DNA Framework-Enabled 3D Organization of Antiarrhythmic Drugs for Radiofrequency Catheter Ablation.

Preorganizing molecular drugs within a microenvironment is crucial for the development of efficient and controllable therapeutic systems. Here, the use of tetrahedral DNA framework (TDF) is reported to preorganize antiarrhythmic drugs (herein doxorubicin, Dox) in 3D for catheter ablation, a minimally invasive treatment for fast heartbeats, aiming to address potential complications linked to collateral tissue damage and the post-ablation atrial fibrillation (AF) recurrence resulting from incomplete ablation. Dox preorganization within TDF transforms its random distribution into a confined, regular spatial arrangement governed by DNA. This, combined with the high affinity between Dox and DNA, significantly increases local Dox concentration. The exceptional capacity of TDF for cellular internalization leads to a 5.5-fold increase in intracellular Dox amount within cardiomyocytes, effectively promoting cellular apoptosis. In vivo investigations demonstrate that administering TDF-Dox reduces the recurrence rate of electrical conduction after radiofrequency catheter ablation (RFCA) to 37.5%, compared with the 77.8% recurrence rate in the free Dox-treated group. Notably, the employed Dox dosage exhibits negligible adverse effects in vivo. This study presents a promising treatment paradigm that strengthens the efficacy of catheter ablation and opens a new avenue for reconciling the paradox of ablation efficacy and collateral damage.

Identification of a longevity gene through evolutionary rate covariation of insect mito-nuclear genomes.

Oxidative phosphorylation, essential for energy metabolism and linked to the regulation of longevity, involves mitochondrial and nuclear genes. The functions of these genes and their evolutionary rate covariation (ERC) have been extensively studied, but little is known about whether other nuclear genes not targeted to mitochondria evolutionarily and functionally interact with mitochondrial genes. Here we systematically examined the ERC of mitochondrial and nuclear benchmarking universal single-copy ortholog (BUSCO) genes from 472 insects, identifying 75 non-mitochondria-targeted nuclear genes. We found that the uncharacterized gene CG11837-a putative ortholog of human DIMT1-regulates insect lifespan, as its knockdown reduces median lifespan in five diverse insect species and Caenorhabditis elegans, whereas its overexpression extends median lifespans in fruit flies and C. elegans and enhances oxidative phosphorylation gene activity. Additionally, DIMT1 overexpression protects human cells from cellular senescence. Together, these data provide insights into the ERC of mito-nuclear genes and suggest that CG11837 may regulate longevity across animals.

Genomic factors shaping codon usage across the Saccharomycotina subphylum.

Codon usage bias, or the unequal use of synonymous codons, is observed across genes, genomes, and between species. The biased use of synonymous codons has been implicated in many cellular functions, such as translation dynamics and transcript stability, but can also be shaped by neutral forces. The Saccharomycotina, the fungal subphylum containing the yeasts Saccharomyces cerevisiae and Candida albicans , has been a model system for studying codon usage. We characterized codon usage across 1,154 strains from 1,051 species to gain insight into the biases, molecular mechanisms, evolution, and genomic features contributing to codon usage patterns across the subphylum. We found evidence of a general preference for A/T-ending codons and correlations between codon usage bias, GC content, and tRNA-ome size. Codon usage bias is also distinct between the 12 orders within the subphylum to such a degree that yeasts can be classified into orders with an accuracy greater than 90% using a machine learning algorithm trained on codon usage. We also characterized the degree to which codon usage bias is impacted by translational selection. Interestingly, the degree of translational selection was influenced by a combination of genome features and assembly metrics that included the number of coding sequences, BUSCO count, and genome length. Our analysis also revealed an extreme bias in codon usage in the Saccharomycodales associated with a lack of predicted arginine tRNAs. The order contains 24 species, and 23 are computationally predicted to lack tRNAs that decode CGN codons, leaving only the AGN codons to encode arginine. Analysis of Saccharomycodales gene expression, tRNA sequences, and codon evolution suggests that extreme avoidance of the CGN codons is associated with a decline in arginine tRNA function. Codon usage bias within the Saccharomycotina is generally consistent with previous investigations in fungi, which show a role for both genomic features and GC bias in shaping codon usage. However, we find cases of extreme codon usage preference and avoidance along yeast lineages, suggesting additional forces may be shaping the evolution of specific codons.

Normal tissue complication probability model of temporal lobe injury following re-irradiation of IMRT for local recurrent nasopharyngeal carcinoma.

Purpose: We tried to establish the normal tissue complication probability (NTCP) model of temporal lobe injury of recurrent nasopharyngeal carcinoma (NPC) patients after two courses of intensity modulated radiotherapy (IMRT) to provide more reliable dose-volume data reference to set the temporal lobe tolerance dose for recurrent NPC patients in the future. Methods and materials: Recurrent NPC patients were randomly divided into training data set and validation data set in a ratio of 2:1, All the temporal lobes (TLs) were re-contoured as R/L structures and named separately in the MIM system. The dose distribution of the initial IMRT plan was deformed into the second course planning CT via MIM software to get the deformed dose. Equivalent dose of TLs in 2Gy fractions was calculated via linear quadratic model, using an α/ß=3 for temporal lobes. NTCP model that correlated the irradiated volume of the temporal lobe and? the clinical variables were evaluated in a multivariate prediction model using AUC analysis. Results: From Jan. 2010 to Dec. 2020, 78 patients were enrolled into our study. Among which 26 (33.3%) developed TLI. The most important factors affecting TLI was the sum-dose d1.5cc of TL, while the possible clinical factors did not reach statistically significant differences in multivariate analysis. According to NTCP model, the TD5 and TD50 EQD2 dose of sum-dose d1.5cc were 65.26Gy (46.72-80.69Gy) and 125.25Gy (89.51-152.18Gy), respectively. For the accumulated EQD2 dose, the area under ROC shadow was 0.8702 (0.7577-0.9828) in model validation, p<0.001. Conclusion: In this study, a NTCP model of temporal lobe injury after a second course of IMRT for recurrent nasopharyngeal carcinoma was established. TD5 and TD50 doses of temporal lobe injury after re-RT were obtained according to the model, and the model was verified by validation set data.

Temporal trends and correlates in multiple hospitalizations among older adults: findings from a nationally representative sample in China.

OBJECTIVE: This study aims to examine the trends and correlates in multiple hospitalizations among older adults in China. METHODS: The data were from the China Health and Retirement Longitudinal Study (CHARLS), and generalized ordered logit model (GOLM) was used to identify the correlates of multiple hospitalizations among older adults aged≥60 years old. RESULTS: Between 2011 and 2018, the proportion of older adults having multiple hospitalizations in the past year showed an increasing trend in the total sample (p value for trend = 0.014). Being older, male, illiterate, living in the middle/western region, having higher annual per capita household expenditure, health insurance, multimorbidity, and being depressed were associated with increased odds of multiple hospitalizations. CONCLUSIONS: Our findings indicated that older adults with multiple hospitalizations may expect an increasing burden on healthcare system. More efforts are needed to improve health insurance and primary healthcare to reduce avoidable hospitalizations.

Tumor cell-derived exosomal miR-193b-3p promotes tumor-associated macrophage activation to facilitate nasopharyngeal cancer cell invasion and radioresistances.

Background: Communication between cancer cells and tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) plays a crucial role in accelerating nasopharyngeal cancer (NPC) metastasis and radioresistance. However, the mechanisms through which NPC cells regulate the properties and activation of TAMs during NPC progression are not yet fully understood. Methods: A high-metastatic NPC subclone (HMC) and a low-metastatic NPC subclone (LMC) were screened from the CNE-2 cell line and exosomes were collected from HMCs and LMCs, respectively. The effects of HMC- and LMC-derived exosomes (HMC-Exos and LMC-Exos) on the regulation of TAM activation were evaluated by assessing the levels of inflammation-related or immunosuppression-related genes. The role of miRNA-193b-3p (miR-193b) in mediating communication between NPCs and TAMs was assessed using real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR), Western blot analysis, Transwell assays, and clonogenic survival assays. Results: HMCs and HMC-Exos exhibited a greater capacity to facilitate macrophage protumorigenic activation than LMCs and LMC-Exos. miR-193b levels derived from HMC-Exos were higher than those from LMC-Exos, and miR-193b levels were higher in metastatic NPC tissue-derived TAMs than in non-metastatic NPC tissue-derived TAMs. The upregulated miR-193b was packaged into exosomes and transferred to macrophages. Functionally, miR-193b up-regulation accelerated TAM activation by directly targeting mitogen-activated protein/ERK kinase kinase 3 (MEKK3). As a result, miR-193b-overexpressed macrophages facilitated NPC cell invasion and radioresistance. Conclusions: These data revealed a critical role for exosomal miR-193b in mediating intercellular communication between NPC cells and macrophages, providing a potential target for NPC treatment.

The discovery of a novel pyrrolo[2,3-b]pyridine as a selective CDK8 inhibitor offers a new approach against psoriasis.

Currently, the drugs used in clinical to treat psoriasis mainly broadly suppress cellular immunity. However, these drugs can only provide temporary and partial symptom relief, they do not cure the condition and may lead to recurrence or even serious toxic side effects. In this study, we describe the discovery of a novel potent CDK8 inhibitor as a treatment for psoriasis. Through structure-based design, compound 46 was identified as the most promising candidate, exhibiting a strong inhibitory effect on CDK8 (IC50 value of 57 nM) along with favourable inhibition against NF-κB. Additionally, it demonstrated a positive effect in an in vitro psoriasis model induced by TNF-α. Furthermore, this compound enhanced the thermal stability of CDK8 and exerted evident effects on the biological function of CDK8, and it had favourable selectivity across the CDK family and tyrosine kinase. This compound showed no obvious inhibitory effect on CYP450 enzyme. Further studies confirmed that compound 46 exhibited therapeutic effect on IMQ-induced psoriasis, alleviated the inflammatory response in mice, and enhanced the expression of Foxp3 and IL-10 in the dorsal skin in vivo. This discovery provides a new strategy for developing selective CDK8 inhibitors with anti-inflammatory activity for the treatment of psoriasis.

Mechanistic exploration of the shenlian formula in the suppression of atherosclerosis progression via network pharmacology and in vivo experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: The Shenlian formula (SL) is a Chinese medicine formula used to curb the development of atherosclerosis (AS) and cardiovascular disease in clinical practice. However, owing to the complexity of compounds and their related multiple targets in traditional Chinese medicine (TCM), it remains difficult and urgent to elucidate the underlying mechanisms at a holistic level. AIM: To investigate the intrinsic mechanisms by which SL suppresses AS progression and to gain new insight into its clinical use. METHODS: We proposed a network pharmacology-based workflow to evaluate the mechanism by which SL affects AS via data analysis, target prediction, PPI network construction, GO and KEGG analyses, and a "drug-core ingredient-potential target-key pathway" network. Then, non-targeted lipidomic analysis was performed to explore the differential lipid metabolites in AS rats, revealing the possible mechanism by which SL affects atherosclerotic progression. Moreover, an AS rabbit model was constructed and gavaged for SL intervention. Serum lipid profiles and inflammatory cytokine indices were tested as an indication of the mitigating effect of SL on AS. RESULTS: A total of 89 bioactive compounds and 298 targets related to SL and AS, which play essential roles in this process, were identified, and a component-target-disease network was constructed. GO and KEGG analyses revealed that SL regulated metabolic pathway, lipids and atherosclerosis, the PI3K-Akt pathway, the MAPK pathway and so on. In vivo experimental validation revealed that a total of 43 different lipid metabolites regulated by SL were identified by non-targeted lipidomics, and glycerophospholipid metabolism was found to be an important mechanism for SL to interfere with AS. SL reduced the plaque area and decreased the levels of inflammatory cytokines (TNF-α and IL-4) and blood lipids (TC, TG, LDL-C, and ApoB) in HFD-induced AS models. In addition, HDL and ApoA1 levels are increased. PLA2 and Lipin1 are highly expressed in AS model, indicating their role in destabilizing glycerophosphatidylcholine metabolism and contributing to the onset and progression of ankylosing spondylitis. Moreover, SL intervention significantly reduced the level of pro-inflammatory cytokines; significantly down-regulated NF-kB/p65 expression, exhibiting anti-inflammatory activity. CONCLUSION: The Shenlian formula (SL) plays a pivotal role in the suppression of AS progression by targeting multiple pathways and mechanisms. This study provides novel insights into the essential genes and pathways associated with the prognosis and pathogenesis of AS.

De novo synthesis of a novel hapten and development of a monoclonal antibody-based immunoassay for the detection of dichlorvos and trichlorfon.

The absence of high-affinity antibodies has hindered the development of satisfactory immunoassays for dichlorvos (DDVP) and trichlorfon (TCP), two highly toxic organophosphorus pesticides. Herein, the de novo synthesis of a novel anti-DDVP hapten was introduced. Subsequently, a specific anti-DDVP monoclonal antibody (Mab) was produced with satisfying affinity to DDVP (IC50: 12.4 ng mL-1). This Mab was highly specific to DDVP, and TCP could readily convert into DDVP under mild alkaline conditions. Leveraging this insight, an indirect competitive ELISA was successfully developed for simultaneous detection of DDVP and TCP. The limit of detection in rice, cabbage and apple for DDVP /TCP was found to be 12.1/14.6 µg kg-1, 7.3/8.8 µg kg-1 and 6.9/8.3 µg kg-1, respectively. This study not only provides an effective strategy for producing a high-quality anti-DDVP Mab but also affords a reliable and cost-effective tool suitable for high-throughput detection of DDVP and TCP in food samples.

Peritendinous Submembrane Access Technique for Management of Acute Ruptures of the Achilles Tendon: A Retrospective Study of 249 Cases.

OBJECTIVE: Percutaneous repair is an alternative to open surgical repair of the Achilles tendon with comparable, functional results and low re-rupture and infection rates; however, sural nerve injury is a known complication. The purpose of this study is to design a new surgical procedure, the minimally invasive peritendinous submembrane access technique (MIS-PSAT). It offers optimal results, with excellent functional outcomes, and with minimal soft tissue complications and sural nerve injury. METHODS: This retrospective study included 249 patients with acute closed Achilles tendon ruptures treated at our institution between 2009 and 2019. All patients underwent MIS-PSAT at our institution and were followed up for 8-48 months. Functional evaluation was based on the Achilles tendon total rupture score (ATRS) and the American Orthopedic Foot and Ankle Society Ankle-Hindfoot Scale (AOFAS-AHS), associated with local complications and isokinetic tests. RESULTS: None of the patients had infection, necrosis, or sural nerve injury. Re-rupture occurred in two cases. The average times to return to work and sports was 10.4 and 31.6 weeks, respectively. The average ATRS and AOFAS-AHS scores were 90.2 and 95.7, respectively, with an excellent rate of 99.5%. Isokinetic tests showed that ankle function on the affected side was comparable with that on the healthy side (p > 0.05). CONCLUSION: The MIS-PSAT for acute Achilles tendon rupture is easy to perform with few complications. Importantly, the surgical technique reduces the risk of sural nerve injuries. Patients have high postoperative satisfaction, low re-rupture rates, and muscle strength, and endurance can be restored to levels similar to those on the healthy side.

The impact of preanalytical variables on the analysis of cell-free DNA from blood and urine samples.

Cell-free DNA (cfDNA), a burgeoning class of molecular biomarkers, has been extensively studied across a variety of biomedical fields. As a key component of liquid biopsy, cfDNA testing is gaining prominence in disease detection and management due to the convenience of sample collection and the abundant wealth of genetic information it provides. However, the broader clinical application of cfDNA is currently impeded by a lack of standardization in the preanalytical procedures for cfDNA analysis. A number of fundamental challenges, including the selection of appropriate preanalytical procedures, prevention of short cfDNA fragment loss, and the validation of various cfDNA measurement methods, remain unaddressed. These existing hurdles lead to difficulties in comparing results and ensuring repeatability, thereby undermining the reliability of cfDNA analysis in clinical settings. This review discusses the crucial preanalytical factors that influence cfDNA analysis outcomes, including sample collection, transportation, temporary storage, processing, extraction, quality control, and long-term storage. The review provides clarification on achievable consensus and offers an analysis of the current issues with the goal of standardizing preanalytical procedures for cfDNA analysis.

Synthesis and Application of Specific N2H4 Fluorescent Probes with AIE Effect Based on Pyrazole Structure.

Two fluorescent probes, Y1-2 were synthesized from 2-acetonaphthone, 4-acetylbiphenyl, and phenyl hydrazine by Vilsmeier-Haack reaction and Knoevenagel condensation. Their recognition efficacies for N2H4 were tested by UV-visible absorption spectroscopy and fluorescence emission spectroscopy. The recognition mechanism were studies by density-functional theory calculations, and the effect of pH on N2H4 recognition was also studied. The results showed that the probe Y1-2 has high selectivity and a low detection limit for N2H4, and the recognition of N2H4 can be accomplished at physiological pH. The probes have had obvious aggregation-induced luminescence effect, large Stokes shift, high sensitivity, and can be successfully applied to live cell imaging.

[Effects of Biochar on Growth and Pollutant Accumulation of Lettuce in Soil Co-contaminated with Tetracycline and Copper].

Through lettuce potting experiments, the effects of different types of biochar (apple branch, corn straw, and modified sorghum straw biochar with phosphoric acid modification) on lettuce growth under tetracycline (TC) and copper (Cu) co-pollution were investigated. The results showed that compared with those under CK, the addition of biochar treatment significantly increased the plant height, root length, shoot fresh weight, and root fresh weight of lettuce (P < 0.05). The addition of different biochars significantly increased the nitrate nitrogen, chlorophyll, and soluble protein content in lettuce physiological indicators to varying degrees, while also significantly decreasing the levels of malondialdehyde, proline content, and catalase activity. The effects of biochar on lettuce physiological indicators were consistent during both the seedling and mature stages. Compared with those in CK, the addition of biochar resulted in varying degrees of reduction in the TC and Cu contents of both the aboveground and underground parts of lettuce. The aboveground TC and Cu levels decreased by 2.49%-92.32% and 12.79%-36.47%, respectively. The underground TC and Cu levels decreased by 12.53%-55.64% and 22.41%-42.29%, respectively. Correlation analysis showed that nitrate nitrogen, chlorophyll, and soluble protein content of lettuce were negatively correlated with TC content, whereas malondialdehyde, proline content, and catalase activity were positively correlated with TC content. The resistance genes of lettuce were positively correlated with TC content (P < 0.05). In general, modified biochar was found to be more effective in improving lettuce growth quality and reducing pollutant accumulation compared to unmodified biochar, with modified sorghum straw biochar showing the best remediation effect.

Analysis of endophytic bacterial diversity in seeds of different genotypes of cotton and the suppression of Verticillium wilt pathogen infection by a synthetic microbial community.

BACKGROUND: In agricultural production, fungal diseases significantly impact the yield and quality of cotton (Gossypium spp.) with Verticillium wilt posing a particularly severe threat. RESULTS: This study is focused on investigating the effectiveness of endophytic microbial communities present in the seeds of disease-resistant cotton genotypes in the control of cotton Verticillium wilt. The technique of 16S ribosomal RNA (16S rRNA) amplicon sequencing identified a significant enrichment of the Bacillus genus in the resistant genotype Xinluzao 78, which differed from the endophytic bacterial community structure in the susceptible genotype Xinluzao 63. Specific enriched strains were isolated and screened from the seeds of Xinluzao 78 to further explore the biological functions of seed endophytes. A synthetic microbial community (SynCom) was constructed using the broken-rod model, and seeds of the susceptible genotype Xinluzao 63 in this community that had been soaked with the SynCom were found to significantly control the occurrence of Verticillium wilt and regulate the growth of cotton plants. Antibiotic screening techniques were used to preliminarily identify the colonization of strains in the community. These techniques revealed that the strains can colonize plant tissues and occupy ecological niches in cotton tissues through a priority effect, which prevents infection by pathogens. CONCLUSION: This study highlights the key role of seed endophytes in driving plant disease defense and provides a theoretical basis for the future application of SynComs in agriculture.

Early embryonic failure caused by a novel mutation in the TUBB8 gene: A case report.

BACKGROUND: This study aimed to explore the relationship between gene mutations and early embryonic development arrest and to provide more possibilities for the diagnosis and treatment of repeated implantation failure. CASE SUMMARY: Here, we collected and described the clinical data of a patient with early embryonic development stagnation after repeated in vitro fertilization attempts for primary infertility at the Department Reproductive Center of Zaozhuang Maternal and Child Healthcare Hospital. We also detected the whole-exon gene of the patient's spouse and parents, and conducted bioinformatics analysis to determine the pathogenesis of the gene. CONCLUSION: A novel mutant of the TUBB8 gene [c.602G>T(p.C201F)] was identified, and this mutant provided new data on the genotype-phenotype relationships of related diseases.

Smart Sensor-Based Monitoring Technology for Machinery Fault Detection.

Rotary machines commonly use rolling element bearings to support rotation of the shafts. Most machine performance imperfections are related to bearing defects. Thus, reliable bearing condition monitoring systems are critically needed in industries to provide early warning of bearing fault so as to prevent machine performance degradation and reduce maintenance costs. The objective of this paper is to develop a smart monitoring system for real-time bearing fault detection and diagnostics. Firstly, a smart sensor-based data acquisition (DAQ) system is developed for wireless vibration signal collection. Secondly, a modified variational mode decomposition (MVMD) technique is proposed for nonstationary signal analysis and bearing fault detection. The proposed MVMD technique has several processing steps: (1) the signal is decomposed into a series of intrinsic mode functions (IMFs); (2) a correlation kurtosis method is suggested to choose the most representative IMFs and construct the analytical signal; (3) envelope spectrum analysis is performed to identify the representative features and to predict bearing fault. The effectiveness of the developed smart sensor DAQ system and the proposed MVMD technique is examined by systematic experimental tests.

Depletion of regulatory T cells enhancing the anti-tumor effect of in situ vaccination in solid tumors.

The emergence of immune checkpoint inhibitors (ICIs) has revolutionized the clinical treatment for tumor. However, the low response rate of ICIs remains the major obstacle for curing patients and effective approaches for patients with primary or secondary resistance to ICIs remain lacking. In this study, immune stimulating agent unmethylated CG-enriched (CpG) oligodeoxynucleotide (ODN) was locally injected into the tumor to trigger a robust immune response to eradicate cancer cells, while anti-CD25 antibody was applied to remove immunosuppressive regulatory T cells, which further enhanced the host immune activity to attack tumor systematically. The combination of CpG and anti-CD25 antibody obtained notable regression in mouse melanoma model. Furthermore, rechallenge of tumor cells in the xenograft model has resulted in smaller tumor volume, which demonstrated that the combinational treatment enhanced the activity of memory T cells. Remarkably, this combinational therapy presented significant efficacy on multiple types of tumors as well and was able to prevent relapse of tumor partially. Taken together, our combinational immunotherapy provides a new avenue to enhance the clinical outcomes of patients who are insensitive or resistant to ICIs treatments.

Machine learning enables identification of an alternative yeast galactose utilization pathway.

How genomic differences contribute to phenotypic differences is a major question in biology. The recently characterized genomes, isolation environments, and qualitative patterns of growth on 122 sources and conditions of 1,154 strains from 1,049 fungal species (nearly all known) in the yeast subphylum Saccharomycotina provide a powerful, yet complex, dataset for addressing this question. We used a random forest algorithm trained on these genomic, metabolic, and environmental data to predict growth on several carbon sources with high accuracy. Known structural genes involved in assimilation of these sources and presence/absence patterns of growth in other sources were important features contributing to prediction accuracy. By further examining growth on galactose, we found that it can be predicted with high accuracy from either genomic (92.2%) or growth data (82.6%) but not from isolation environment data (65.6%). Prediction accuracy was even higher (93.3%) when we combined genomic and growth data. After the GALactose utilization genes, the most important feature for predicting growth on galactose was growth on galactitol, raising the hypothesis that several species in two orders, Serinales and Pichiales (containing the emerging pathogen Candida auris and the genus Ogataea, respectively), have an alternative galactose utilization pathway because they lack the GAL genes. Growth and biochemical assays confirmed that several of these species utilize galactose through an alternative oxidoreductive D-galactose pathway, rather than the canonical GAL pathway. Machine learning approaches are powerful for investigating the evolution of the yeast genotype-phenotype map, and their application will uncover novel biology, even in well-studied traits.