Initial therapeutic evidence of a borosilicate bioactive glass (BSG) and Fe3O4 magnetic nanoparticle scaffold on implant-associated Staphylococcal aureus bone infection.

Implant-associated Staphylococcus aureus (S. aureus) osteomyelitis is a severe challenge in orthopedics. While antibiotic-loaded bone cement is a standardized therapeutic approach for S. aureus osteomyelitis, it falls short in eradicating Staphylococcus abscess communities (SACs) and bacteria within osteocyte-lacuna canalicular network (OLCN) and repairing bone defects. To address limitations, we developed a borosilicate bioactive glass (BSG) combined with ferroferric oxide (Fe3O4) magnetic scaffold to enhance antibacterial efficacy and bone repair capabilities. We conducted comprehensive assessments of the osteoinductive, immunomodulatory, antibacterial properties, and thermal response of this scaffold, with or without an alternating magnetic field (AMF). Utilizing a well-established implant-related S. aureus tibial infection rabbit model, we evaluated its antibacterial performance in vivo. RNA transcriptome sequencing demonstrated that BSG + 5%Fe3O4 enhanced the immune response to bacteria and promoted osteogenic differentiation and mineralization of MSCs. Notably, BSG + 5%Fe3O4 upregulated gene expression of NOD-like receptor and TNF pathway in MSCs, alongside increased the expression of osteogenic factors (RUNX2, ALP and OCN) in vitro. Flow cytometry on macrophage exhibited a polarization effect towards M2, accompanied by upregulation of anti-inflammatory genes (TGF-ß1 and IL-1Ra) and downregulation of pro-inflammatory genes (IL-6 and IL-1ß) among macrophages. In vivo CT imaging revealed the absence of osteolysis and periosteal response in rabbits treated with BSG + 5%Fe3O4 + AMF at 42 days. Histological analysis indicated complete controls of SACs and bacteria within OLCN by day 42, along with new bone formation, signifying effective control of S. aureus osteomyelitis. Further investigations will focus on the in vivo biosafety and biological mechanism of this scaffold within infectious microenvironment.

The expression of ERAP1 is favorable for the prognosis and immunotherapy in colorectal cancer: a study based on the bioinformatic and immunohistochemical analysis.

BACKGROUND: Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an emerging pharmacological target in cancer immunotherapy. This study was set out to examine the expression profiles and implications for prognosis and immunotherapy of ERAP1 in CRC. METHODS: Based on bioinformatics and immunohistochemical analysis, we analyzed ERAP1 for potential diagnostic and prognostic significance in CRC. Functional enrichment analysis was conducted to detect the pathways associated with ERAP1, thus determining possible mechanisms. ESTIMATE, TIMER, and CIBESORT probed the links between ERAP1 and tumor-infiltrating immune cells. Lastly, we examined how ERAP1 expression correlated with the sensitivity to immunotherapy. RESULTS: Tumor tissues had decreased levels of ERAP1 expression relative to normal tissues. Patients whose ERAP1 expression was low suffered a worse chance of survival. Besides, it was shown that ERAP1 expression was associated with the advanced M stage and pathologic stage. Survival analysis revealed that low ERAP1 expression, age, pathologic stage, T stage, and M stage were independent indicators for unfavorable CRC patients' prognoses. The 1-, 3-, and 5-year OS calibration curves all fit well with the ideal model, suggesting that the age-ERAP1-T-stage-M-stage nomogram is a reliable predictor of OS. Additionally, we discovered that ERAP1 expression was associated with immune response and infiltration of various immune cells, such as down-regulated inhibitory immune cells and up-regulated stimulating immune cells. Sensitivity to PD-1 and CTLA4 inhibitors was associated with high ERAP1 levels. CONCLUSIONS: In summary, ERAP1 has potential as a diagnostic and prognostic biological marker, highlighting new insights into the study of CRC and the design of effective therapies.

Physical activity promotes brain development through serotonin during early childhood.

Early childhood serves as a critical period for neural development and skill acquisition when children are extremely susceptible to the external environment and experience. As a crucial experiential stimulus, physical activity is believed to produce a series of positive effects on brain development, such as cognitive function, social-emotional abilities, and psychological well-being. The World Health Organization recommends that children engage in sufficient daily physical activity, which has already been strongly advocated in the practice of preschool education. However, the mechanisms by which physical activity promotes brain development are still unclear. The role of neurotransmitters, especially serotonin, in promoting brain development through physical activity has received increasing attention. Physical activity has been shown to stimulate the secretion of serotonin by increasing the bioavailability of free tryptophan and enriching the diversity of gut microbiota. Due to its important role in modulating neuronal proliferation, differentiation, synaptic morphogenesis, and synaptic transmission, serotonin can regulate children's explicit cognitive and social interaction behavior in the early stages of life. Therefore, we hypothesized that serotonin emerges as a pivotal transmitter that mediates the relationship between physical activity and brain development during early childhood. Further systematic reviews and meta-analyses are needed to specifically explore whether the type, intensity, dosage, duration, and degree of voluntariness of PA may affect the role of serotonin in the relationship between physical activity and brain function. This review not only helps us understand the impact of exercise on development but also provides a solid theoretical basis for increasing physical activity during early childhood.

Impact of COVID-19 on emotional and behavioral problems among preschool children: a meta-analysis.

The impact of the Coronavirus Disease 2019 (COVID-19) on society is continuous, resulting in negative psychological consequences. Given the vulnerability and sensitivity to the environment among preschool children, their emotional and behavioral problems deserve more attention. The current study aimed to explore the impact of the epidemic on preschool children's mental health by determining the pooled prevalence of emotional and behavioral problems amidst the Coronavirus Disease 2019 pandemic and to reveal potential reasons for variations between studies. Published studies were searched in Embase, PubMed, ProQuest, PsycINFO, Web of Science, CNKI, and Wanfang. Based on the inclusion criteria outlined in this study, a total of 10 studies encompassing 38,059 participants were incorporated. Employing a random-effect model for estimating the prevalence of emotional and behavioral problems, the results revealed a pooled prevalence rate of 24.3% (95% CI, 0.15-0.38; I²=99.9%) among preschool children. This rate surpasses the pre-outbreak prevalence observed in different countries, signifying a detrimental influence of the epidemic on the mental well-being of preschoolers. Therefore, mental health care and recovery are essential for the vulnerable group during and after the public health crisis. Specific emotional and behavioral problems among preschool children are expected to be researched in the future to provide more targeted guidance for intervention.

A Review on Autism Spectrum Disorder Screening by Artificial Intelligence Methods.

PURPOSE: With the increasing prevalence of autism spectrum disorders (ASD), the importance of early screening and diagnosis has been subject to considerable discussion. Given the subtle differences between ASD children and typically developing children during the early stages of development, it is imperative to investigate the utilization of automatic recognition methods powered by artificial intelligence. We aim to summarize the research work on this topic and sort out the markers that can be used for identification. METHODS: We searched the papers published in the Web of Science, PubMed, Scopus, Medline, SpringerLink, Wiley Online Library, and EBSCO databases from 1st January 2013 to 13th November 2023, and 43 articles were included. RESULTS: These articles mainly divided recognition markers into five categories: gaze behaviors, facial expressions, motor movements, voice features, and task performance. Based on the above markers, the accuracy of artificial intelligence screening ranged from 62.13 to 100%, the sensitivity ranged from 69.67 to 100%, the specificity ranged from 54 to 100%. CONCLUSION: Therefore, artificial intelligence recognition holds promise as a tool for identifying children with ASD. However, it still needs to continually enhance the screening model and improve accuracy through multimodal screening, thereby facilitating timely intervention and treatment.

Revealing the gut microbiome mystery: A meta-analysis revealing differences between individuals with autism spectrum disorder and neurotypical children.

The brain-gut axis intricately links gut microbiota (GM) dysbiosis to the development or worsening of autism spectrum disorder (ASD). However, the precise GM composition in ASD and the effectiveness of probiotics are unclear. To address this, we performed a thorough meta-analysis of 28 studies spanning PubMed, PsycINFO, Web of Science, Scopus, and MEDLINE, involving 1,256 children with ASD and 1042 neurotypical children, up to February 2024. Using Revman 5.3, we analyzed the relative abundance of 8 phyla and 64 genera. While individuals with ASD did not exhibit significant differences in included phyla, they exhibited elevated levels of Parabacteroides, Anaerostipes, Faecalibacterium, Clostridium, Dorea, Phascolarctobacterium, Lachnoclostridium, Catenibacterium, and Collinsella along with reduced percentages of Barnesiella, Odoribacter, Paraprevotella, Blautia, Turicibacter, Lachnospira, Pseudomonas, Parasutterella, Haemophilus, and Bifidobacterium. Notably, discrepancies in Faecalibacterium, Clostridium, Dorea, Phascolarctobacterium, Catenibacterium, Odoribacter, and Bifidobacterium persisted even upon systematic exclusion of individual studies. Consequently, the GM of individuals with ASD demonstrates an imbalance, with potential increases or decreases in both beneficial and harmful bacteria. Therefore, personalized probiotic interventions tailored to ASD specifics are imperative, rather than a one-size-fits-all approach.

Recruitment of ubiquitin E2 enzymes is determined jointly by the U-box domains and substrates of E3 ligases.

Ubiquitination is a cascade reaction involving E1, E2, and E3 enzymes. The orthogonal ubiquitin transfer (OUT) method has been previously established to identify potential substrates of E3 ligases. In this study, we verified the ubiquitination of five substrates mediated by the E3 ligases CHIP and E4B. To further explore the activity of U-box domains of E3 ligases, two mutants with the U-box domains interchanged between CHIP and E4B were generated. They exhibited a significantly reduced ubiquitination ability. Additionally, different E3s recruited similar E2 ubiquitin-conjugating enzymes when ubiquitinating the same substrates, highlighting that U-box domains determined the E2 recruitment, while the substrate determined the E2 selectivity. This study reveals the influence of substrates and U-box domains on E2 recruitment, providing a novel perspective on the function of U-box domains of E3 ligases.

ABHD6 suppresses colorectal cancer progression via AKT signaling pathway.

Colorectal cancer (CRC) continues to be a prevalent malignancy, posing a significant risk to human health. The involvement of alpha/beta hydrolase domain 6 (ABHD6), a serine hydrolase family member, in CRC development was suggested by our analysis of clinical data. However, the role of ABHD6 in CRC remains unclear. This study seeks to elucidate the clinical relevance, biological function, and potential molecular mechanisms of ABHD6 in CRC. We investigated the role of ABHD6 in clinical settings, conducting proliferation, migration, and cell cycle assays. To determine the influence of ABHD6 expression levels on Oxaliplatin sensitivity, we also performed apoptosis assays. RNA sequencing and KEGG analysis were utilized to uncover the potential molecular mechanisms of ABHD6. Furthermore, we validated its expression levels using Western blot and reactive oxygen species (ROS) detection assays. Our results demonstrated that ABHD6 expression in CRC tissues was notably lower compared to adjacent normal tissues. This low expression correlated with a poorer prognosis for CRC patients. Moreover, ABHD6 overexpression impeded CRC cell proliferation and migration while inducing G0/G1 cell cycle arrest. In vivo experiments revealed that downregulation of ABHD6 resulted in an increase in tumor weight and volume. Mechanistically, ABHD6 overexpression inhibited the activation of the AKT signaling pathway and decreased ROS levels in CRC cells, suggesting the role of ABHD6 in CRC progression via the AKT signaling pathway. Our findings demonstrate that ABHD6 functions as a tumor suppressor, primarily by inhibiting the AKT signaling pathway. This role establishes ABHD6 as a promising prognostic biomarker and a potential therapeutic target for CRC patients.

Application of Single-Cell Sequencing Technology in Research on Colorectal Cancer.

Colorectal cancer (CRC) is the third most prevalent and second most lethal cancer globally, with gene mutations and tumor metastasis contributing to its poor prognosis. Single-cell sequencing technology enables high-throughput analysis of the genome, transcriptome, and epigenetic landscapes at the single-cell level. It offers significant insights into analyzing the tumor immune microenvironment, detecting tumor heterogeneity, exploring metastasis mechanisms, and monitoring circulating tumor cells (CTCs). This article provides a brief overview of the technical procedure and data processing involved in single-cell sequencing. It also reviews the current applications of single-cell sequencing in CRC research, aiming to enhance the understanding of intratumoral heterogeneity, CRC development, CTCs, and novel drug targets. By exploring the diverse molecular and clinicopathological characteristics of tumor heterogeneity using single-cell sequencing, valuable insights can be gained into early diagnosis, therapy, and prognosis of CRC. Thus, this review serves as a valuable resource for identifying prognostic markers, discovering new therapeutic targets, and advancing personalized therapy in CRC.

Ag nanoparticle modified porous Si microspheres as high-performance anodes for Li-ion batteries.

This study aimed to address the challenges associated with silicon (Si) anode materials in Li-ion batteries, such as their large volume effect and poor electrical conductivity. To overcome these limitations, a novel composite microsphere called pSi/Ag was developed using quartz waste through a combination of high-energy ball-milling, spray drying, and magnesiothermic reduction techniques. The morphology and structure of the pSi/Ag composite were thoroughly characterized using various methods, including X-ray diffraction, field-emission scanning electron microscopy, and transmission electron microscopy. The results revealed that the Ag nanoparticles were uniformly dispersed within the porous micron-sized Si sphere particles, leading to enhanced electrochemical performance compared to pure porous silicon that did not undergo the spray drying process. The use of micron-sized Si prevented the excessive formation of the solid electrolyte interphase film, and the pSi/Ag-5 anode, prepared with 5 wt% AgNO3 as a precursor, demonstrated an impressive initial Coulombic efficiency of 92.8%. Moreover, a high specific capacity of 1251.4 mA h g-1 over 300 cycles at a current density of 4000 mA g-1 was attributed to the improved conductivity provided by the Ag nanoparticles in the Si matrix. The straightforward synthesis method employed in this study to produce pSi/Ag presents a promising approach for the future development of high-performance silicon anodes in Li-ion batteries.

Sequential annulation and isomerisation reaction of 3-acylmethylidene oxindoles with Huisgen zwitterions and synthesis of 5-(3-oxindolyl)oxazoles.

Herein, we report a facile synthesis of 5-(3-oxindolyl)oxazole derivatives via a sequential annulation and isomerisation reaction of 3-acylmethylidene oxindoles with in situ generated Huisgen zwitterions (HZs) from PPh3 and azodicarboxylates. This reaction exhibits good functional group tolerance with 30 examples of structurally diverse products prepared with moderate to good efficiencies (up to 88% yield), thus providing a generally applicable route to the biologically important 5-(3-indolyl)oxazole structural motifs. Key to the success of this sequential one-pot strategy is the utilization of DBU as a base to promote the isomerisation process of the corresponding intermediate annulation products.

Histone deacetylase-mediated tumor microenvironment characteristics and synergistic immunotherapy in gastric cancer.

Background: Studies have shown that the expression of histone deacetylases (HDACs) is significantly related to the tumor microenvironment (TME) in gastric cancer. However, the expression of a single molecule or several molecules does not accurately reflect the TME characteristics or guide immunotherapy in gastric cancer. Methods: We constructed an HDAC score (HDS) based on the expression level of HDACs. The single-cell transcriptome was used to analyze the underlying factors contributing to differences in immune infiltration between patients with a high and low HDS. In vitro and in vivo experiments validated the strategy of transforming cold tumors into hot tumors to guide immunotherapy. Results: According to the expression characteristics of HDACs, we constructed an HDS model to characterize the TME. We found that patients with a high HDS had stronger immunogenicity and could benefit more from immunotherapy than those with a low score. The AUC value of the HDS combined with the combined positive score (CPS)for predicting the efficacy of immunotherapy was as high as 0.96. By single-cell and paired bulk transcriptome sequencing analysis, we found that the infiltration levels of CD4+ T cells, CD8+ T cells and NK cells were significantly decreased in the low HDS group, which may be induced by MYH11+ fibroblasts, CD234+ endothelial cells and CCL17+ pDCs via the MIF signaling pathway. Inhibition of the MIF signaling pathway was confirmed to potentially enhance immune infiltration. In addition, our analysis revealed that GPX4 inhibitors might be effective for patients with a low HDS. GPX4 knockout significantly inhibited PD-L1 expression and promoted the infiltration and activation of CD8+ T cells. Conclusion: We constructed an HDS model based on the HDAC expression characteristics of gastric cancer. This model was used to evaluate TME characteristics and predict immunotherapy efficacy. Inhibition of the MIF signaling pathway in the TME and GPX4 expression in tumor cells may be an important strategy for cold tumor synergistic immunotherapy for gastric cancer.

Characteristics of alpha-fetoprotein-positive gastric cancer revealed by analysis of cancer databases and transcriptome sequencing data.

Gastric cancer is one of the most common malignant tumors in the world. Alpha fetoprotein (AFP)-positive gastric cancer (AFPP-GC) is considered a special entity among gastric cancers. There is still controversy regarding the clinicopathological characteristics and prognosis of AFPP-GC, and the potential mechanism underlying its high malignant potential is still unclear. A comprehensive description of AFPP-GC genomic characteristics and regulatory mechanisms is lacking. This study analyzed the pathological characteristics and prognosis of AFPP-GC by utilizing clinical samples. The results showed that AFPP-GC has a poor prognosis and a high of risk liver metastasis. Tissue transcriptome sequencing showed that genes with high expression in AFPP-GC were involved in the activation of various cancer pathways, and genes with low expression were involved in the immune response. Single-sample gene set enrichment analysis showed that overexpression of AFP in AFPP-GC significantly inhibited the infiltration of CD8+ T cells. To further explore the genomic characteristics of AFPP-GC, the signaling pathway by which AFP regulates the invasion and metastasis of AFPP-GC cells was discussed. The results showed that AFPP-GC may promote cell invasion by regulating the PTEN/AKT1/SOX5/CES1 signaling axis. This study reveals the molecular mechanism underlying the increased malignant potential of AFPP-GC vs. AFP-negative gastric cancer (AFPN-GC). This provides important information for individualized treatment of AFPP-GC.

SLC25A51 promotes tumor growth through sustaining mitochondria acetylation homeostasis and proline biogenesis.

Solute carrier family 25 member 51 (SLC25A51) was recently identified as the mammalian mitochondrial NAD+ transporter essential for mitochondria functions. However, the role of SLC25A51 in human disease, such as cancer, remains undefined. Here, we report that SLC25A51 is upregulated in multiple cancers, which promotes cancer cells proliferation. Loss of SLC25A51 elevates the mitochondrial proteins acetylation levels due to SIRT3 dysfunctions, leading to the impairment of P5CS enzymatic activity, which is the key enzyme in proline biogenesis, and the reduction in proline contents. Notably, we find fludarabine phosphate, an FDA-approved drug, is able to bind with and inhibit SLC25A51 functions, causing mitochondrial NAD+ decrease and proteins hyperacetylation, which could further synergize with aspirin to reinforce the anti-tumor efficacy. Our study reveals that SLC25A51 is an attractive anti-cancer target, and provides a novel drug combination of fludarabine phosphate with aspirin as a potential cancer therapy strategy.

IDH1 K224 acetylation promotes colorectal cancer via miR-9-5p/NHE1 axis-mediated regulation of acidic microenvironment.

The acidic microenvironment is considered an important factor in colorectal cancer (CRC) that contributes to malignant transformation. However, the underlying mechanism remains unclear. In a previous study, we confirmed that IDH1 K224 deacetylation promotes enzymatic activity and the production of α-KG. Here, we further investigate the effect of IDH1 hyperacetylation on the CRC acidic microenvironment. We demonstrate that increased α-KG affects hydroxylation of Ago2 and mediates miR-9-5p targeting NHE1 protein. Knockdown of NHE1 dramatically attenuates CRC cell proliferation and migration by restricting transport of intracellular H+ out of cells. Furthermore, we show that miR-9-5p is the microRNA with the most significant difference in the alteration of IDH1 K224 acetylation and can downregulate NHE1 mRNA. Our data also indicate that hydroxylation stabilizes Ago2, which in turn promotes miR-9-5p activity. Taken together, our results reveal a novel mechanism through which IDH1 deacetylation regulates the cellular acidic microenvironment and inhibits CRC metastasis.

Reshaping the tumour immune microenvironment in solid tumours via tumour cell and immune cell DNA methylation: from mechanisms to therapeutics.

In recent years, the tumour microenvironment (TME) of solid tumours has attracted more and more attention from researchers, especially those non-tumour components such as immune cells. Infiltration of various immune cells causes tumour immune microenvironment (TIME) heterogeneity, and results in different therapeutic effects. Accumulating evidence showed that DNA methylation plays a crucial role in remodelling TIME and is associated with the response towards immune checkpoint inhibitors (ICIs). During carcinogenesis, DNA methylation profoundly changes, specifically, there is a global loss of DNA methylation and increased DNA methylation at the promoters of suppressor genes. Immune cell differentiation is disturbed, and exclusion of immune cells from the TME occurs at least in part due to DNA methylation reprogramming. Therefore, pharmaceutical interventions targeting DNA methylation are promising. DNA methyltransferase inhibitors (DNMTis) enhance antitumor immunity by inducing transcription of transposable elements and consequent viral mimicry. DNMTis upregulate the expression of tumour antigens, mediate immune cells recruitment and reactivate exhausted immune cells. In preclinical studies, DNMTis have shown synergistic effect when combined with immunotherapies, suggesting new strategies to treat refractory solid tumours.

Prognostic Biomarker SPOCD1 and Its Correlation with Immune Infiltrates in Colorectal Cancer.

The biological role of the spen paralogue and orthologue C-terminal domain containing 1 (SPOCD1) has been investigated in human malignancies, but its function in colorectal cancer (CRC) is unclear. This study investigated the association between SPOCD1 expression and clinicopathological features of CRC cases, as well as its prognostic value and biological function based on large-scale databases and clinical samples. The results showed that the expression level of SPOCD1 was elevated in CRC, which was generally associated with shortened survival time and poor clinical indexes, including advanced T, N, and pathologic stages. Multivariate Cox regression analysis showed that elevated SPOCD1 expression was an independent factor for poor prognosis in CRC patients. Functional enrichment analysis of SPOCD1 and its co-expressed genes revealed that SPOCD1 could act as an oncogene by regulating gene expression in essential functions and pathways of tumorigenesis, such as extracellular matrix organization, chemokine signaling pathways, and calcium signaling pathways. In addition, immune cell infiltration results showed that SPOCD1 expression was associated with various immune cells, especially macrophages. Furthermore, our findings suggested a possible function for SPOCD1 in the polarization of macrophages from M1 to M2 in CRC. In conclusion, SPOCD1 is a promising diagnostic and prognostic marker for CRC, opening new avenues for research and treatment.

Copper-Catalyzed Chemo- and Enantioselective Radical 1,2-Carbophosphonylation of Styrenes.

The copper-catalyzed enantioselective radical difunctionalization of alkenes from readily available alkyl halides and organophosphorus reagents possessing a P-H bond provides an appealing approach for the synthesis of α-chiral alkyl phosphorus compounds. The major challenge arises from the easy generation of a P-centered radical from the P-H-type reagent and its facile addition to the terminal side of alkenes, leading to reverse chemoselectivity. We herein disclose a radical 1,2-carbophosphonylation of styrenes in a highly chemo- and enantioselective manner. The key to the success lies in not only the implementation of dialkyl phosphites with a strong bond dissociation energy to promote the desired chemoselectivity but also the utilization of an anionic chiral N,N,N-ligand to forge the chiral C(sp3 )-P bond. The developed Cu/N,N,N-ligand catalyst has enriched our library of single-electron transfer catalysts in the enantioselective radical transformations.