Lactylation: the novel histone modification influence on gene expression, protein function, and disease.

Lactic acid, traditionally considered as a metabolic waste product arising from glycolysis, has undergone a resurgence in scientific interest since the discovery of the Warburg effect in tumor cells. Numerous studies have proved that lactic acid could promote angiogenesis and impair the function of immune cells within tumor microenvironments. Nevertheless, the precise molecular mechanisms governing these biological functions remain inadequately understood. Recently, lactic acid has been found to induce a posttranslational modification, lactylation, that may offer insight into lactic acid's non-metabolic functions. Notably, the posttranslational modification of proteins by lactylation has emerged as a crucial mechanism by which lactate regulates cellular processes. This article provides an overview of the discovery of lactate acidification, outlines the potential "writers" and "erasers" responsible for protein lactylation, presents an overview of protein lactylation patterns across different organisms, and discusses the diverse physiological roles of lactylation. Besides, the article highlights the latest research progress concerning the regulatory functions of protein lactylation in pathological processes and underscores its scientific significance for future investigations.

Unveiling the molecular complexity of proliferative diabetic retinopathy through scRNA-seq, AlphaFold 2, and machine learning.

Background: Proliferative diabetic retinopathy (PDR), a major cause of blindness, is characterized by complex pathogenesis. This study integrates single-cell RNA sequencing (scRNA-seq), Non-negative Matrix Factorization (NMF), machine learning, and AlphaFold 2 methods to explore the molecular level of PDR. Methods: We analyzed scRNA-seq data from PDR patients and healthy controls to identify distinct cellular subtypes and gene expression patterns. NMF was used to define specific transcriptional programs in PDR. The oxidative stress-related genes (ORGs) identified within Meta-Program 1 were utilized to construct a predictive model using twelve machine learning algorithms. Furthermore, we employed AlphaFold 2 for the prediction of protein structures, complementing this with molecular docking to validate the structural foundation of potential therapeutic targets. We also analyzed protein-protein interaction (PPI) networks and the interplay among key ORGs. Results: Our scRNA-seq analysis revealed five major cell types and 14 subcell types in PDR patients, with significant differences in gene expression compared to those in controls. We identified three key meta-programs underscoring the role of microglia in the pathogenesis of PDR. Three critical ORGs (ALKBH1, PSIP1, and ATP13A2) were identified, with the best-performing predictive model demonstrating high accuracy (AUC of 0.989 in the training cohort and 0.833 in the validation cohort). Moreover, AlphaFold 2 predictions combined with molecular docking revealed that resveratrol has a strong affinity for ALKBH1, indicating its potential as a targeted therapeutic agent. PPI network analysis, revealed a complex network of interactions among the hub ORGs and other genes, suggesting a collective role in PDR pathogenesis. Conclusion: This study provides insights into the cellular and molecular aspects of PDR, identifying potential biomarkers and therapeutic targets using advanced technological approaches.

TransPTM: a transformer-based model for non-histone acetylation site prediction.

Protein acetylation is one of the extensively studied post-translational modifications (PTMs) due to its significant roles across a myriad of biological processes. Although many computational tools for acetylation site identification have been developed, there is a lack of benchmark dataset and bespoke predictors for non-histone acetylation site prediction. To address these problems, we have contributed to both dataset creation and predictor benchmark in this study. First, we construct a non-histone acetylation site benchmark dataset, namely NHAC, which includes 11 subsets according to the sequence length ranging from 11 to 61 amino acids. There are totally 886 positive samples and 4707 negative samples for each sequence length. Secondly, we propose TransPTM, a transformer-based neural network model for non-histone acetylation site predication. During the data representation phase, per-residue contextualized embeddings are extracted using ProtT5 (an existing pre-trained protein language model). This is followed by the implementation of a graph neural network framework, which consists of three TransformerConv layers for feature extraction and a multilayer perceptron module for classification. The benchmark results reflect that TransPTM has the competitive performance for non-histone acetylation site prediction over three state-of-the-art tools. It improves our comprehension on the PTM mechanism and provides a theoretical basis for developing drug targets for diseases. Moreover, the created PTM datasets fills the gap in non-histone acetylation site datasets and is beneficial to the related communities. The related source code and data utilized by TransPTM are accessible at https://www.github.com/TransPTM/TransPTM.

Advances in Microfluidic Paper-Based Analytical Devices (µPADs): Design, Fabrication, and Applications.

Microfluidic Paper-based Analytical Devices (µPADs) have emerged as a new class of microfluidic systems, offering numerous advantages over traditional microfluidic chips. These advantages include simplicity, cost-effectiveness, stability, storability, disposability, and portability. As a result, various designs for different types of assays are developed and investigated. In recent years, µPADs are combined with conventional detection methods to enable rapid on-site detection, providing results comparable to expensive and sophisticated large-scale testing methods that require more time and skilled personnel. The application of µPAD techniques is extensive in environmental quality control/analysis, clinical diagnosis, and food safety testing, paving the way for on-site real-time diagnosis as a promising future development. This review focuses on the recent research advancements in the design, fabrication, material selection, and detection methods of µPADs. It provides a comprehensive understanding of their principles of operation, applications, and future development prospects.

Age-Related Macular Degeneration: A Disease of Cellular Senescence and Dysregulated Immune Homeostasis.

Age-related macular degeneration (AMD) is a degenerative ocular disease primarily affecting central vision in the elderly. Its pathogenesis is complex, involving cellular senescence and immune homeostasis dysregulation. This review investigates the interaction between these two critical biological processes in AMD pathogenesis and their impact on disease progression. Initially, cellular senescence is analyzed, with particular emphasis on retinal damage induced by senescent retinal pigment epithelial cells. Subsequently, the occurrence of immune homeostasis dysregulation within the retina and its mechanistic role in AMD areis explored. Furthermore, the paper also discusses in detail the interplay between cellular senescence and immune responses, forming a vicious cycle that exacerbates retinal damage and may influence treatment outcomes. In summary, a deeper understanding of the interrelation between cellular senescence and immune dysregulation is vital for the developing innovative therapeutic strategies for AMD.

A novel long non-coding RNA SLNCR1 promotes proliferation, migration, and invasion of melanoma via transcriptionally regulating SOX5.

Steroid receptor RNA activator (SRA)-like non-coding RNA (SLNCR1) has been implicated in various tumorigenic processes, but the precise regulatory role in melanoma progression remains uncertain. We performed a comprehensive analysis to investigate the prognostic value of SLNCR1 expression in patients with melanoma by TCGA database and melanoma tissue samples via the Kaplan-Meier method. Subsequently, we conducted qRT-PCR and Fluorescence in Situ Hybridization (FISH) assays to identify SLNCR1 expression levels and localization in tissues and cells, respectively. Loss-of-function assays utilizing shRNAs vectors were used to investigate the potential impact of SLNCR1. Our data showed that SLNCR1 is significantly up-regulated in human malignant melanoma tissues and cell lines and functions as an oncogene. Silencing of SLNCR1 suppressed melanoma cell proliferation, migration, invasion, and inhibited tumorigenesis in a mouse xenograft model. Additionally, we employed bioinformatic predictive analysis, combined with dual-luciferase reporter analysis and functional rescue assays, to elucidate the mechanistic target of the SLNCR1/SOX5 axis in melanoma. Mechanistically, we discovered that SLNCR1 promotes EMT of human melanoma by targeting SOX5, as downregulation of SLNCR1 expression leads to a decrease in SOX5 protein levels and inhibits melanoma tumorigenesis. Our research offers promising insights for more precise diagnosis and treatment of human melanoma.

High-performance asymmetric supercapacitors assembled with novel disc-like MnCo2O4 microstructures as advanced cathode material.

Herein, porous MnCo2O4 with disc-like (MnCo2O4-discs) and ring-like (MnCo2O4-rings) microstructures were respectively synthesized using an initial hydrothermal method at different temperatures and a calcination treatment in air. The electrochemical properties of these MnCo2O4 materials were investigated in three-electrode and two-electrode systems, and as such, MnCo2O4 presented a battery-like electrochemical response. The specific capacity of MnCo2O4-discs was determined to be 296.1C/g at 1 A/g, superior to 246.3C/g for MnCo2O4-rings. An asymmetric supercapacitor (ASC) was assembled with MnCo2O4 as the cathode and activated carbon (AC) as the anode to evaluate the potential for practical application. The MnCo2O4-discs//AC ASC exhibited an energy density (Ed) of 35.8 W h kg-1 at a power density (Pd) of 927.5 W kg-1. For the MnCo2O4-rings//AC ASC, an inferior Ed of 31.4 W h kg-1 under 890.9 W kg-1 was achieved. Furthermore, the two ASCs presented outstanding cyclic performance after 5000 cycles at 6 A/g. The exceptional properties of MnCo2O4 microstructures can be applied to the assembly of ASC devices, which can have promising potential for application in electrochemical energy storage. This synthetic method is straightforward, cost-effective, and can be extended to fabricate similar electrode materials with superior electrochemical performance.

Biohybrid Flexible Sperm-like Microrobot for Targeted Chemo-Photothermal Therapy.

Magnetic micro/nanorobots are promising platforms for targeted drug delivery, and their construction with soft and flexible features has received extensive attention for practical applications. Despite significant efforts in this field, facile fabrication of magnetic microrobots with flexible structures and versatility in targeted therapy remains a big challenge. Herein, we proposed a novel universal strategy to fabricate a biohybrid flexible sperm-like microrobot (BFSM) based on a Chlorella (Ch.) cell and artificial flagella, which showed great potential for targeted chemo-photothermal therapy for the first time. In this approach, microspherical Ch. cells were utilized to construct the microrobotic heads, which were intracellularly deposited with core-shell Pd@Au, extracellularly magnetized with Fe3O4, and further loaded with anticancer drug. The magnetic heads with excellent photothermal and chemotherapeutic capability were further assembled with flexible polypyrrole nanowires via biotin-streptavidin bonding to construct the BFSMs. Based on the exquisite head-to-tail structures, the BFSMs could be effectively propelled under precessing magnetic fields and move back and forth without a U-turn. Moreover, in vitro chemo-photothermal tests were conducted to verify their performance of targeted drug delivery toward localized HeLa cells. Due to this superior versatility and facile fabrication, the BFSMs demonstrated great potential for targeted anticancer therapy.

Sonochemical synthesis of CoNi layered double hydroxide as a cathode material for assembling high performance hybrid supercapacitor.

Fabricating battery-type electrode materials with large specific surface area and mesopores is an efficient method for enhancing the electrochemical performance of supercapacitors. This method may provide more active sites for Faradic reactions and shorten the ion-diffusion paths. In this study, the CoNi layered double hydroxides (LDHs) with the morphology of nanoflowers and nanoflakes were prepared in solutions with pH values of 7.5 (CoNi LDH-7.5) and 8.5 (CoNi LDH-8.5) via a simple sonochemical approach. These CoNi LDHs possessed large specific surface areas and favourable electrochemical properties. The CoNi LDH-7.5 delivered a specific capacity of 740.8C/g at a current density of 1 A/g, surpassing CoNi LDH-8.5 with 668.1C/g. The hybrid supercapacitor (HSC) was assembled with activated carbon as the anode and CoNi LDH as the cathode to assess its practical application potential in the field of electrochemical energy storage. The CoNi LDH-7.5//AC HSC achieved the highest energy density of 35.6 W h kg-1 at a power density of 781.1 W kg-1. In addition, both HSCs exhibited little capacity decay over 5,000 cycles at a high current load of 8 A/g. These electrochemical properties of CoNi LDHs make them promising candidates for battery-type electrode materials. The current sonochemical method is simple and can be applied to the preparation of other LDHs-based electrode materials with favourable electrochemical performance.

Neuropathological characteristics of abnormal white matter functional signaling in adolescents with major depression.

BACKGROUND: Major depression disorder (MDD) constitutes a significant mental health concern. Epidemiological surveys indicate that the lifetime prevalence of depression in adolescents is much higher than that in adults, with a corresponding increased risk of suicide. In studying brain dysfunction associated with MDD in adole-scents, research on brain white matter (WM) is sparse. Some researchers even mistakenly regard the signals generated by the WM as noise points. In fact, studies have shown that WM exhibits similar blood oxygen level-dependent signal fluctuations. The alterations in WM signals and their relationship with disease severity in adolescents with MDD remain unclear. AIM: To explore potential abnormalities in WM functional signals in adolescents with MDD. METHODS: This study involved 48 adolescent patients with MDD and 31 healthy controls (HC). All participants were assessed using the Patient Health Questionnaire-9 Scale and the mini international neuropsychiatric interview (MINI) suicide inventory. In addition, a Siemens Skyra 3.0T magnetic resonance scanner was used to obtain the subjects' image data. The DPABI software was utilized to calculate the WM signal of the fractional amplitude of low frequency fluctuations (fALFF) and regional homogeneity, followed by a two-sample t-test between the MDD and HC groups. Independent component analysis (ICA) was also used to evaluate the WM functional signal. Pearson's correlation was performed to assess the relationship between statistical test results and clinical scales. RESULTS: Compared to HC, individuals with MDD demonstrated a decrease in the fALFF of WM in the corpus callosum body, left posterior limb of the internal capsule, right superior corona radiata, and bilateral posterior corona radiata [P < 0.001, family-wise error (FWE) voxel correction]. The regional homogeneity of WM increased in the right posterior limb of internal capsule and left superior corona radiata, and decreased in the left superior longitudinal fasciculus (P < 0.001, FWE voxel correction). The ICA results of WM overlapped with those of regional homo-geneity. The fALFF of WM signal in the left posterior limb of the internal capsule was negatively correlated with the MINI suicide scale (P = 0.026, r = -0.32), and the right posterior corona radiata was also negatively correlated with the MINI suicide scale (P = 0.047, r = -0.288). CONCLUSION: Adolescents with MDD involves changes in WM functional signals, and these differences in brain regions may increase the risk of suicide.

Auxochrome Dimethyl-Dihydroacridine Improves Fluorophores for Prolonged Live-Cell Super-Resolution Imaging.

Superior photostability, minimal phototoxicity, red-shifted absorption/emission wavelengths, high brightness, and an enlarged Stokes shift are essential characteristics of top-tier organic fluorophores, particularly for long-lasting super-resolution imaging in live cells (e.g., via stimulated emission depletion (STED) nanoscopy). However, few existing fluorophores possess all of these properties. In this study, we demonstrate a general approach for simultaneously enhancing these parameters through the introduction of 9,9-dimethyl-9,10-dihydroacridine (DMA) as an electron-donating auxochrome. DMA not only induces red shifts in emission wavelengths but also suppresses photooxidative reactions and prevents the formation of triplet states in DMA-based fluorophores, greatly improving photostability and remarkably minimizing phototoxicity. Moreover, the DMA group enhances the fluorophores' brightness and enlarges the Stokes shift. Importantly, the "universal" benefits of attaching the DMA auxochrome have been exemplified in various fluorophores including rhodamines, difluoride-boron complexes, and coumarin derivatives. The resulting fluorophores successfully enabled the STED imaging of organelles and HaloTag-labeled membrane proteins.

Development of Plant-Derived Bispecific Monoclonal Antibody Targeting PD-L1 and CTLA-4 against Mouse Colorectal Cancer.

Checkpoint blockade immunotherapy has revolutionized cancer treatment, with monoclonal antibodies targeting immune checkpoints, yielding promising clinical benefits. However, with the advent of resistance to immune checkpoint inhibitor treatment in clinical trials, developing next-generation antibodies with potentially increased efficacy is critical. Here, we aimed to generate a recombinant bispecific monoclonal antibody for dual inhibition of programmed cell death protein 1/programmed cell death ligand 1 and cytotoxic T-lymphocyte-associated protein 4 axes. The plant system was used as an alternative platform for bispecific monoclonal antibody production. Dual variable domain immunoglobulin atezolizumab × 2C8 is a plant-derived bispecific monoclonal antibody that combines both programmed cell death ligand 1 and cytotoxic T-lymphocyte-associated protein 4 blockade into a single molecule. Dual variable domain immunoglobulin atezolizumab × 2C8 was transiently expressed in Nicotiana benthamiana and the expression level was determined to be the highest after 4 days of infiltration. The size and assembly of the purified bispecific monoclonal antibody were determined, and its function was investigated in vitro and in vivo. The molecular structures of plant-produced dual variable domain immunoglobulin atezolizumab × 2C8 are as expected, and it was mostly present as a monomer. The plant-produced dual variable domain immunoglobulin atezolizumab × 2C8 showed in vitro binding to programmed cell death ligand 1 and cytotoxic T-lymphocyte-associated protein 4 proteins. The antitumor activity of plant-produced bispecific monoclonal antibody was tested in vivo by treating humanized Balb/c mice bearing a CT26 colorectal tumor. Plant-produced dual variable domain immunoglobulin atezolizumab × 2C8 significantly inhibited tumor growth by reducing tumor volume and weight. Body weight changes indicated that the plant-produced bispecific monoclonal antibody was safe and tolerable. Overall, this proof of concept study demonstrated the viability of plants to produce functional plant-based bispecific immunotherapy.

Phantom study and clinical application of total-body 18F-FDG PET/CT imaging: How to use small voxel imaging better?

BACKGROUND: Conventional PET/CT imaging reconstruction is typically performed using voxel size of 3.0-4.0 mm in three axes. It is hypothesized that a smaller voxel sizes could improve the accuracy of small lesion detection. This study aims to explore the advantages and conditions of small voxel imaging on clinical application. METHODS: Both NEMA IQ phantom and 30 patients with an injected dose of 3.7 MBq/kg were scanned using a total-body PET/CT (uEXPLORER). Images were reconstructed using matrices of 192 × 192, 512 × 512, and 1024 × 1024 with scanning duration of 3 min, 5 min, 8 min, and 10 min, respectively. RESULTS: In the phantom study, the contrast recovery coefficient reached the maximum in matrix group of 512 × 512, and background variability increased as voxel size decreased. In the clinical study, SUVmax, SD, and TLR increased, while SNR decreased as the voxel size decreased. When the scanning duration increased, SNR increased, while SUVmax, SD, and TLR decreased. The SUVmean was more reluctant to the changes in imaging matrix and scanning duration. The mean subjective scores for all 512 × 512 groups and 1024 × 1024 groups (scanning duration ≥ 8 min) were over three points. One false-positive lesion was found in groups of 512 × 512 with scanning duration of 3 min, 1024 × 1024 with 3 min and 5 min, respectively. Meanwhile, the false-negative lesions found in group of 192 × 192 with duration of 3 min and 5 min, 512 × 512 with 3 min and 1024 × 1024 with 3 min and 5 min were 5, 4, 1, 4, and 1, respectively. The reconstruction time and storage space occupation were significantly increased as the imaging matrix increased. CONCLUSIONS: PET/CT imaging with smaller voxel can improve SUVmax and TLR of lesions, which is advantageous for the diagnosis of small or hypometabolic lesions if with sufficient counts. With an 18F-FDG injection dose of 3.7 MBq/kg, uEXPLORER PET/CT imaging using matrix of 512 × 512 with 5 min or 1024 × 1024 with 8 min can meet the image requirements for clinical use.

Enzyme-Directed and Organelle-Specific Sphere-to-Fiber Nanotransformation Enhances Photodynamic Therapy in Cancer Cells.

Employing responsive nanoplatforms as carriers for photosensitizers represents an effective strategy to overcome the challenges associated with photodynamic therapy (PDT), including poor solubility, low bioavailability, and high systemic toxicity. Drawing inspiration from the morphology transitions in biological systems, a general approach to enhance PDT that utilizes enzyme-responsive nanoplatforms is developed. The transformation of phosphopeptide/photosensitizer co-assembled nanoparticles is first demonstrated into nanofibers when exposed to cytoplasmic enzyme alkaline phosphatase. This transition is primarily driven by alkaline phosphatase-induced changes of the nanoparticles in the hydrophilic and hydrophobic balance, and intermolecular electrostatic interactions within the nanoparticles. The resulting nanofibers exhibit improved ability of generating reactive oxygen species (ROS), intracellular accumulation, and retention in cancer cells. Furthermore, the enzyme-responsive nanoplatform is expanded to selectively target mitochondria by mitochondria-specific enzyme sirtuin 5 (SIRT5). Under the catalysis of SIRT5, the succinylated peptide/photosensitizer co-assembled nanoparticles can be transformed into nanofibers specifically within the mitochondria. The resulting nanofibers exhibit excellent capability of modulating mitochondrial activity, enhanced ROS formation, and significant anticancer efficacy via PDT. Consequently, the enzyme-instructed in situ fibrillar transformation of peptide/photosensitizers co-assembled nanoparticles provides an efficient pathway to address the challenges associated with photosensitizers. It is envisaged that this approach will further expand the toolbox for enzyme-responsive biomaterials for cancer therapy.

Genome-wide transcriptional profiling and functional analysis of long noncoding RNAs and mRNAs in chicken macrophages associated with the infection of avian pathogenic E. coli.

BACKGROUND: Avian pathogenic E. coli (APEC) can cause localized or systemic infections, collectively known as avian colibacillosis, resulting in huge economic losses to poultry industry globally per year. In addition, increasing evidence indicates that long non-coding RNAs (lncRNAs) play a critical role in regulating host inflammation in response to bacterial infection. However, the role of lncRNAs in the host response to APEC infection remains unclear. RESULTS: Here, we found 816 differentially expressed (DE) lncRNAs and 1,798 DE mRNAs in APEC infected chicken macrophages by RNAseq. The identified DE lncRNA-mRNAs were involved in Toll like receptor signaling pathway, VEGF signaling pathway, fatty acid metabolism, phosphatidylinositol signaling system, and other types of O-glycan biosynthesis. Furthermore, we found the novel lncRNA TCONS_00007391 as an important immune regulator in APEC infection was able to regulate the inflammatory response by directly targeting CD86. CONCLUSION: These findings provided a better understanding of host response to APEC infection and also offered the potential drug targets for therapy development against APEC infection.

Catalyst-free late-stage functionalization to assemble α-acyloxyenamide electrophiles for selectively profiling conserved lysine residues.

Covalent probes coupled with chemical proteomics represent a powerful method for investigating small molecule and protein interactions. However, the creation of a reactive warhead within various ligands to form covalent probes has been a major obstacle. Herein, we report a convenient and robust process to assemble a unique electrophile, an α-acyloxyenamide, through a one-step late-stage coupling reaction. This procedure demonstrates remarkable tolerance towards other functional groups and facilitates ligand-directed labeling in proteins of interest. The reactive group has been successfully incorporated into a clinical drug targeting the EGFR L858R mutant, erlotinib, and a pan-kinase inhibitor. The resulting probes have been shown to be able to covalently engage a lysine residue proximal to the ATP-binding pocket of the EGFR L858R mutant. A series of active sites, and Mg2+, ATP-binding sites of kinases, such as K33 of CDK1, CDK2, CDK5 were detected. This is the first report of engaging these conserved catalytic lysine residues in kinases with covalent inhibition. Further application of this methodology to natural products has demonstrated its success in profiling ligandable conserved lysine residues in whole proteome. These findings offer insights for the development of new targeted covalent inhibitors (TCIs).

HDAC6-Activatable Multifunctional Near-Infrared Probe for Glioma Cell Detection and Elimination.

Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor associated with limited treatment options and high drug resistance, presenting significant challenges in the pursuit of effective treatment strategies. Epigenetic modifications have emerged as promising diagnostic biomarkers and therapeutic targets for GBM. For instance, histone deacetylase 6 (HDAC6) has been identified as a potential pharmacological target for GBM. Furthermore, the overexpression of monoamine oxidase A (MAO A) in glioma has been linked to tumor progression, making it an attractive target for therapy. In this study, we successfully engineered HDAC-MB, an activatable multifunctional small-molecule probe with the goal of efficiently detecting and killing glioma cells. HDAC-MB can be selectively activated by HDAC6, leading to the "turn on" of near-infrared fluorescence and effective inhibition of MAO A, along with potent photodynamic therapy (PDT) effects. Consequently, HDAC-MB not only enables the imaging of HDAC6 in live glioma cells but also exhibits the synergistic effect of MAO A inhibition and PDT, effectively inhibiting glioma invasion and inducing cellular apoptosis. The distinctive combination of features displayed by HDAC-MB positions it as a versatile and highly effective tool for the accurate diagnosis and treatment of glioma cells. This opens up opportunities to enhance therapy outcomes and explore future applications in glioma theranostics.

The biogenesis, identification, and functionality of circWWP2 in lipopolysaccharide stimulated macrophages.

CircRNA, a non-coding RNA, is an ideal biomarker and a suitable potential therapeutic target for various disease due to its high stability, species conservation and cell/tissue specificity. Our previous study has found a circular RNA WWP2 (circWWP2) was significantly decreased in chicken macrophages during bacterial infection. However, the function of circWWP2 in chicken macrophages remains unclear. In this study, it was demonstrated that circWWP2 was a stable circular RNA created by back-splicing of exons 2 to 4 of WWP2 via PCR amplification, Sanger sequencing, RNase R exonuclease digestion, and RT-qPCR. Moreover, bioinformatics analysis showed circWWP2 could interact with 13 miRNAs and target 3,264 genes, which were significantly enriched in lysosomes, IgA-producing intestinal immune networks for IgA production, and Notch signaling pathway. Furthermore, CCK8 and RT-qPCR indicated that overexpression of circWWP2 could promote lipopolysaccharide (LPS)-induced cellular injury by decreasing cell viability and increasing the expression levels of pro-inflammatory cytokines and pro-apoptosis genes, and NO production. CircWWP2 may exert a potential target for the treatment of bacterial infection. Further experiments are necessary to validate the specific mechanism that circWWP2 regulates LPS induced cellular immune responses.

Genetic analyses identify brain imaging-derived phenotypes associated with the risk of intracerebral hemorrhage.

Previous observational studies have reported associations between brain imaging-derived phenotypes (IDPs) and intracerebral hemorrhage (ICH), but the causality between them remains uncertain. We aimed to investigate the potential causal relationship between IDPs and ICH by a two-sample Mendelian randomization (MR) study. We selected genetic instruments for 363 IDPs from a genome-wide association study (GWASs) based on the UK Biobank (n = 33,224). Summary-level data on ICH was derived from a European-descent GWAS with 1,545 cases and 1,481 controls. Inverse variance weighted MR method was applied in the main analysis to investigate the associations between IDPs and ICH. Reverse MR analyses were performed for significant IDPs to examine the reverse causation for the identified associations. Among the 363 IDPs, isotropic or free water volume fraction (ISOVF) in the anterior limb of the left internal capsule was identified to be associated with the risk of ICH (OR per 1-SD increase, 4.62 [95% CI, 2.18-9.81], P = 6.63 × 10-5). In addition, the reverse MR analysis indicated that ICH had no effect on ISOVF in the anterior limb of the left internal capsule (beta, 0.010 [95% CI, -0.010-0.030], P = 0.33). MR-Egger regression analysis showed no directional pleiotropy for the association between ISOVF and ICH, and sensitivity analyses with different MR models further confirmed these findings. ISOVF in the anterior limb of the left internal capsule might be a potential causal mediator of ICH, which may provide predictive guidance for the prevention of ICH. Further studies are warranted to replicate our findings and clarify the underlying mechanisms.

Lung ultrasound score as a tool to predict severity of bronchopulmonary dysplasia in neonates born ≤25 weeks of gestational age.

OBJECTIVE: The primary aim was to evaluate whether the addition of the posterior lung aided in diagnostic accuracy of predicting bronchopulmonary dysplasia (BPD) vs moderate-severe BPD (msBPD); the secondary aim was to explore the diagnostic accuracy of two protocols for BPD vs msBPD. STUDY DESIGN: This was a single-center prospective observational study. Preterm infants with a gestational age ≤ 25 weeks were included. Two LUS score protocols were evaluated on the 14th day of life (DOL): (A) evaluating the anterolateral (LUS score-al) lung and (B) the anterolateral combined with posterior (LUS score-alp) lung. The LUS score range for the two protocols was 0-32 and 0-48, respectively. RESULTS: A total of eighty-nine infants were enrolled. Both the LUS score-al and LUS score-alp were higher in neonates developing BPD and msBPD than in the rest of the cohort (LUS score-al 24 (23,26) vs 22 (20,23); LUS score-alp 36 (34,39) vs 28 (25,32)) (LUS score-al 25 (24,26) vs 23 (21,24); LUS score-alp 40 (39,40) vs 34 (28,36)). The LUS score-al on the 14th DOL showed a moderate diagnostic accuracy to predict BPD and msBPD (AUC 95% CI: 0.797 [0.697-0.896]; 0.811[0.713-0.909]), while the LUS score-alp significantly improved diagnostic accuracy of BPD and msBPD (AUC 95% CI: 0.902 [0.834-0.970]; 0.922 [0.848-0.996]). A cutoff of 25 points in the LUS score-al provided a sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of 76.9%, 79.4%, 3.7, and 0.3 respectively to predict msBPD. Meanwhile, that of 39 points in the LUS score-alp provided a sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of 81%, 98.4%, 50.5 and 0.19 to predict msBPD, respectively. CONCLUSIONS: The LUS score on the 14th DOL can predict BPD and msBPD with moderate diagnostic accuracy. Apart from that, scanning posterior enhanced diagnostic accuracy.