Ultrasound-responsive microfibers promoted infected wound healing with neuro-vascularization by segmented sonodynamic therapy and electrical stimulation.

Bacteria-infected wounds pose challenges to healing due to persistent infection and associated damage to nerves and vessels. Although sonodynamic therapy can help kill bacteria, it is limited by the residual oxidative stress, resulting in prolonged inflammation. To tackle these barriers, novel 4 octyl itaconate-coated Li-doped ZnO/PLLA piezoelectric composite microfibers are developed, offering a whole-course "targeted" treatment under ultrasound therapy. The inclusion of Li atoms causes the ZnO lattice distortion and increases the band gap, enhancing the piezoelectric and sonocatalytic properties of the composite microfibers, collaborated by an aligned PLLA conformation design. During the infection and inflammation stages, the piezoelectric microfibers exhibit spatiotemporal-dependent therapeutic effects, swiftly eliminating over 94.2 % of S. aureus within 15 min under sonodynamic therapy. Following this phase, the microfibers capture reactive oxygen species and aid macrophage reprogramming, restoring mitochondrial function, achieving homeostasis, and shortening inflammation cycles. As the wound progresses through the healing stages, bioactive Zn2+ and Li + ions are continuously released, improving cell recruitment, and the piezoelectrical stimulation enhances wound recovery with neuro-vascularization. Compared to commercially available dressings, our microfibers accelerate the closure of rat wounds (Φ = 15 mm) without scarring in 12 days. Overall, this "one stone, four birds" wound management strategy presents a promising avenue for infected wound therapy.

A tunable LDI-MS platform assisted by metal-phenolic network-coated AuNPs for sensitive and customized detection of amino acids.

This study introduces a novel approach for the sensitive and accurate detection of small molecule metabolites, employing metal-phenolic network (MPN) functionalized AuNPs as both adsorbent and matrix to enhance laser desorption/ionization mass spectrometry (LDI-MS) performance. The MPN comprising tannic acid (TA) and transition metal ions (Fe3+, Co2+, Ni2+, Cu2+, or Zn2+) was coated on the surface of AuNPs, forming metal-TA network-coated AuNPs (M-TA@AuNPs). The M-TA@AuNPs provided a tunable surface for specific interactions with analytes, displaying distinct enrichment efficacies for different amino acids, especially for Cu-TA@AuNPs exhibiting the highest affinity for histidine (His). Under the optimized condition, the proposed method enabled ultrasensitive detection of His, with good linearity (R2 = 0.9627) in the low-concentration range (50 nM-1 µM) and a limit of detection (LOD) as low as 0.9 nM. Furthermore, the method was successfully applied to detect His from human urine samples, showcasing its practical applications in clinical diagnostics, particularly in the realm of amino acid-based targeted metabolomics.

Microglial Melatonin Receptor 1 Degrades Pathological Alpha-Synuclein Through Activating LC3-Associated Phagocytosis In Vitro.

AIMS: Parkinson's disease (PD) is characterized by the formation of Lewy bodies (LBs), primarily constituted of α-synuclein (α-Syn). Microglial cells exhibit specific reactivity toward misfolded proteins such as α-Syn. However, the exact clearance mechanism and related molecular targets remain elusive. METHODS: BV2 cells, primary microglia from wild-type and MT1 knockout mice, and primary cortical neurons were utilized as experimental models. The study investigated relevant mechanisms by modulating microglial MT1 expression through small RNA interference (RNAi) and lentiviral overexpression techniques. Furthermore, pathological aggregation of α-Syn was induced using pre-formed fibrils (PFF) α-Syn. Co-immunoprecipitation, immunofluorescence, Western blot (WB), and quantitative real-time PCR were used to elucidate the mechanisms of molecular regulation. RESULTS: In this study, we elucidated the regulatory role of the melatonin receptor 1 (MT1) in the microglial phagocytic process. Following MT1 knockout, the ability of microglial cells to engulf latex beads and zymosan particles decreased, subsequently affecting the phagocytic degradation of fibrillar α-Syn by microglial cells. Furthermore, the loss of MT1 receptors in microglial cells exacerbates the aggregation of α-Syn in neurons induced by pre-formed fibrils (PFF) α-Syn. Mechanistically, MT1 influences the phagocytic function of microglial cells by regulating the Rubicon-dependent LC3-associated phagocytosis (LAP) pathway. CONCLUSION: Taken together, the results suggest the neuroprotective function of microglial cells in clearing α-Syn through MT1-mediated LAP, highlighting the potential key role of MT1 in pathogenic mechanisms associated with α-Syn.

Structure-preserved integration of scRNA-seq data using heterogeneous graph neural network.

The integration of single-cell RNA sequencing (scRNA-seq) data from multiple experimental batches enables more comprehensive characterizations of cell states. Given that existing methods disregard the structural information between cells and genes, we proposed a structure-preserved scRNA-seq data integration approach using heterogeneous graph neural network (scHetG). By establishing a heterogeneous graph that represents the interactions between multiple batches of cells and genes, and combining a heterogeneous graph neural network with contrastive learning, scHetG concurrently obtained cell and gene embeddings with structural information. A comprehensive assessment covering different species, tissues and scales indicated that scHetG is an efficacious method for eliminating batch effects while preserving the structural information of cells and genes, including batch-specific cell types and cell-type specific gene co-expression patterns.

Exploratory Analysis of the Association Between Plasma Ceramide Alterations and Cognitive Dysfunction in Parkinson's Disease.

OBJECTIVE: Prior research has underscored the importance of sphingolipid metabolism in Parkinson's disease (PD) pathogenesis. Our objective was to explore the associations between plasma ceramide levels and PD patients with cognitive dysfunction (PD-CD). METHODS: We enrolled two study populations from Eastern China and the Parkinson's Progression Markers Initiative (PPMI), comprising 290 (100 HCs, 160 PDs, and 30 MSAs) and 429 (125 HCs and 304 PDs) participants, respectively. The plasma levels of ceramides (Cer 16:0, Cer 18:0, Cer 24:0, and Cer 24:1) were tested via HPLC-MS/MS analysis. RESULTS: Compared with those in the HC group, the plasma levels of Cer 18:0, Cer 24:1, Cer 16:0/Cer 24:0, Cer 18:0/Cer 24:0, and Cer 24:1/Cer 24:0 were higher in both the PD and MSA groups. Significant differences in the plasma levels of Cer 16:0/Cer 24:0, Cer 18:0/Cer 24:0, and Cer 24:1/Cer 24:0 were observed among the PD-NC (PD with normal cognition), PD-MCI (PD with mild cognitive impairment), and PDD (PD dementia) groups, with the PDD group exhibiting the highest levels. PD patients with higher baseline levels of plasma ceramides (specifically, Cer 18:0, Cer 16:0/Cer 24:0, Cer 18:0/Cer 24:0, and Cer 24:1/Cer 24:0) demonstrated accelerated cognitive decline compared with individuals who had lower baseline plasma ceramide levels during the 5-year follow-up period. A biomarker panel including Cer 18:0/Cer 24:0 and Cer 24:1/Cer 24:0 could effectively differentiate PD-CD from PD-NC with notable diagnostic accuracy. CONCLUSIONS: Our results indicate that plasma ceramide levels could potentially be used as diagnostic biomarkers for PD-CD.

Discovering Photoswitchable Molecules for Drug Delivery with Large Language Models and Chemist Instruction Training.

Background: As large language models continue to expand in size and diversity, their substantial potential and the relevance of their applications are increasingly being acknowledged. The rapid advancement of these models also holds profound implications for the long-term design of stimulus-responsive materials used in drug delivery. Methods: The large model used Hugging Face's Transformers package with BigBird, Gemma, and GPT NeoX architectures. Pre-training used the PubChem dataset, and fine-tuning used QM7b. Chemist instruction training was based on Direct Preference Optimization. Drug Likeness, Synthetic Accessibility, and PageRank Scores were used to filter molecules. All computational chemistry simulations were performed using ORCA and Time-Dependent Density-Functional Theory. Results: To optimize large models for extensive dataset processing and comprehensive learning akin to a chemist's intuition, the integration of deeper chemical insights is imperative. Our study initially compared the performance of BigBird, Gemma, GPT NeoX, and others, specifically focusing on the design of photoresponsive drug delivery molecules. We gathered excitation energy data through computational chemistry tools and further investigated light-driven isomerization reactions as a critical mechanism in drug delivery. Additionally, we explored the effectiveness of incorporating human feedback into reinforcement learning to imbue large models with chemical intuition, enhancing their understanding of relationships involving -N=N- groups in the photoisomerization transitions of photoresponsive molecules. Conclusions: We implemented an efficient design process based on structural knowledge and data, driven by large language model technology, to obtain a candidate dataset of specific photoswitchable molecules. However, the lack of specialized domain datasets remains a challenge for maximizing model performance.

The impact and mechanisms of parent-child relationship quality and its changes on adolescent depression: A four-wave longitudinal study.

Parent-child relationships play a crucial role in shaping adolescent depression. However, existing research has predominantly focused on isolated time points when examining the impact of parent-child relationship quality, overlooking the effect of parent-child relationship changes on depression. Using a four-wave longitudinal study of 951 adolescents, the current study investigated the impact of parent-child relationship quality and its changes on adolescent depression, while also examining the moderating role of interpersonal sensitivity and potential gender differences in these moderation patterns. Herein, we report that higher parent-child relationship quality is associated with lower levels of adolescent depression, while parent-child relationship changes are linked to higher depression. Interpersonal sensitivity moderates the association between parent-child relationship quality, relationship changes, and depression, with the moderation varying by gender. Specifically, in males with high interpersonal sensitivity, parent-child relationships negatively predict depression, while relationship fluctuations positively predict depression. In females with high interpersonal sensitivity, a rapid decline in the quality of the parent-child relationship seems to be associated with an increase in depression. The present study highlights the impact and mechanisms of parent-child relationship quality and its effects on depression, and provides a reference for the intervention of depression based on parent-child relationship changes.

Agmatine attenuates the severity of immunometabolic disorders by suppressing macrophage polarization: an in vivo study using an ulcerative colitis mouse model.

Agmatine, an endogenous polyamine generated by the gut microbiota, positively affects host lifespan by regulating mononuclear cell or macrophage function. Although the regulatory pathways governing monocyte/macrophage differentiation have been well studied, the influence of the microbiome and its metabolites on monocyte/macrophage function have not been fully elucidated. To address this, we aimed to investigate the mechanisms whereby agmatine inhibits immunometabolic disorders using the colon of ulcerative colitis (UC) model mice. Agmatine (10 mM) attenuated pathological damage to colonic tissue and significantly improved the survival rate of UC model mice. In particular, treatment of UC model mice with 0.4, 2, and 10 mM agmatine resulted in mortality rates of 70 %, 20 %, 10 %, and 0 %, respectively. In a macrophage-depletion model, agmatine regulated the inflammatory microenvironment by affecting macrophages: it reduced the proportion of M1 macrophages and increased that of M2 macrophages in UC model mice. In cultured macrophages, agmatine inhibited lipopolysaccharide-induced inflammatory cytokine and NO secretion, as detected by enzyme-linked immunosorbent assay and the Griess assay, respectively. Agmatine partially reduced inflammatory factor production by inhibiting histone deacetylase, as detected by fluorometric assay. These findings provide evidence that agmatine efficiently suppresses macrophage polarization in UC mice, highlighting its potential as an anti-inflammatory agent against UC.

Discovery of a novel KV7.2/7.3 channels agonist for the treatment of neuropathic pain.

Here, we designed, synthesized and evaluated a series of compounds as KV7.2/7.3 channels (or KCNQ2/3) agonists. The new compounds were assayed in vitro for KCNQ2/3 and other receptors binding affinity. The desired compound 16 showed high activity for KCNQ2/3 (EC50 = 1.03 ± 0.07 µM) without acute liver injury compared to flupirtine. It demonstrated powerful dose-dependent effects in multiple analgesic models, such as chronic constriction injury (CCI, ED50 = 12.02 mg/kg) and streptozotocin-induced diabetic peripheral neuropathic pain (DPNP, ED50 = 9.63 mg/kg) models. Additionally, compound 16 showed low affinity for human ether-a-go-go-related gene (hERG), high thresholds for acute toxicity, good motor performance in the rotarod test and acceptable pharmacokinetic properties. These results suggest the potentiality of compound 16 for the treatment of neuropathic pain.

Comparative analysis of intestinal structure, enzyme activity, intestinal microbiota and gene expression in different segments of pufferfish (Takifugu Obscurus).

The structure of fish intestines does not have a clear regional division, while the function of the intestines may be related to their structure. Therefore, in this study, the delimitation of intestinal segments in pufferfish (Takifugu obscurus) was achieved by morphological analysis. Subsequently, enzyme activity, intestinal microbiota, and gene expression were examined to compare the differences among the pufferfish various segments. According to four morphological parameters: height of mucosa folds (HF), width of mucosa folds (WF), thickness of muscularis (TM), and cross-sectional area (CSA), the pufferfish's intestine was divided into anterior intestine (AI), middle intestine (MI), and posterior intestine (PI). The activity levels of amylase, lipase, and trypsin in the AI and MI were significantly higher than these in the PI. According to the analysis of 16S rDNA, the dominant microbiota at the phylum level in the different segments were Epsilonbacteraeota, Spirochaetes, and Proteobacteria. At the genus level, there were variations observed in the relative abundance of Brevinema, Mycobacterium, Bradyrhizobium, and Microvirga. α diversity analysis revealed that the richness indexes (Ace and Chao1) were the lowest in the MI, while ß diversity analysis revealed significant difference in intestinal microbial community composition among the three intestinal segments. Furthermore, RNA-Seq was used to identify differential expression genes (DEGs) and biological pathways among the different intestinal segments. The DEGs between the AI and MI were enriched in pancreatic secretion and protein digestion and absorption, those between AI and PI were involved in ascorbate and aldarate metabolism and glutathione metabolism, and those between MI and PI were involved in steroid biosynthesis, fat digestion and absorption, vitamin digestion and absorption, and glycine, serine and threonine metabolism. In conclusion, the presented results compare and analyze the differences in various intestinal segments of pufferfish, which will be conductive to future exploration of the functions of these different segments.

Effect of prehabilitation exercises on postoperative frailty in patients undergoing laparoscopic colorectal cancer surgery.

Background: To improve perioperative frailty status in patients undergoing laparoscopic colorectal cancer surgery (LCCS), we explored a new intensive prehabilitation program that combines prehabilitation exercises with standard enhanced recovery after surgery (ERAS) and explored its impact. Methods: We conducted a prospective randomized controlled trial. Between April 2021 to August 2021, patients undergoing elective LCCS were randomized into the standardized ERAS (S-ERAS) group or ERAS based on prehabilitation (group PR-ERAS). Patients in the PR-ERAS group undergoing prehabilitation exercises in the perioperative period in addition to standard enhanced recovery after surgery. We explored the effects of this prehabilitation protocol on frailty, short-term quality of recovery (QoR), psychological status, postoperative functional capacity, postoperative outcomes, and pain. Results: In total, 125 patients were evaluated, and 95 eligible patients were enrolled and randomly allocated to the S-ERAS (n = 45) and PR-ERAS (n = 50) groups. The Fried score was higher in the PR-ERAS group on postoperative day (7 (2(2,3) vs. 3(2,4), P = 0.012). The QoR-9 was higher in the PR-ERAS group than in the S-ERAS group on the 1st, 2nd, 3rd, and 7th postoperative days. The PR-ERAS group had an earlier time to first ambulation (P < 0.050) and time to first flatus (P < 0.050). Conclusion: Prehabilitation exercises can improve postoperative frailty and accelerate recovery in patients undergoing LCCS but may not improve surgical safety. Therefore, better and more targeted prehabilitation recovery protocols should be explored. Clinical trial registration: www.clinicaltrials.org , identifier NCT04964856.

Punicalagin Inhibits African Swine Fever Virus Replication by Targeting Early Viral Stages and Modulating Inflammatory Pathways.

African swine fever (ASF), caused by the African swine fever virus (ASFV), has resulted in significant losses in the global pig industry. Considering the absence of effective vaccines, developing drugs against ASFV may be a crucial strategy for its prevention and control in the future. In this study, punicalagin, a polyphenolic substance extracted from pomegranate peel, was found to significantly inhibit ASFV replication in MA-104, PK-15, WSL, and 3D4/21 cells by screening an antiviral compound library containing 536 compounds. Time-of-addition studies demonstrated that punicalagin acted on early viral replication stages, impinging on viral attachment and internalization. Meanwhile, punicalagin could directly inactivate the virus according to virucidal assay. RT-qPCR and Western blot results indicated that punicalagin modulated the NF-κB/STAT3/NLRP3 inflammasome signaling pathway and reduced the levels of inflammatory mediators induced by ASFV. In conclusion, this study reveals the anti-ASFV activity of punicalagin and the mechanism of action, which may have great potential for developing effective drugs against ASFV.

Proteomic and metabolomic analysis of plasma for pain at different labor stages.

Labor pain has an important impact on maternal labor experience, mood, and postpartum depression. It is of great emotional significance to pay attention to the pain stress response of pregnant women and take necessary intervention measures in the labor process to weaken the sense of delivery experience and reduce the risk of complications. To better understand the molecular alteration of pain and stress changes during the delivery, we analyzed the metabolomic and proteomic of the plasma collected during the labor process at different stages, revealing the significant changes in metabolites and proteins and the key regulatory pathways. The KEGG enrichment analysis showed the differentially expressed metabolites and differentially expressed proteins were mainly enriched in glutamate metabolism, glutathione metabolism, oxidative phosphorylation, glycolysis/gluconeogenesis, and citrate cycle (TCA cycle). In particular, the glutathione metabolism played a major role in the metabolic pathway of the whole labor process. The result demonstrated the potential significance of the glutathione metabolic pathway in pain regulation.

Addition of ruxolitinib and decitabine to modified busulfan/cyclophosphamide conditioning regimen for prophylaxis relapse in high-risk acute myeloid leukemia: the phase 2 prospective study.

The prognosis of patients with high-risk acute myeloid leukemia (AML) is dismal even after allogeneic stem cell transplantation (allo-HSCT), with relapse remaining the leading cause of treatment failure. Here, we investigated whether ruxolitinib and decitabine plus modified busulfan-cyclophosphamide (mBu/Cy) conditioning could reduce relapse in high-risk AML after allo-HSCT. This prospective, single-arm, phase II trial enrolled 37 patients who received allo-HSCT between September 2020 and March 2022 at the First Medical Center of Chinese People's Liberation Army (PLA) General Hospital. Eligible patients (10-62 years) had relapsed/refractory, positive measurable residual disease (MRD) prior to conditioning or adverse genetic abnormalities. Ruxolitinib (35 mg twice daily, days - 15 to - 10) and decitabine (20 mg/m2/day, days - 15 to - 10) were administered followed by mBu/Cy conditioning. All patients achieved engraftment. The cumulative incidences (CIs) of acute graft-versus-host disease (GVHD) grades II-IV and III-IV were 35.0% and 10.5%, respectively. The 1-year cumulative incidence of chronic GVHD was 8.1%. The 1-year CI of relapse was 29.7% among all patients, 0% in patients who achieved the first complete remission (CR1) prior to conditioning, and 0% in those with MRD-negative prior to conditioning. The 1-year non-relapse mortality was 5.4%. The 1-year probabilities of overall survival, disease-free survival, and GVHD-free relapse-free survival were 70.3%, 62.2%, and 54.1%, respectively. In conclusion, the novel conditioning showed primary efficacy in terms of a reduction in relapse in high-risk patients with AML after allo-HSCT, especially in those who achieved CR1 and MRD-negative prior to conditioning. Also, the new conditioning regimen may help reduce the incidence of chronic GVHD. ClinicalTrials.gov identifier: NCT04582604.

Therapeutic potential of Canna edulis RS3-resistant starch in alleviating neuroinflammation and apoptosis in a Parkinson's disease rat model.

This study aimed to investigate the effects of Miao medicinal Canna edulis RS3-resistant starch on behavioral performance and substantia nigra neuron apoptosis-related indicators in a rat model of Parkinson's disease (PD). Among the experimental groups, except for the control group, we induced PD rat models by subcutaneous injection of rotenone in the neck and back. After model induction, a 28-day drug intervention was conducted. Various techniques have been employed, including behavioral analysis, Real-time Polymerase Chain Reaction (RT-PCR), western blotting, enzyme-linked immunosorbent assay (ELISA), immunofluorescence, and terminal deoxynucleotidyltransferase-mediated UTP nick-ends. labeling (TUNEL) and Nissl staining to investigate the effect of Canna edulis RS3-resistant starch on the substantia nigra and neuronal apoptosis-related markers in the brains of PD model rats. Our study revealed that Canna edulis RS3, a resistant starch, significantly reduced the climbing time of PD model rats, prolonged their hanging time, lowered the expression levels of the inflammatory factors IL-1ß, IL-6, and TNF-α, increased the number of TH-positive neurons in the substantia nigra, and decreased the levels of IL-1ß, IL-6, and TNF-α. Furthermore, Canna edulis RS3 elevated the protein expression levels of tyrosine hydroxylase (TH) and Bcl-2 while reducing those of Bax, TLR4, NLRP3,and p-P65, and mitigated apoptosis and morphological changes in dopaminergic neurons in the substantia nigra region. Our results suggest that Canna edulis RS3-resistant starch may offer therapeutic benefits for PD patients with PD by potentially influencing inflammation and apoptosis in the dopaminergic system.

Spatial distribution and hydrogeochemical processes of high iodine groundwater in the Hetao Basin, China.

To understand the genesis and spatial distribution of high iodine groundwater in the Hetao Basin, 540 groundwater samples were analyzed for the chemistry and isotope. Total iodine concentrations in groundwater range from 1.32 to 2897 µg/L, with a mean value of 159.2 µg/L. The groundwater environment was mainly characterized by the weakly alkaline and reducing conditions, with the iodide as the main species of groundwater iodine. High iodine groundwater (I > 100 µg/L) was mainly distributed in shallow aquifers (< 30 m) of Hangjinhouqi near the Langshan Mountain and the discharge areas along the main drainage channels. The δ18O and δ2H values ranged from -12.09 ‰ to -3.99 ‰ and - 91.58 ‰ to -52.80 ‰, respectively, and the correlation between groundwater iodine and isotopes indicates the dominant role of evapotranspiration in the enrichment of iodine in the shallow groundwater with depth <30 m. It was further evidenced by the correlation between groundwater iodine and Cl/Br molar ratio, and significant contributions of climate factors identified from the random forest and XGBoost. Moreover, irrigation practices contribute to high iodine levels, with surface water used for irrigation containing up to 537.8 µg/L of iodine, which can be introduced into shallow aquifer directly. The iodine in irrigation water can be retained in the soil or shallow sediment, and later leach into groundwater under favorable conditions.

Association between sleep traits and risk of colorectal cancer: a bidirectional Mendelian randomization study.

Background: Sleep traits have been linked to diseases; particularly, their impact on cancer has received increasing attention. This study aimed to investigate whether sleep traits have a causal relationship with colorectal cancer (CRC) using two-sample Mendelian randomization (TSMR). Methods: Genetic instrumental variables (IVs) for seven sleep traits (sleep duration, ease of getting up in the morning, morning chronotype, daytime napping, insomnia symptoms, snoring, and daytime dozing) were selected from pooled data from published genome-wide association studies (GSWSs). Two-sample multivariate Mendelian randomization (MR) analyses were conducted to assess the causal association between sleep traits and CRC. Reverse MR analyses were performed to determine the causal relationship between CRC and sleep traits. Inverse variance weighted (IVW), MR-Egger, and weighted medians were calculated for all MR analyses. Results: The multivariable MR (MVMR) analysis found that appropriate sleep duration [odds ratio (OR) =0.989; 95% confidence interval (CI): 0.980, 0.999; P=0.04] and ease of getting up in the morning (OR =0.990; 95% CI: 0.980, 1.000; P=0.04) were protective factors for CRC. Snoring (OR =1.021; 95% CI: 1.002, 1.041; P=0.03) was associated with the risk of CRC. Ease of getting up in the morning (OR =0.990; 95% CI: 0.983, 0.997; P=0.003) was associated with reduced risk of colon cancer. Morning chronotype (OR =1.004; 95% CI: 1.000, 1.007; P=0.04) was associated with the risk of colon cancer. Insomnia symptoms (OR =0.995; 95% CI: 0.990, 0.999; P=0.03) were a protective factor for rectal cancer. There was no evidence found for a causal association between other sleep traits and CRC, colon, or rectal cancer. Conclusions: Proper sleep duration and ease of getting up in the morning may be protective factors against CRC, and snoring may increase the risk of CRC.