Heterogeneity of immune cells and their communications unveiled by transcriptome profiling in acute inflammatory lung injury.

Background: Acute Respiratory Distress Syndrome (ARDS) or its earlier stage Acute lung injury (ALI), is a worldwide health concern that jeopardizes human well-being. Currently, the treatment strategies to mitigate the incidence and mortality of ARDS are severely restricted. This limitation can be attributed, at least in part, to the substantial variations in immunity observed in individuals with this syndrome. Methods: Bulk and single cell RNA sequencing from ALI mice and single cell RNA sequencing from ARDS patients were analyzed. We utilized the Seurat program package in R and cellmarker 2.0 to cluster and annotate the data. The differential, enrichment, protein interaction, and cell-cell communication analysis were conducted. Results: The mice with ALI caused by pulmonary and extrapulmonary factors demonstrated differential expression including Clec4e, Retnlg, S100a9, Coro1a, and Lars2. We have determined that inflammatory factors have a greater significance in extrapulmonary ALI, while multiple pathways collaborate in the development of pulmonary ALI. Clustering analysis revealed significant heterogeneity in the relative abundance of immune cells in different ALI models. The autocrine action of neutrophils plays a crucial role in pulmonary ALI. Additionally, there was a significant increase in signaling intensity between B cells and M1 macrophages, NKT cells and M1 macrophages in extrapulmonary ALI. The CXCL, CSF3 and MIF, TGFß signaling pathways play a vital role in pulmonary and extrapulmonary ALI, respectively. Moreover, the analysis of human single-cell revealed DCs signaling to monocytes and neutrophils in COVID-19-associated ARDS is stronger compared to sepsis-related ARDS. In sepsis-related ARDS, CD8+ T and Th cells exhibit more prominent signaling to B-cell nucleated DCs. Meanwhile, both MIF and CXCL signaling pathways are specific to sepsis-related ARDS. Conclusion: This study has identified specific gene signatures and signaling pathways in animal models and human samples that facilitate the interaction between immune cells, which could be targeted therapeutically in ARDS patients of various etiologies.

A new mouse model of depression induced by chronic restraint stress combined with lipopolysaccharide.

The aim of this study was to establish a multi-factor-induced depression model in mice within a relatively short period, specifically through the combination of intraperitoneal injection of lipopolysaccharide (LPS) and chronic restraint stress (CRS), and to evaluate the differences in depressive-like behaviors among three different strains of mice, seeking mouse strains more suitable for this combined model. The mice of each strain were randomly divided into the normal group and model group. The mice in the model group received a single intraperitoneal injection of LPS once daily (1 mg/kg/d for 7 days) and subsequent CRS for 6 h, to induce depression, while the mice in the normal group received no treatment. Behavioral tests: sucrose preference test (SPT), open field test (OFT), forced swim test (FST), and tail suspension test (TST) were conducted to assess depressive-like behaviors in the mice. Data analysis showed that there were significant intergroup differences in depressive-like behaviors in ICR and C57BL/6 J mice, while KM mice exhibited minor differences with relatively high deviation in individual behavioral score. This study indicated that the combined depression mouse model could successfully induce significant depressive-like behaviors in ICR and C57BL/6 J mice.

TOP CAR with TMIGD2 as a safe and effective costimulatory domain in CAR cells treating human solid tumors.

Chimeric antigen receptor (CAR)-T cell therapy shows impressive efficacy treating hematologic malignancies but requires further optimization in solid tumors. Here, we developed a TMIGD2 optimized potent/persistent (TOP) CAR that incorporated the costimulatory domain of TMIGD2, a T and NK cell costimulator, and monoclonal antibodies targeting the IgV domain of B7-H3, an immune checkpoint expressed on solid tumors and tumor vasculature. Comparing second- and third-generation B7-H3 CARs containing TMIGD2, CD28, and/or 4-1BB costimulatory domains revealed superior antitumor responses in B7-H3.TMIGD2 and B7-H3.CD28.4-1BB CAR-T cells in vitro. Comparing these two constructs using in vivo orthotopic human cancer models demonstrated that B7-H3.TMIGD2 CAR-T cells had equivalent or superior antitumor activity, survival, expansion, and persistence. Mechanistically, B7-H3.TMIGD2 CAR-T cells maintained mitochondrial metabolism; produced less cytokines; and established fewer exhausted cells, more central memory cells, and a larger CD8/CD4 T cell ratio. These studies demonstrate that the TOP CAR with TMIGD2 costimulation offered distinct benefits from CD28.41BB costimulation and is effective against solid tumors.

Machine-Learning-Assisted Development of Gel Polymer Electrolytes for Protecting Zn Metal Anodes from the Corrosion of Water Molecules.

Rechargeable aqueous zinc-ion batteries (RAZIBs) offer low cost, high energy density, and safety but struggle with anode corrosion and dendrite formation. Gel polymer electrolytes (GPEs) with both high mechanical properties and excellent electrochemical properties are a powerful tool to aid the practical application of RAZIBs. In this work, guided by a machine learning (ML) model constructed based on experimental data, polyacrylamide (PAM) with a highly entangled structure was chosen to prepare GPEs for obtaining high-performance RAZIBs. By controlling the swelling degree of the PAM, the obtained GPEs effectively suppressed the growth of Zn dendrites and alleviated the corrosion of Zn metal caused by water molecules, thus improving the cycling lifespan of the Zn anode. These results indicate that using ML models based on experimental data can effectively help screen battery materials, while highly entangled PAMs are excellent GPEs capable of balancing mechanical and electrochemical properties.

Trends and hotspots in tea and Alzheimer's disease research from 2014 to 2023: A bibliometric and visual analysis.

Objectives: The positive effects of tea on Alzheimer's disease (AD) have increasingly captured researchers' attention. Nevertheless, the quantitative comprehensive analysis in the relevant literatur is lack. This paper aims to thoroughly examine the current research status and hotspots from 2014 to 2023, providing a valuable reference for subsequent research. Methods: Documents spanning from 2014 to 2023 were searched from the Web of Science, and the R software, VOSviewer, and Citespace software were used for analysis and visualization. Results: A total of 374 documents were contained in the study. The rate of article publications exhibited a consistent increase each year from 2014 to 2023. Notably, China emerged as the leading country in terms of published articles, followed by the United States and India. Simultaneously, China is also in a leading position in cooperation with other countries. Molecules emerged as the most frequently published journal, while the Journal of Alzheimer's Disease secured the top spot in terms of citations. The identified main keywords included oxidative stress, amyloid, epigallocatechin gallate, and green tea polyphenol, among others. These focal areas delved into the antioxidative and anti-amyloid aggregation actions of tea's polyphenolic components. Furthermore, the particularly way in which epigallocatechin gallate delivers neuroprotective outcomes by influencing molecules related to AD represents a focal point of research. Conclusion: The increasing attention from researchers on the role of tea in ameliorating AD positions it as a hot spot in the development of anti-AD drugs in the development of future. Through our generalized analysis of the current landscape and hotspots regarding tea's application in AD, this study provides an estimable reference for future research endeavors.

SemiSynBio: A new era for neuromorphic computing.

Neuromorphic computing has the potential to achieve the requirements of the next-generation artificial intelligence (AI) systems, due to its advantages of adaptive learning and parallel computing. Meanwhile, biocomputing has seen ongoing development with the rise of synthetic biology, becoming the driving force for new generation semiconductor synthetic biology (SemiSynBio) technologies. DNA-based biomolecules could potentially perform the functions of Boolean operators as logic gates and be used to construct artificial neural networks (ANNs), providing the possibility of executing neuromorphic computing at the molecular level. Herein, we briefly outline the principles of neuromorphic computing, describe the advances in DNA computing with a focus on synthetic neuromorphic computing, and summarize the major challenges and prospects for synthetic neuromorphic computing. We believe that constructing such synthetic neuromorphic circuits will be an important step toward realizing neuromorphic computing, which would be of widespread use in biocomputing, DNA storage, information security, and national defense.

Protection of Si Nanowires against Aß Toxicity by the Inhibition of Aß Aggregation.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the accumulation of amyloid beta (Aß) plaques in the brain. Aß1-42 is the main component of Aß plaque, which is toxic to neuronal cells. Si nanowires (Si NWs) have the advantages of small particle size, high specific surface area, and good biocompatibility, and have potential application prospects in suppressing Aß aggregation. In this study, we employed the vapor-liquid-solid (VLS) growth mechanism to grow Si NWs using Au nanoparticles as catalysts in a plasma-enhanced chemical vapor deposition (PECVD) system. Subsequently, these Si NWs were transferred to a phosphoric acid buffer solution (PBS). We found that Si NWs significantly reduced cell death in PC12 cells (rat adrenal pheochromocytoma cells) induced by Aß1-42 oligomers via double staining with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and fluorescein diacetate/propyl iodide (FDA/PI). Most importantly, pre-incubated Si NWs largely prevented Aß1-42 oligomer-induced PC12 cell death, suggesting that Si NWs exerts an anti-Aß neuroprotective effect by inhibiting Aß aggregation. The analysis of Fourier Transform Infrared (FTIR) results demonstrates that Si NWs reduce the toxicity of fibrils and oligomers by intervening in the formation of ß-sheet structures, thereby protecting the viability of nerve cells. Our findings suggest that Si NWs may be a potential therapeutic agent for AD by protecting neuronal cells from the toxicity of Aß1-42.

Temporal patterns of organ dysfunction in COVID-19 patients hospitalized in the intensive care unit: A group-based multitrajectory modeling analysis.

BACKGROUND: The course of organ dysfunction (OD) in Corona Virus Disease 2019 (COVID-19) patients is unknown. Herein, we analyze the temporal patterns of OD in intensive care unit-admitted COVID-19 patients. METHODS: Sequential organ failure assessment scores were evaluated daily within 2 weeks of admission to determine the temporal trajectory of OD using group-based multitrajectory modeling (GBMTM). RESULTS: A total of 392 patients were enrolled with a 28-day mortality rate of 53.6%. GBMTM identified four distinct trajectories. Group 1 (mild OD, n = 64), with a median APACHE II score of 13 (IQR 9-21), had an early resolution of OD and a low mortality rate. Group 2 (moderate OD, n = 140), with a median APACHE II score of 18 (IQR 13-22), had a 28-day mortality rate of 30.0%. Group 3 (severe OD, n = 117), with a median APACHR II score of 20 (IQR 13-27), had a deterioration trend of respiratory dysfunction and a 28-day mortality rate of 69.2%. Group 4 (extremely severe OD, n = 71), with a median APACHE II score of 20 (IQR 17-27), had a significant and sustained OD affecting all organ systems and a 28-day mortality rate of 97.2%. CONCLUSIONS: Four distinct trajectories of OD were identified, and respiratory dysfunction trajectory could predict nonpulmonary OD trajectories and patient prognosis.

Feature shared multi-decoder network using complementary learning for Photon counting CT ring artifact suppression.

BACKGROUND: Photon-counting computed tomography (Photon counting CT) utilizes photon-counting detectors to precisely count incident photons and measure their energy. These detectors, compared to traditional energy integration detectors, provide better image contrast and material differentiation. However, Photon counting CT tends to show more noticeable ring artifacts due to limited photon counts and detector response variations, unlike conventional spiral CT. OBJECTIVE: To comprehensively address this issue, we propose a novel feature shared multi-decoder network (FSMDN) that utilizes complementary learning to suppress ring artifacts in Photon counting CT images. METHODS: Specifically, we employ a feature-sharing encoder to extract context and ring artifact features, facilitating effective feature sharing. These shared features are also independently processed by separate decoders dedicated to the context and ring artifact channels, working in parallel. Through complementary learning, this approach achieves superior performance in terms of artifact suppression while preserving tissue details. RESULTS: We conducted numerous experiments on Photon counting CT images with three-intensity ring artifacts. Both qualitative and quantitative results demonstrate that our network model performs exceptionally well in correcting ring artifacts at different levels while exhibiting superior stability and robustness compared to the comparison methods. CONCLUSIONS: In this paper, we have introduced a novel deep learning network designed to mitigate ring artifacts in Photon counting CT images. The results illustrate the viability and efficacy of our proposed network model as a new deep learning-based method for suppressing ring artifacts.

Mechanisms of the effect of fertility policies on the labor-capital income gap.

This paper investigates the impact mechanism by which an incentive-based fertility policy may reduce the labor income share. First, the specific paths through which this impact mechanism is realized are analyzed using the production function. It is found that an incentive-based fertility policy triggers high savings, which implies more, cheaper, and more readily available capital to be invested in production. A distribution system that earns income based on factor contributions results in more gains for capital than labor, i.e., a lower share of labor income and a wider income gap between labor and capital. Second, the impact mechanism includes three theoretical hypotheses. They are that an encouraging fertility policy is negatively related to labor income share; this relationship is valid provided that the study subject is in a closed economy; and that capital intensification is a mediator variable of fertility policy affecting labor income share. Finally, to further corroborate the impact mechanism in this paper, a Hansen threshold panel model is applied to verify that the effect of fertility policy on labor income share has a threshold effect. This indicates that the effect of the former on the latter changes significantly before and after the change in fertility policy, confirming the existence of an impact mechanism. The established literature has paid little attention to the impact of incentivised fertility policies on the labour income gap. Using capital intensification as the mediating variable, this paper demonstrates the existence of the former effect on the latter. In view of this, under the encouraged fertility policy, this paper proposes specific measures to enhance the labor income share in order to narrow the income gap between labor and capital.

Unilateral Biportal Endoscopy for the Resection of Thoracic Intradural Extramedullary Tumors: Technique Case Report and Literature Review.

This study describes a patient with an intradural extramedullary (IDEM) tumor removed entirely using the unilateral biportal endoscopic technique (UBE), achieving satisfactory clinical outcomes. A 60-year-old woman had a diagnosis of meningioma with sensations and motor dysfunction in the lower extremities and perineum and gait disturbances for three years, which has worsened over the last month. Preoperative imaging data showed a sizeable IDEM tumor at the T10 level, significantly compressing the thoracic spinal cord to the right side, with 80% intraspinal encroachment. The IDEM tumor was removed entirely by UBE surgery. To the best of our knowledge, this study may be the first to report the application of UBE techniques for IDEM tumor treatment. In this case, UBE provides a magnified and clear surgical field, greater maneuverability, and a less invasive surgical procedure. The procedure objectives were pathological confirmation, spinal cord decompression, and complete tumor removal; all were met. The patient was satisfied with her dramatically improved clinical symptoms. UBE may be an alternative surgical treatment option for benign IDEM tumors presenting with symptomatic, especially the non-giant lateral and posterior tumors.

Rituximab potentially improves clinical outcomes of CAR-T therapy for r/r B-ALL via sensitizing leukemia cells to CAR-T-mediated cytotoxicity and reducing CAR-T exhaustion.

PURPOSE: Despite chimeric antigen receptor (CAR) T-cell therapy has achieved great advances in recent year, approximately 50% of relapsed/refractory B cell acute lymphoblastic leukemia (r/r B-ALL) patients treated with CAR-T experience relapse 6 months post CAR-T treatment. CD20 express on 30 to 50% of B-ALL, which makes CD20 Monoclonal Antibody as one of the potential therapy strategies to decrease the tumor burden and improve the efficacy of CAR-T therapy. Adding Rituximab to chemotherapy protocol had been demonstrated to improve the outcome for CD20-positive ALL. However, rare study explored the influence of Rituximab combined with CAR-T therapy. METHODS: We retrospectively analyzed 20 r/r B-ALL patients who received CAR-T therapy, all of whom had failed multiple lines of therapy. Before CAR-T infusion, we administered Rituximab to 10 patients with high CD20 expression at a dose of 375 mg/m2 for 1 day. Meanwhile, we selected 10 patients with the comparable features who underwent CAR-T treatment without Rituximab in the same period as the control group. In vitro, the surface molecule expression and killing of CAR-T post Rituximab-treated B-ALL cells co-incubated with CAR-T cells were detected by flow cytometry. RESULTS: The median follow-up of Rituximab and Control groups were 29.27 and 9.83 months. We found that adding Rituximab may confer a favorable prognosis compared with Control group. The 2-year overall survival (OS) and leukemia-free survival (LFS) rates both were longer in the Rituximab group (90% vs. 26.7%, p = 0.0342; 41.7% vs. 25%, p = 0.308). In vitro, we observed that Rituximab-treated tumour cells are more sensitive to CAR-T killing and a broad range of cytokines and chemokines were produced when Rituximab-treated Nalm-6 cells co-cultured with 19-22CAR-T cells, such as interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2). To investigate whether Rituximab has an effect on CAR-T persistence, we stimulated CAR-T cells repeatedly in vitro with Rituximab-treated Nalm-6 to evaluate the changes in CAR-T surface exhaustion molecules at different times. We found that the expression of exhaustion molecules (LAG-3, PD-1, TIM-3) on CAR-T cells were significantly lower in the Rituximab group than in the Control group. CONCLUSION: Rituximab combined with CAR-T therapy is effective for improving the long-term prognosis of B-ALL patients who have failed multiple lines of therapy. In vitro, we observed that rituximab potentially improves CAR-T efficacy by sensitizing ALL to CART-mediated cytotoxicity and reducing CAR-T exhaustion.

Blood cellular membrane-coated Au/polydopamine nanoparticle-targeted NIR-II antibacterial therapy.

Bacterial infections are the primary causes of infectious diseases in humans. In recent years, the abuse of antibiotics has led to the widespread enhancement of bacterial resistance. Concerns have been raised about the identification of a common treatment platform for bacterial infections. In this study, a composite nanomaterial was used for near-infrared II (NIR-II) photothermal antibacterial treatment. Red blood cell membrane was peeled and coated onto the surface of the Au/polydopamine nanoparticle-containing aptamer. The composite nanomaterials based on Au/polydopamine exhibit highest photothermal conversion capability. Moreover, these assembled nanoparticles can quickly enter the body's circular system with a specific capability to recognise bacteria. In vivo experiments demonstrated that the composites could kill bacteria from infected blood while significantly reducing the level of bacteria in various organs. Such assemblies offer a paradigm for the treatment of bacterial infections caused by the side effects of antibiotics.

Systematical explorations of forensic feature and population genetic diversity of the Chinese Mongolian group from northwest China via a self-constructed Multi-InDel panel.

This study aimed to investigate the genetic polymorphisms and population characteristics of Chinese Mongolian group from northwest China (NCM) through a self-developed panel including 43 autosomal insertion/deletion (A-InDel) polymorphism genetic markers. Herein, 288 unrelated healthy individuals from the NCM group were employed to obtain the genetic data of 43 A-InDels through multiplex PCR amplification and InDel genotyping using capillary electrophoresis platform. In addition, multiplex population genetic analyses were performed between the NCM group and 27 reference populations. There were no deviations at 43 loci from Hardy-Weinberg equilibrium in the NCM group. The observed heterozygosity (Ho) values ranged from 0.312 8 to 0.559 2, and the combined power of discrimination (CPD) and cumulative probability of exclusion (CPE) values in the NCM group were 0.999 999 999 999 999 998 77 and 0.999 814, respectively. The forensic parameter values indicated that this panel was polymorphic and informative in the NCM group and could be used as an effective tool for forensic personal identification. Furthermore, the results of pairwise genetic distances, principal component analysis, multidimensional scaling analysis, phylogenetic tree construction, and admixture analysis among the NCM group and 27 reference populations revealed that there were closer genetic relationships between the NCM group and East Asian populations, especially Chinese Hui group (CHH) from the northwest China, which is consistent with the geographical location. These present findings contributed to the ongoing genetic explorations and insights into the genetic architecture of the NCM group.

Renal interstitial fibrotic assessment using non-Gaussian diffusion kurtosis imaging in a rat model of hyperuricemia.

BACKGROUND: To investigate the feasibility of Diffusion Kurtosis Imaging (DKI) in assessing renal interstitial fibrosis induced by hyperuricemia. METHODS: A hyperuricemia rat model was established, and the rats were randomly split into the hyperuricemia (HUA), allopurinol (AP), and AP + empagliflozin (AP + EM) groups (n = 19 per group). Also, the normal rats were selected as controls (CON, n = 19). DKI was performed before treatment (baseline) and on days 1, 3, 5, 7, and 9 days after treatment. The DKI indicators, including mean kurtosis (MK), fractional anisotropy (FA), and mean diffusivity (MD) of the cortex (CO), outer stripe of the outer medulla (OS), and inner stripe of the outer medulla (IS) were acquired. Additionally, hematoxylin and eosin (H&E) staining, Masson trichrome staining, and nuclear factor kappa B (NF-κB) immunostaining were used to reveal renal histopathological changes at baseline, 1, 5, and 9 days after treatment. RESULTS: The HUA, AP, and AP + EM group MKOS and MKIS values gradually increased during this study. The HUA group exhibited the highest MK value in outer medulla. Except for the CON group, all the groups showed a decreasing trend in the FA and MD values of outer medulla. The HUA group exhibited the lowest FA and MD values. The MKOS and MKIS values were positively correlated with Masson's trichrome staining results (r = 0.687, P < 0.001 and r = 0.604, P = 0.001, respectively). The MDOS and FAIS were negatively correlated with Masson's trichrome staining (r = -626, P < 0.0014 and r = -0.468, P = 0.01, respectively). CONCLUSION: DKI may be a non-invasive method for monitoring renal interstitial fibrosis induced by hyperuricemia.

Effect of different buried depth on the disintegration characteristic of red-bed soft rock and the evolution model of disintegration breakage under cyclic drying-wetting.

The disintegration of red-bed soft rock exhibits a strong correlation with various geological disasters. However, the investigation into the evolutionary mechanisms underlying disintegration breakage has not yet received extensive exploration. In order to comprehensively examine the disintegration characteristics of red-bed soft rock, the slake durability tests were conducted to red-bed soft rocks of varying burial depths. Subsequently, an investigation was carried out to examine the disintegration characteristics and the evolution of disintegration parameters, including the coefficient of uniformity (Cu), coefficient of curvature (Cc), disintegration rate (DRE), disintegration ratio (Dr), and fractal dimension (D), throughout the disintegration process. Finally, employing the energy dissipation theory, an energy dissipation model was developed to predicate the disintegration process of samples at various burial depths. The findings demonstrate a decrease in the abundance of large particles and a concurrent increase in the abundance of small particles as the number of drying-wetting cycles increases. Furthermore, as the number of drying-wetting cycles increases, a significant alteration is observed in the content of particles larger than 10 mm, whereas the content of particles smaller than 10 mm undergoes only minor changes. The disintegration parameters, including the curvature coefficient, non-uniformity coefficient, disintegration rate, and fractal dimension, exhibit a positive correlation with the number of drying-wetting cycles. Conversely, the disintegration index demonstrates a decreasing trend with the increasing number of cycles. Nevertheless, as the burial depth increases, a notable trend emerges in the disintegration process, characterized by a gradual increase in the content of large particles alongside a progressive decrease in the content of small particles. Concurrently, the curvature coefficient, non-uniformity coefficient, disintegration rate, and fractal dimension exhibit a gradual decline, while the durability index experiences a gradual increase. In addition, based on the principle of energy dissipation, it is revealed that the surface energy increment of red-bed soft rock increases with the increase of the number of drying-wetting cycles, but decreases with the increase of burial depth. Ultimately, by leveraging the outcomes of energy dissipation analyses, a theoretical model is constructed to elucidate the correlation between surface energy and both the number of drying-wetting cycles and burial depth. This model serves as a theoretical reference for predicting the disintegration behavior of samples, offering valuable insights for future research endeavors.

Dnttip2 is essential for 18S rRNA processing and digestive organ development in zebrafish.

Dnttip2 is one of the components of the small subunit (SSU) processome. In yeast, depletion of dnttip2 leads to an inefficient processing of pre-rRNA and a decrease in synthesis of the mature 18S rRNA. However, the biological roles of Dnttip2 in higher organisms are poorly defined. In this study, we demonstrate that dnttip2 is a maternal gene in zebrafish. Depletion of Dnttip2 leads to embryonic lethal with severe digestive organs hypoplasia. The loss of function of Dnttip2 also leads to partial defects in cleavage at the A0-site and E-site during 18S rRNA processing. In conclusion, Dnttip2 is essential for 18S rRNA processing and digestive organ development in zebrafish.

Diffusion-Based Generative Network for de Novo Synthetic Promoter Design.

Computer-aided promoter design is a major development trend in synthetic promoter engineering. Various deep learning models have been used to evaluate or screen synthetic promoters, but there have been few works on de novo promoter design. To explore the potential ability of generative models in promoter design, we established a diffusion-based generative model for promoter design in Escherichia coli. The model was completely driven by sequence data and could study the essential characteristics of natural promoters, thus generating synthetic promoters similar to natural promoters in structure and component. We also improved the calculation method of FID indicator, using a convolution layer to extract the feature matrix of the promoter sequence instead. As a result, we got an FID equal to 1.37, which meant synthetic promoters have a distribution similar to that of natural ones. Our work provides a fresh approach to de novo promoter design, indicating that a completely data-driven generative model is feasible for promoter design.

SIRT4 promotes neuronal apoptosis in models of Alzheimer's disease via the STAT2-SIRT4-mTOR pathway.

Alzheimer's disease (AD) is the leading cause of dementia and presents a considerable disease burden. Its pathology involves substantial neuronal loss, primarily attributed to neuronal apoptosis. Although sirtuin 4 (SIRT4) has been implicated in regulating apoptosis in various diseases, the role of SIRT4 in AD pathology remains unclear. The study employed APP/PS1 mice as an animal model of AD and amyloid-ß (Aß)1-42-treated HT-22 cells as an AD cell model. SIRT4 expression was determined by quantitative real-time polymerase chain reaction, western blot, and immunofluorescence. A Sirt4 knockdown model was established by intracranial injection of lentivirus-packaged sh-SIRT4 and cellular lentivirus transfection. Immunohistochemistry and flow cytometry were used to examine Aß deposition in mice and apoptosis, respectively. Protein expression was assessed by western blot analysis. The UCSC and JASPAR databases were used to predict upstream transcription factors of SIRT4. Subsequently, the binding of transcription factors to SIRT4 was analyzed using a dual-luciferase assay and chromatin immunoprecipitation. SIRT4 expression was upregulated in both APP/PS1 mice and Aß-treated HT-22 cells in comparison to their respective control groups. Sirt4 knockdown in animal and cellular models of AD resulted in reduced apoptosis, decreased Aß deposition, and amelioration of learning and memory impairments in mice. Mechanistically, SIRT4 modulates apoptosis via the mTOR pathway and is negatively regulated by the transcription factor signal transducer and activator of transcription 2 (STAT2). Our study findings suggest that targeting the STAT2-SIRT4-mTOR axis may offer a new treatment approach for AD.