pro-inflammatory cytokines TNF-α, IL-6, and IL-1β, and elevated the expression of anti-inflammatory cytokine IL-10 in the colon tissues and serum of DSS-induced colitis mice by suppressing NF-κB signaling pathway. Furthermore, LPS-induced inflammation in RAW264.7 cells was also reversed by GSPE. Taken together, our results confirm that GSPE can ameliorate inflammatory response in experimental colitis via inhibiting NF-κB signaling pathway. This study advances the research progress on a potentially effective therapeutic strategy for inflammatory bowel diseases., (© 2024 The Authors. Environmental Toxicology published by Wiley Periodicals LLC.)