Acupuncture and Escitalopram for Treating Major Depression Clinical Study (AE-TMDCS): protocol for a factorial randomised controlled trial.

INTRODUCTION: Major depressive disorder (MDD), the second leading cause of disability globally, is considered to be associated with a consequent deterioration in the quality of life and can lead to a major economic burden on medical service and suicide-related costs. Previous research has shown that acupuncture may be beneficial for treating MDD. However, there is a lack of rigorous evidence from previous studies comparing acupuncture with antidepressant medications. This study aims to assess the therapeutic potential of acupuncture in the management of depressive disorders. METHODS AND ANALYSIS: A multicentre, randomised, participant-blind, sham-controlled, 2×2 factorial clinical trial, Acupuncture and Escitalopram for Treating Major Depression Clinical Study, aims to compare the efficacy of acupuncture versus escitalopram in treating depression. This study will be conducted at three hospitals in China, enrolling 260 patients with moderate-to-severe major depression, as defined by DSM-5 criteria and Hamilton Depression Rating Scale (HDRS-17) Scores above 17. Participants will be randomly assigned in equal proportions to one of four groups (acupuncture/escitalopram, sham acupuncture/escitalopram, acupuncture/placebo and sham acupuncture/placebo) and undergo 30 sessions across 10 weeks. The primary outcome is change in HDRS-17 Score and secondary outcomes include BDI, Clinical Global Impression, Generalised Anxiety Disorder-7 and Mini-Mental State Examination Scores, alongside potential biological markers. ETHICS AND DISSEMINATION: Ethical approval for the study was granted by the Ethics Committees of the Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine (2023-7th-HIRB-020), Shanghai Mental Health Centre (2022-86) and Shanghai Pudong New Area Hospital of Traditional Chinese Medicine (2023-003). Informed consent will be obtained from all participants. The study's findings are intended for publication in a scholarly journal. TRIAL REGISTRATION: NCT05901571.

Transcriptome analysis of Citrus Aurantium L. to study synephrine biosynthesis during developmental stages.

Citrus aurantium L., sometimes known as "sour orange," is an important Chinese herb with young, immature fruits, or "zhishi," that are high in synephrine. Synephrine is a commonly utilized natural chemical with promising applications in effectively increasing metabolism, heat expenditure, energy level, oxidative fat, and weight loss. However, little is known about the genes and pathways involved in synephrine production during the critical developmental stages of C. aurantium L., which limits the development of the industry. According to this study, the concentration of synephrine gradually decreased as the fruit developed. Transcriptome sequencing was used to examine the DEGs associated with synephrine connections and served as the foundation for creating synephrine-rich C. aurantium L. Comparisons conducted between different developmental stages to obtain DEGs, and the number of DEGs varied from 690 to 3,019. Tyrosine and tryptophan biosynthesis, glycolysis/gluconeogenesis, pentose phosphate pathway, phenylalanine, and tyrosine metabolism were the main KEGG pathways that were substantially enriched. The results showed that 25 genes among these KEGG pathways may be related to synephrine synthesis. The WGCNA and one-way ANOVA analysis adoption variance across the groups suggested that 11 genes might play a crucial role in synephrine synthesis and should therefore be further analyzed. We also selected six DEGs at random and analyzed their expression levels by RT-qPCR, and high repeatability and reliability were demonstrated by our finished RNA-seq study results. These results may be useful in selecting or modifying genes to increase the quantity of synephrine in sour oranges.

First-Principles Insights into the Selective Separation of MoS42- and WO42-: Crucial Role of Hydration Structures.

The selective separation of MoS42- and WO42- using quaternary ammonium salt through solvent extraction or ion exchange methods has been well-established in the metallurgical industry. However, the conventional electrostatic adsorption theory falls short in explaining the separation mechanism. Through first-principles density functional theory (DFT) calculations and newly self-developed deep potential molecular dynamics (DPMD) simulation method, our work first reveals that the disparity in hydration structures of MoS42- and WO42- plays a crucial role in their selective separation. It is proposed that MoS42- and WO42- anions undergo hydration to form [MoS4(H2O)n]2- and [WO4(H2O)n]2-, respectively, facilitated by hydrogen bond (H-bond) interactions. Emphasis is placed on the discrepancy between MoS42- and WO42- in hydration structures by the hydration energy, Hirshfeld charge, evaluation of weak interactions, hydration radius, hydration coordination number, and H-bonds distribution. MoS42- presents a larger first hydration radius and a lower first hydration coordination number due to weaker interactions with H2O, while WO42- is subjected to enhanced hydration shielding, resulting in MoS42- anions being more susceptible to be selectively separated by a quaternary ammonium salt. This insight paves the way for the selective separation of MoS42- and WO42-, further bridging the gap between theory and industry applications.

Degradation prediction of fuel cell systems based on different operating conditions in dynamic cycling condition.

In this paper, the degradation of PEMFC under different operating conditions in dynamic cycle condition is studied. Firstly, according to the failure mechanism of PEMFC, various operating conditions in dynamic cycle condition are classified, and the health indexes are established. Simultaneously, the rates and degrees of the output voltage decline of the PEMFC under different operating conditions during the dynamic cycling process were compared. Then, a model based on variational mode decomposition and long short-term memory with attention mechanism (VMD-LSTM-ATT) is proposed. Aiming at the performance of PEMFC is affected by the external operation, VMD is used to capture the global information and details, and filter out interference information. To improve the prediction accuracy, ATT is used to assign weight to the features. Finally, in order to verify the effectiveness and superiority of VMD-LSTM-ATT, we respectively apply it to three current conditions under dynamic cycle conditions. The experimental results show that under the same test conditions, RMSE of VMD-LSTM-ATT is increased by 56.11 % and MAE is increased by 28.26 % compared with GRU attention. Compared with SVM, RNN, LSTM and LSTM-ATT, RMSE of VMD-LSTM-ATT is at least 17.26 % higher and MAE is at least 5.65 % higher.

Gefitinib (an EGFR tyrosine kinase inhibitor) plus anlotinib (an multikinase inhibitor) for untreated, EGFR-mutated, advanced non-small cell lung cancer (FL-ALTER): a multicenter phase III trial.

Dual inhibition of vascular endothelial growth factor and epidermal growth factor receptor (EGFR) signaling pathways offers the prospect of improving the effectiveness of EFGR-targeted therapy. In this phase 3 study (ClinicalTrial.gov: NCT04028778), 315 patients with treatment-naïve, EGFR-mutated, advanced non-small cell lung cancer (NSCLC) were randomized (1:1) to receive anlotinib or placebo plus gefitinib once daily on days 1-14 per a 3-week cycle. At the prespecified final analysis of progression-free survival (PFS), a significant improvement in PFS was observed for the anlotinib arm over the placebo arm (hazards ratio [HR] = 0.64, 95% CI, 0.48-0.80, P = 0.003). Particularly, patients with brain metastasis and those harboring EGFR amplification or high tumor mutation load gained significant more benefits in PFS from gefitinib plus anlotinib. The incidence of grade 3 or higher treatment-emergent adverse events was 49.7% of the patients receiving gefitinib plus anlotinib versus 31.0% of the patients receiving gefitinib plus placebo. Anlotinib plus gefitinib significantly improves PFS in patients with treatment-naïve, EGFR-mutated, advanced NSCLC, with a manageable safety profile.

Adaptive roles of cytokinins in enhancing plant resilience and yield against environmental stressors.

Innovative agricultural strategies are essential for addressing the urgent challenge of food security in light of climate change, population growth, and various environmental stressors. Cytokinins (CKs) play a pivotal role in enhancing plant resilience and productivity. These compounds, which include isoprenoid and aromatic types, are synthesized through pathways involving key enzymes such as isopentenyl transferase and cytokinin oxidase. Under abiotic stress conditions, CKs regulate critical physiological processes by improving photosynthetic efficiency, enhancing antioxidant enzyme activity, and optimizing root architecture. They also reduce the levels of reactive oxygen species and malondialdehyde, resulting in improved plant performance and yield. CKs interact intricately with other phytohormones, including abscisic acid, ethylene, salicylic acid, and jasmonic acid, to modulate stress-responsive pathways. This hormonal cross-talk is vital for finely tuning plant responses to stress. Additionally, CKs influence nutrient uptake and enhance responses to heavy metal stress, thereby bolstering overall plant resilience. The application of CKs helps plants maintain higher chlorophyll levels, boost antioxidant systems, and promote root and shoot growth. The strategic utilization of CKs presents an adaptive approach for developing robust crops capable of withstanding diverse environmental stressors, thus contributing to sustainable agricultural practices and global food security. Ongoing research into the mechanisms of CK action and their interactions with other hormones is essential for maximizing their agricultural potential. This underscores the necessity for continued innovation and research in agricultural practices, in alignment with global goals of sustainable productivity and food security.

Erratum: DNA Extraction and Comparison Between Old and Fresh Necrophilic Fly Samples.

This corrects the article 10.3791/66737.

Multi-dimensional comparison of abdominal obesity indices and insulin resistance indicators for assessing NAFLD.

BACKGROUND: The prevalence of non-alcoholic fatty liver disease (NAFLD) keeps increasing annually worldwide. Non-invasive assessment tools for evaluating the risk and severity of the disease are still limited. Insulin resistance (IR) and abdominal obesity (ABO) are closely related to NAFLD. METHODS: A retrospective large-scale, population-based study was conducted based on the data from the 2017-2018 cycle of the National Health and Nutrition Examination Survey (NHANES). Three ABO indices, namely lipid accumulation product (LAP), visceral obesity index (VAI), waist circumference-triglyceride index (WTI), and three IR indices, including triglyceride glucose index (TyG), homeostasis model assessment of insulin resistance (HOMA-IR) and metabolic score for insulin resistance (METS-IR), were analyzed and compared for their relationships with NAFLD based on weighted multivariable logistic regression, spearman correlation heatmap, smooth curve fittings. The area under the curve (AUC) of receiver-operating characteristic (ROC) curve was used to evaluate the diagnostic capability of these indices for NAFLD. Differences among the AUCs were calculated and compared by Delong test. RESULTS: In total, 3095 participants were included in our study among which 1368 adults were diagnosed with NAFLD. All six indices presented positive associations with NAFLD. There was a claw-shaped curve between HOMA-IR, VAI, LAP and NAFLD while a smooth semi-bell curve was observed in TyG, METS-IR and WTI. LAP and HOMA-IR had the best diagnostic capability for NAFLD (LAP: AUC = 0.8, Youden index = 0.48; HOMA-IR: AUC = 0.798, Youden index = 0.472) while VAI (AUC = 0.728, Youden index = 0.361) showed the lowest predictive value. The correlation heat map indicated positive correlations between all six indices and liver function, hepatic steatosis and fibrosis severity. In the NAFLD group, IR indicators presented a stronger association with alanine aminotransferase (ALT) compared with ABO indices. CONCLUSIONS: All six indices can screen NAFLD withLAP and HOMA-IR being possibly optimal predictors. IR indices may be more sensitive to identify acute hepatic injury in NAFLD patients than ABO indices.

Two-dimensional perovskitoids enhance stability in perovskite solar cells.

Two-dimensional (2D) and three-dimensional (3D) perovskite heterostructures have played a key role in advancing the performance of perovskite solar cells1,2. However, the migration of cations between 2D and 3D layers results in the disruption of octahedral networks, leading to degradation in performance over time3,4. We hypothesized that perovskitoids, with robust organic-inorganic networks enabled by edge- and face-sharing, could impede ion migration. We explored a set of perovskitoids of varying dimensionality and found that cation migration within perovskitoid-perovskite heterostructures was suppressed compared with the 2D-3D perovskite case. Increasing the dimensionality of perovskitoids improves charge transport when they are interfaced with 3D perovskite surfaces-this is the result of enhanced octahedral connectivity and out-of-plane orientation. The 2D perovskitoid (A6BfP)8Pb7I22 (A6BfP: N-aminohexyl-benz[f]-phthalimide) provides efficient passivation of perovskite surfaces and enables uniform large-area perovskite films. Devices based on perovskitoid-perovskite heterostructures achieve a certified quasi-steady-state power conversion efficiency of 24.6% for centimetre-area perovskite solar cells. We removed the fragile hole transport layers and showed stable operation of the underlying perovskitoid-perovskite heterostructure at 85 °C for 1,250 h for encapsulated large-area devices in ambient air.

VASE: A High-Entropy Alloy Short-Range Order Structural Descriptor for Machine Learning.

The short-range order (SRO) structure in high-entropy alloys (HEAs) is closely associated with many properties, which can be studied through density functional theory (DFT) calculations. Atomic-scale modeling and calculations require substantial computational resources, and machine learning can provide rapid estimations of DFT results. To describe SRO information in HEAs, a new descriptor based on Voronoi Analysis and Shannon Entropy (VASE) is proposed. Based on Voronoi analysis, the Shannon entropy is introduced to directly characterize atomic spatial arrangement information except for composition and atomic interactions, which is necessary for describing the disorder atomic occupancy in HEAs. The new descriptor is used for predicting the formation energy of FeCoNiAlTiCu system based on machine learning model, which is more accurate than other descriptors (Coulomb matrices, partial radial distribution functions, and Voronoi analysis). Moreover, the model trained based on VASE descriptors exhibits the best predictive performance for unrelaxed structures (24.06 meV/atom). The introduction of Shannon entropy provides an effective representation of atomic arrangement information in HEAs, which is a powerful tool for investigating the SRO phenomena.

The role of AMPKα subunit in Alzheimer's disease: In-depth analysis and future prospects.

The AMP-activated protein kinase α (AMPKα) subunit is the catalytic subunit in the AMPK complex, playing a crucial role in AMPK activation. It has two isoforms: AMPKα1 and AMPKα2. Emerging evidence suggests that the AMPKα subunit exhibits subtype-specific effects in Alzheimer's disease (AD). This review discusses the role of the AMPKα subunit in the pathogenesis of AD, including its impact on ß-amyloid (Aß) pathology, Tau pathology, metabolic disorders, inflammation, mitochondrial dysfunction, inflammasome and pyroptosis. Additionally, it reviews the distinct roles of its isoforms, AMPKα1 and AMPKα2, in AD, which may provide more precise targets for future drug development in AD.

Genome-wide identification and characterization of the JAZ gene family in Gynostemma pentaphyllum reveals the COI1/JAZ/MYC2 complex potential involved in the regulation of the MeJA-induced gypenoside biosynthesis.

The Jasmonate ZIM domain (JAZ) proteins, functioning as critical suppressors for jasmonic acid (JA) signal transduction in plants, occupy crucial roles in multiple biological processes, particularly in the orchestration of secondary metabolic pathways. However, the mechanism underlying the JA-induced gypenosides accumulation in Gynostemma pentaphyllum remains poorly elucidated. Our research led to the identification of 11 distinct JAZ members in G. pentaphyllum (GpJAZs). According to the classification approach of AtJAZ, we allocated these members into five subgroups that shared similar conserved motif compositions. Subsequently, we identified the presence of various cis-acting elements associated with light stimuli, hormone responses, and stress signals within the promoter regions of the GpJAZ gene family. The expression levels of GpJAZ genes in different tissues were quite different, and the majority of GpJAZ genes exhibited varying degrees of response to methyl jasmonate (MeJA) induction. Yeast two-hybrid (Y2H) assays revealed interactions between GpJAZ1/2/4/5/7/9/10 and GpMYC2, whereas GpCOI1 protein was found to interact with GpJAZ1/2/4/5, thereby forming the COI1/JAZ/MYC2 complex. Furthermore, as an activator of gypenoside metabolic pathway, GpMYC2 could activate the promoter activity of the gypenoside metabolism-related genes to varying degrees by binding to their promoters, indicating that the COI1/JAZ/MYC2 module involved in the MeJA-induced regulation of gypenosides. In summary, our findings present an exhaustive examination of the JAZ gene family, furnishing a significant lead for delving deeper into the molecular mechanisms that drive the MeJA-induced enhancement of gypenosides accumulation in G. pentaphyllum.

Central nervous system efficacy of aumolertinib versus gefitinib in patients with untreated, EGFR-mutated, advanced non-small cell lung cancer: data from a randomized phase III trial (AENEAS).

BACKGROUND: The initial randomized, double-blinded, actively controlled, phase III ANEAS study (NCT03849768) demonstrated that aumolertinib showed superior efficacy relative to gefitinib as first-line therapy in epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). Metastatic disease in the central nervous system (CNS) remains a challenge in the management of NSCLC. This study aimed to compare the efficacy of aumolertinib versus gefitinib among patients with baseline CNS metastases in the ANEAS study. METHODS: Eligible patients were enrolled and randomly assigned in a 1:1 ratio to orally receive either aumolertinib or gefitinib in a double-blinded fashion. Patients with asymptomatic, stable CNS metastases were included. Follow-up imaging of the same modality as the initial CNS imaging was performed every 6 weeks for 15 months, then every 12 weeks. CNS response was assessed by a neuroradiological blinded, independent central review (neuroradiological-BICR). The primary endpoint for this subgroup analysis was CNS progression-free survival (PFS). RESULTS: Of the 429 patients enrolled and randomized in the ANEAS study, 106 patients were found to have CNS metastases (CNS Full Analysis Set, cFAS) at baseline by neuroradiological-BICR, and 60 of them had CNS target lesions (CNS Evaluable for Response, cEFR). Treatment with aumolertinib significantly prolonged median CNS PFS compared with gefitinib in both cFAS (29.0 vs. 8.3 months; hazard ratio [HR] = 0.31; 95% confidence interval [CI], 0.17-0.56; P < 0.001) and cEFR (29.0 vs. 8.3 months; HR = 0.26; 95% CI, 0.11-0.57; P < 0.001). The confirmed CNS overall response rate in cEFR was 85.7% and 75.0% in patients treated with aumolertinib and gefitinib, respectively. Competing risk analysis showed that the estimated probability of CNS progression without prior non-CNS progression or death was consistently lower with aumolertinib than with gefitinib in patients with and without CNS metastases at baseline. No new safety findings were observed. CONCLUSIONS: These results indicate a potential advantage of aumolertinib over gefitinib in terms of CNS PFS and the risk of CNS progression in patients with EGFR-mutated advanced NSCLC with baseline CNS metastases. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT03849768.

Label-Free Monitoring of Endometrial Cancer Progression Using Multiphoton Microscopy.

Endometrial cancer is the most common gynecological cancer in the developed world. However, the accuracy of current diagnostic methods is still unsatisfactory and time-consuming. Here, we presented an alternate approach to monitoring the progression of endometrial cancer via multiphoton microscopy imaging and analysis of collagen, which is often overlooked in current endometrial cancer diagnosis protocols but can offer a crucial signature in cancer biology. Multiphoton microscopy (MPM) based on the second-harmonic generation and two-photon excited fluorescence was introduced to visualize the microenvironment of endometrium in normal, hyperplasia without atypia, atypical hyperplasia, and endometrial cancer specimens. Furthermore, automatic image analysis based on the MPM image processing algorithm was used to quantify the differences in the collagen morphological features among them. MPM enables the visualization of the morphological details and alterations of the glands in the development process of endometrial cancer, including irregular changes in the structure of the gland, increased ratio of the gland to the interstitium, and atypical changes in the glandular epithelial cells. Moreover, the destructed basement membrane caused by gland proliferation and fusion is clearly shown in SHG images, which is a key feature for identifying endometrial cancer progression. Quantitative analysis reveals that the formation of endometrial cancer is accompanied by an increase in collagen fiber length and width, a progressive linearization and loosening of interstitial collagen, and a more random arrangement of interstitial collagen. Observation and quantitative analysis of interstitial collagen provide invaluable information in monitoring the progression of endometrial cancer. Label-free multiphoton imaging reported here has the potential to become an in situ histological tool for effective and accurate early diagnosis and detection of malignant lesions in endometrial cancer.

Characterizing defective lipid metabolism in the lateral septum of mice treated with olanzapine: implications for its side effects.

Schizophrenia significantly impacts cognitive and behavioral functions and is primarily treated with second-generation antipsychotics (SGAs) such as olanzapine. Despite their efficacy, these drugs are linked to serious metabolic side effects which can diminish patient compliance, worsen psychiatric symptoms and increase cardiovascular disease risk. This study explores the hypothesis that SGAs affect the molecular determinants of synaptic plasticity and brain activity, particularly focusing on the lateral septum (LS) and its interactions within hypothalamic circuits that regulate feeding and energy expenditure. Utilizing functional ultrasound imaging, RNA sequencing, and weighted gene co-expression network analysis, we identified significant alterations in the functional connection between the hypothalamus and LS, along with changes in gene expression in the LS of mice following prolonged olanzapine exposure. Our analysis revealed a module closely linked to increases in body weight and adiposity, featuring genes primarily involved in lipid metabolism pathways, notably Apoa1, Apoc3, and Apoh. These findings suggest that olanzapine may influence body weight and adiposity through its impact on lipid metabolism-related genes in the LS. Therefore, the neural circuits connecting the LS and LH, along with the accompanying alterations in lipid metabolism, are likely crucial factors contributing to the weight gain and metabolic side effects associated with olanzapine treatment.

Corrosion Behavior of Al-Containing CoNiV Medium Entropy Alloy Coating Fabricated by Laser Cladding.

CoNiV medium entropy alloys (MEAs) have been widely recognized for their superior corrosion resistance. Nonetheless, their extensive application has been hindered by high production costs and complex fabrication processes. In this study, CoNiVAlx MEA coatings were synthesized on AISI 304 stainless steel substrates via laser cladding technology. The microstructure, phase composition, corrosion resistance, and corrosion mechanisms of the coatings were systematically investigated by using advanced characterization techniques, including optical microscopy, scanning electron microscopy, transmission electron microscopy, X-ray diffractometry, and electrochemical workstation analysis. The ratio of O2-/OH- in the passivation film of the coated surface exhibited a gradual increase with the addition of Al. The formation of the Al-containing precipitated phase L21 was observed at x = 0.3 and 0.4. The results demonstrated that moderate Al doping (x ≤ 0.2) enhanced corrosion resistance by improving the stability of the passivation film and reducing the thermodynamic tendency toward corrosion. In contrast, excessive Al doping (x > 0.2) led to the formation of the L21 phase, which increased the susceptibility to localized corrosion, thus compromising the overall corrosion resistance.

Benmelstobart, anlotinib and chemotherapy in extensive-stage small-cell lung cancer: a randomized phase 3 trial.

Immunochemotherapy is the first-line standard for extensive-stage small-cell lung cancer (ES-SCLC). Combining the regimen with anti-angiogenesis may improve efficacy. ETER701 was a multicenter, double-blind, randomized, placebo-controlled phase 3 trial that investigated the efficacy and safety of benmelstobart (a novel programmed death-ligand 1 (PD-L1) inhibitor) with anlotinib (a multi-target anti-angiogenic small molecule) and standard chemotherapy in treatment-naive ES-SCLC. The ETER701 trial assessed two primary endpoints: Independent Review Committee-assessed progression-free survival per RECIST 1.1 and overall survival (OS). Here the prespecified final progression-free survival and interim OS analysis is reported. Patients randomly received benmelstobart and anlotinib plus etoposide/carboplatin (EC; n = 246), placebo and anlotinib plus EC (n = 245) or double placebo plus EC ('EC alone'; n = 247), followed by matching maintenance therapy. Compared with EC alone, median OS was prolonged with benmelstobart and anlotinib plus EC (19.3 versus 11.9 months; hazard ratio 0.61; P = 0.0002), while improvement of OS was not statistically significant with anlotinib plus EC (13.3 versus 11.9 months; hazard ratio 0.86; P = 0.1723). The incidence of grade 3 or higher treatment-related adverse events was 93.1%, 94.3% and 87.0% in the benmelstobart and anlotinib plus EC, anlotinib plus EC, and EC alone groups, respectively. This study of immunochemotherapy plus multi-target anti-angiogenesis as first-line treatment achieved a median OS greater than recorded in prior randomized studies in patients with ES-SCLC. The safety profile was assessed as tolerable and manageable. Our findings suggest that the addition of anti-angiogenesis therapy to immunochemotherapy may represent an efficacious and safe approach to the management of ES-SCLC. ClinicalTrials.gov identifier: NCT04234607 .

Inhibition of neddylation disturbs zygotic genome activation through histone modification change and leads to early development arrest in mouse embryos.

Post-translational modification and fine-tuned protein turnover are of great importance in mammalian early embryo development. Apart from the classic protein degradation promoting ubiquitination, new forms of ubiquitination-like modification are yet to be fully understood. Here, we demonstrate the function and potential mechanisms of one ubiquitination-like modification, neddylation, in mouse preimplantation embryo development. Treated with specific inhibitors, zygotes showed a dramatically decreased cleavage rate and almost all failed to enter the 4-cell stage. Transcriptional profiling showed genes were differentially expressed in pathways involving cell fate determination and cell differentiation, including several down-regulated zygotic genome activation (ZGA) marker genes. A decreased level of phosphorylated RNA polymerase II was detected, indicating impaired gene transcription inside the embryo cell nucleus. Proteomic data showed that differentially expressed proteins were enriched in histone modifications. We confirmed the lowered in methyltransferase (KMT2D) expression and a decrease in histone H3K4me3. At the same time, acetyltransferase (CBP/p300) reduced, while deacetylase (HDAC6) increased, resulting in an attenuation in histone H3K27ac. Additionally, we observed the up-regulation in YAP1 and RPL13 activities, indicating potential abnormalities in the downstream response of Hippo signaling pathway. In summary, we found that inhibition of neddylation induced epigenetic changes in early embryos and led to abnormalities in related downstream signaling pathways. This study sheds light upon new forms of ubiquitination regulating mammalian embryonic development and may contribute to further investigation of female infertility pathology.

NmTHC: a hybrid error correction method based on a generative neural machine translation model with transfer learning.

BACKGROUNDS: The single-pass long reads generated by third-generation sequencing technology exhibit a higher error rate. However, the circular consensus sequencing (CCS) produces shorter reads. Thus, it is effective to manage the error rate of long reads algorithmically with the help of the homologous high-precision and low-cost short reads from the Next Generation Sequencing (NGS) technology. METHODS: In this work, a hybrid error correction method (NmTHC) based on a generative neural machine translation model is proposed to automatically capture discrepancies within the aligned regions of long reads and short reads, as well as the contextual relationships within the long reads themselves for error correction. Akin to natural language sequences, the long read can be regarded as a special "genetic language" and be processed with the idea of generative neural networks. The algorithm builds a sequence-to-sequence(seq2seq) framework with Recurrent Neural Network (RNN) as the core layer. The before and post-corrected long reads are regarded as the sentences in the source and target language of translation, and the alignment information of long reads with short reads is used to create the special corpus for training. The well-trained model can be used to predict the corrected long read. RESULTS: NmTHC outperforms the latest mainstream hybrid error correction methods on real-world datasets from two mainstream platforms, including PacBio and Nanopore. Our experimental evaluation results demonstrate that NmTHC can align more bases with the reference genome without any segmenting in the six benchmark datasets, proving that it enhances alignment identity without sacrificing any length advantages of long reads. CONCLUSION: Consequently, NmTHC reasonably adopts the generative Neural Machine Translation (NMT) model to transform hybrid error correction tasks into machine translation problems and provides a novel perspective for solving long-read error correction problems with the ideas of Natural Language Processing (NLP). More remarkably, the proposed methodology is sequencing-technology-independent and can produce more precise reads.