Domain-knowledge enabled ensemble learning of 5-formylcytosine (f5C) modification sites.

5-formylcytidine (f5C) is a unique post-transcriptional RNA modification found in mRNA and tRNA at the wobble site, playing a crucial role in mitochondrial protein synthesis and potentially contributing to the regulation of translation. Recent studies have unveiled that the f5C modifications may drive mitochondrial mRNA translation to power cancer metastasis. Accurate identification of f5C sites is essential for further unraveling their molecular functions and regulatory mechanisms, but there are currently no computational methods available for predicting their locations. In this study, we introduce an innovative ensemble approach, successfully enabling the computational recognition of Saccharomyces cerevisiae f5C. We conducted a comprehensive model selection process that involved multiple basic machine learning and deep learning algorithms such as recurrent neural networks, convolutional neural networks and Transformer-based models. Initially trained only on sequence information, these individual models achieved an AUROC ranging from 0.7104 to 0.7492. Through the integration of 32 novel domain-derived genomic features, the performance of individual models has significantly improved to an AUROC between 0.7309 and 0.8076. To further enhance accuracy and robustness, we then constructed the ensembles of these individual models with different combinations. The best performance attained by our ensemble models reached an AUROC of 0.8391. Shapley additive explanations were conducted to explain the significant contributions of genomic features, providing insights into the putative distribution of f5C across various topological regions and potentially paving the way for revealing their functional relevance within distinct genomic contexts. A freely accessible web server that allows real-time analysis of user-uploaded sites can be accessed at: www.rnamd.org/Resf5C-Pred.

GL-V9 induce apoptosis of CML cells via MAPK signaling pathway.

GL-V9, a derivative of wogonin, has shown potent antitumor effects in various cancers, yet its impact on chronic myeloid leukemia (CML) remains unexplored. In this study, we found that GL-V9 significantly decreased the viability of CML cells. Annexin V/PI staining demonstrated that GL-V9 induced apoptosis in a concentration-dependent manner. The JC-1 assay indicated a significant reduction in mitochondrial membrane potential (ΔΨm) in cells treated with GL-V9. Additionally, GL-V9 altered reactive oxygen species (ROS) levels in CML cells. Through transcriptomic sequencing and Western blot analysis, we further revealed that GL-V9 activated the MAPK pathway. These results suggest that GL-V9 is a promising therapeutic candidate for CML.

Association between the guardians' educational levels and unintentional injuries in children aged 6-18 in Shenzhen, China.

BACKGROUND: Unintentional injuries is the leading cause of death in children aged 6-18 in China. Previous studies on the association between the guardians' educational levels and unintentional injuries in children have been inconclusive, and it remains unclear among the Chinese population. Therefore, this study aimed to identify the association between guardians' educational levels and unintentional injuries in children aged 6-18 in Shenzhen, China. METHODS: This cross-sectional study enrolled 9,903 children aged 6-18 in Shenzhen in 2020 using a multistage cluster sampling method. Information on the children and guardians were collected, and unintentional injuries in the past year was examined by using two nested questions. Logistic regression analyses were used to test the association between the guardians' educational levels and unintentional injuries in children aged 6-18, and the crude odds ratios (ORs) and adjusted ORs with 95% confidence intervals (95% CI) were calculated. RESULTS: 275 of the 9,903 children reported experiencing at least one unintentional injuries in the past year, and the weighted incidence of unintentional injuries was 6.3% (95% CI: 5.8-6.8%) in children aged 6-18 in Shenzhen, China. The incidence of unintentional injuries differed significantly in the guardians' education levels (P < 0.05). After adjustment for the children's variables, multiple binary logistic regression analysis showed that compared to children whose guardians' educational levels were low, children whose guardians' educational levels were high (adjusted OR = 0.57, 95% CI: 0.37-0.87) and medium (adjusted OR = 0.56, 95% CI: 0.39-0.81) had a lower odds of unintentional injuries. Similar results were also observed when further adjustment for both the children's and guardians' variables. CONCLUSION: The overall incidence of unintentional injuries in children aged 6-18 in Shenzhen was low, and it was associated with the guardians' educational levels. Children whose guardians' educational levels were low should be given special concern to prevent unintentional injuries, and it is suggested to reduce the incidence of unintentional injuries in children by improving the guardians' educational levels.

Agonists and Inhibitors of the cGAS-STING Pathway.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is pivotal in immunotherapy. Several agonists and inhibitors of the cGAS-STING pathway have been developed and evaluated for the treatment of various diseases. The agonists aim to activate STING, with cyclic dinucleotides (CDNs) being the most common, while the inhibitors aim to block the enzymatic activity or DNA binding ability of cGAS. Meanwhile, non-CDN compounds and cGAS agonists are also gaining attention. The omnipresence of the cGAS-STING pathway in vivo indicates that its overactivation could lead to undesired inflammatory responses and autoimmune diseases, which underscores the necessity of developing both agonists and inhibitors of the cGAS-STING pathway. This review describes the molecular traits and roles of the cGAS-STING pathway and summarizes the development of cGAS-STING agonists and inhibitors. The information is supposed to be conducive to the design of novel drugs for targeting the cGAS-STING pathway.

Reduced inhibitory synaptic transmission onto striatopallidal neurons may underlie aging-related motor skill deficits.

Human beings are living longer than ever before and aging is accompanied by an increased incidence of motor deficits, including those associated with the neurodegenerative conditions, Parkinson's disease (PD) and Huntington's disease (HD). However, the biological correlates underlying this epidemiological finding, especially the functional basis at the synapse level, have been elusive. This study reveals that motor skill performance examined via rotarod, beam walking and pole tests is impaired in aged mice. This study, via electrophysiology recordings, further identifies an aging-related reduction in the efficacy of inhibitory synaptic transmission onto dorsolateral striatum (DLS) indirect-pathway medium spiny neurons (iMSNs), i.e., a disinhibition effect on DLS iMSNs. In addition, pharmacologically enhancing the activity of DLS iMSNs by infusing an adenosine A2A receptor (A2AR) agonist, which presumably mimics the disinhibition effect, impairs motor skill performance in young mice, simulating the behavior in aged naïve mice. Conversely, pharmacologically suppressing the activity of DLS iMSNs by infusing an A2AR antagonist, in order to offset the disinhibition effect, restores motor skill performance in aged mice, mimicking the behavior in young naïve mice. In conclusion, this study identifies a functional inhibitory synaptic plasticity in DLS iMSNs that likely contributes to the aging-related motor skill deficits, which would potentially serve as a striatal synaptic basis underlying age being a prominent risk factor for neurodegenerative motor deficits.

Fighting bacteria with bacteria: A biocompatible living hydrogel patch for combating bacterial infections and promoting wound healing.

Bacterial infections are among the most critical global health challenges that seriously threaten the security of human. To address this issue, a biocompatible engineered living hydrogel patch was developed by co-embedding engineered photothermal bacteria (EM), photosensitizer (porphyrin) and reactive oxygen species amplifier (laccase) in a protein hydrogel. Remarkably, the genetice engineered bacteria can express melanin granules in vivo and this allows them to exhibit photothermal response upon being exposed to NIR-II laser (1064 nm) irradiation. Besides, electrostatically adhered tetramethylpyridinium porphyrin (TMPyP) on the bacterial surface and encapsulated laccase (Lac) in protein gel can generate highly toxic singlet oxygen (1O2) and hydroxyl radical (·OH) in the presence of visible light and lignin, respectively. Interestingly, the engineered bacteria hydrogel patch (EMTL@Gel) was successfully applied in synergistic photothermal, photodynamic and chemodynamic therapy, in which it was able to efficiently treat bacterial infection in mouse wounds and enhance wound healing. This work demonstrates the concept of "fighting bacteria with bacteria" combining bacterial engineering and material engineering into an engineered living hydrogel path that can synergistically boost the therapeutic outcome. STATEMENT OF SIGNIFICANCE: Genetically engineered bacteria produce melanin granules in vivo, exhibiting remarkable photothermal properties. These bacteria, along with a photosensitizer (TMPyP) and a reactive oxygen species amplifier (laccase), are incorporated into a biocompatible protein hydrogel patch. Under visible light, the patch generates toxic singlet oxygen (1O2) and hydroxyl radical (·OH), demonstrates outstanding synergistic effects in photothermal, photodynamic, and chemodynamic therapy, effectively treating bacterial infections and promoting wound healing in mice.

Preoperative prediction of perineural invasion of rectal cancer based on a magnetic resonance imaging radiomics model: A dual-center study.

BACKGROUND: Perineural invasion (PNI) has been used as an important pathological indicator and independent prognostic factor for patients with rectal cancer (RC). Preoperative prediction of PNI status is helpful for individualized treatment of RC. Recently, several radiomics studies have been used to predict the PNI status in RC, demonstrating a good predictive effect, but the results lacked generalizability. The preoperative prediction of PNI status is still challenging and needs further study. AIM: To establish and validate an optimal radiomics model for predicting PNI status preoperatively in RC patients. METHODS: This retrospective study enrolled 244 postoperative patients with pathologically confirmed RC from two independent centers. The patients underwent pre-operative high-resolution magnetic resonance imaging (MRI) between May 2019 and August 2022. Quantitative radiomics features were extracted and selected from oblique axial T2-weighted imaging (T2WI) and contrast-enhanced T1WI (T1CE) sequences. The radiomics signatures were constructed using logistic regression analysis and the predictive potential of various sequences was compared (T2WI, T1CE and T2WI + T1CE fusion sequences). A clinical-radiomics (CR) model was established by combining the radiomics features and clinical risk factors. The internal and external validation groups were used to validate the proposed models. The area under the receiver operating characteristic curve (AUC), DeLong test, net reclassification improvement (NRI), integrated discrimination improvement (IDI), calibration curve, and decision curve analysis (DCA) were used to evaluate the model performance. RESULTS: Among the radiomics models, the T2WI + T1CE fusion sequences model showed the best predictive performance, in the training and internal validation groups, the AUCs of the fusion sequence model were 0.839 [95% confidence interval (CI): 0.757-0.921] and 0.787 (95%CI: 0.650-0.923), which were higher than those of the T2WI and T1CE sequence models. The CR model constructed by combining clinical risk factors had the best predictive performance. In the training and internal and external validation groups, the AUCs of the CR model were 0.889 (95%CI: 0.824-0.954), 0.889 (95%CI: 0.803-0.976) and 0.894 (95%CI: 0.814-0.974). Delong test, NRI, and IDI showed that the CR model had significant differences from other models (P < 0.05). Calibration curves demonstrated good agreement, and DCA revealed significant benefits of the CR model. CONCLUSION: The CR model based on preoperative MRI radiomics features and clinical risk factors can preoperatively predict the PNI status of RC noninvasively, which facilitates individualized treatment of RC patients.

Liquid-Liquid Phase Separation-Mediated Photocatalytic Subcellular Hybrid System for Highly Efficient Hydrogen Production.

Plant chloroplasts have a highly compartmentalized interior, essential for executing photocatalytic functions. However, the construction of a photocatalytic reaction compartment similar to chloroplasts in inorganic-biological hybrid systems (IBS) has not been reported. Drawing inspiration from the compartmentalized chloroplast and the phenomenon of liquid-liquid phase separation, herein, a new strategy is first developed for constructing a photocatalytic subcellular hybrid system through liquid-liquid phase separation technology in living cells. Photosensitizers and in vivo expressed hydrogenases are designed to coassemble within the cell to create subcellular compartments for synergetic photocatalysis. This compartmentalization facilitates efficient electron transfer and light energy utilization, resulting in highly effective H2 production. The subcellular compartments hybrid system (HM/IBSCS) exhibits a nearly 87-fold increase in H2 production compared to the bare bacteria/hybrid system. Furthermore, the intracellular compartments of the photocatalytic reactor enhance the system's stability obviously, with the bacteria maintaining approximately 81% of their H2 production activity even after undergoing five cycles of photocatalytic hydrogen production. The research brings forward visionary prospects for the field of semi-artificial photosynthesis, offering new possibilities for advancements in areas such as renewable energy, biomanufacturing, and genetic engineering.

Dimethyl fumarate covalently modifies Cys673 of NLRP3 to exert anti-inflammatory effects.

The NLRP3 inflammasome plays a pivotal role in various chronic inflammation-driven human diseases. However, no drugs specifically targeting NLRP3 inflammasome have been approved by the Food and Drug Administration (FDA) of the United States. In our current study, we showed that dimethyl fumarate (DMF) efficiently suppressed the activation of the NLRP3 inflammasome induced by multiple agonists and covalently modified Cys673 of NLRP3, thereby impeding the interaction between NLRP3 and NEK7. The inhibitory effect of DMF was nullified by anaplerosis of the Cys673 mutant (but not the wild-type) NLRP3 in Nlrp3-/- THP-1 cells. In vivo experiments, DMF demonstrated protective effects in the dextran sodium sulfate (DSS)-induced ulcerative colitis of WT mice, but not in Nlrp3-/- mice. In summary, our study identified DMF as a direct covalent inhibitor of NLRP3 and a potential candidate for the treatment of NLRP3 inflammasome-mediated diseases.

Analysis of physical activity and prescription opioid use among US adults: a cross-sectional study.

BACKGROUND: Opioid crisis has become a global concern, but whether physical activity (PA) can effectively reduce prescription opioid use remains unclear. The study aimed to examine the relationship of different domains of PA (e.g., occupation-related PA [OPA], transportation-related PA [TPA], leisure-time PA [LTPA]) with prescription opioid use and duration of prescription opioid use. METHODS: This cross-sectional study was conducted on 27,943 participants aged ≥ 18 years from National Health and Nutrition Examination Survey (NHANES, 2007- March 2020). We examined the relationship of different domains of PA with prescription opioid use and duration of prescription opioid use using multivariable logistic regression. Stratified analysis and a series of sensitivity analysis were used to elevate robustness. All analyses were conducted using appropriate sampling weights. RESULTS: Of the 27,943 participants, the mean age was 45.10 years, with 14,018 [weighted, 50.0%] females and 11,045 [weighted, 66.0%] non-Hispanic White. After multivariable adjustment, inverse associations between PA and prescription opioid use were observed for sufficient (≥ 150 min/week) total PA (OR,0.68 95%CI [0.56-0.81]), TPA (OR,0.73 95%CI [0.58-0.92]), and LTPA (OR,0.60 95%CI [0.48-0.75]) compared with insufficient PA(< 150 min/week), but not for sufficient OPA (OR,0.93 95%CI [0.79-1.10]). In addition, the associations were dose-responsive, participants had 22-40%, 27-36%, and 26-47% lower odds of using prescription opioids depending on the duration of total PA, TPA, and LTPA, respectively. Nevertheless, the impact of PA on prescription opioid use varied by duration of opioid use. Sufficient total PA was associated with elevated odds of short-term use of prescription opioids (< 90 days). Comparatively, sufficient total PA, TPA, and LTPA had different beneficial effects on reducing long-term use of prescription opioids (≥ 90 days) depending on the strength of opioids. CONCLUSIONS: This study demonstrated sufficient total PA, TPA, and LTPA were inversely associated with prescription opioid use and varied depending on the duration and strength of prescription opioid use. These findings highlight PA can provide policy guidance to address opioid crisis.