Metal-Doping Strategy for Carbon-Based Sonosensitizer in Sonodynamic Therapy of Glioblastoma.

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor and known for its challenging prognosis. Sonodynamic therapy (SDT) is an innovative therapeutic approach that shows promise in tumor elimination by activating sonosensitizers with low-intensity ultrasound. In this study, a novel sonosensitizer is synthesized using Cu-doped carbon dots (Cu-CDs) for the sonodynamic treatment of GBM. Doping with copper transforms the carbon dots into a p-n type semiconductor having a bandgap of 1.58 eV, a prolonged lifespan of 10.7 µs, and an improved electron- and hole-separation efficiency. The sonodynamic effect is efficiency enhanced. Western blot analysis reveals that the Cu-CDs induces a biological response leading to cell death, termed as cuproptosis. Specifically, Cu-CDs upregulate dihydrosulfanyl transacetylase expression, thereby establishing a synergistic therapeutic effect against tumor cell death when combined with SDT. Furthermore, Cu-CDs exhibit excellent permeability through the blood-brain barrier and potent anti-tumor activity. Importantly, the Cu-CDs effectively impede the growth of glioblastoma tumors and prolong the survival of mice bearing these tumors. This study provides support for the application of carbon-based nanomaterials as sonosensitizers in tumor therapy.

[Clinical diagnosis and treatment analysis of spontaneous cerebrospinal fluid otorrhoea].

Objective:To investigate the clinical features, imaging findings, surgical methods， diagnostic and treatment experience of spontaneous cerebrospinal fluid otorrhoea. Methods:The clinical data of 11 patients with spontaneous cerebrospinal fluid otorrhoea treated surgically at our hospital from May 2018 to May 2023 were retrospectively analyzed. The medical data included medical history, imaging data, leak location, surgical repair method, treatment effect and postoperative follow-up. Results:Among the 11 surgical patients, 4 patients were initially diagnosed with secretory otitis media, 1 was initially diagnosed with purulent otitis media, and 5 patients had a history of meningitis or presented because meningitis as the initial diagnosis. There were 2 cases of cerebrospinal fluid leakage repaired through the ear canal pathway and 9 cases of cerebrospinal fluid leakage repaired through the mastoid pathway. During the operation, leaks were located in the stapes floor plate in 4 cases, sinus meningeal angle in 1 case, posterior cranial fossa combined with middle cranial fossa in 1 case, middle cranial fossa in 4 cases, and labyrinthine segment of the internal auditory canal and facial nerve canal in 1 case. Ten patient was successfully repaired, and another patient developed intracranial hypertension after surgery, with symptoms alleviated by a lateral ventriculoperitoneal shunt. Postoperative follow-up ranged from 6 months to 4 years, and there was no CSF otorrhoea and meningitis recurrence. Conclusion:The incidence of spontaneous cerebrospinal fluid otorrhea is low, the clinical symptoms are atypical, and the rate of delayed diagnosis or missed diagnosis and misdiagnosis is high. Surgery is currently the preferred treatment for spontaneous cerebrospinal fluid otorrhoea, and satisfactory results are usually achieved; During diagnosis and treatment, it is crucial to be vigilant for intracranial hypertension to prevent serious complications and irreversible damage.

Bone Marrow Mesenchymal Stem Cell-Derived Nanovesicles Containing H8 Improve Hepatic Glucose and Lipid Metabolism and Exert Ameliorative Effects in Type 2 Diabetes.

Purpose: Nanovesicles (NVs) derived from bone mesenchymal stem cells (BMSCs) as drug delivery systems are considered an effective therapeutic strategy for diabetes. However, its mechanism of action remains unclear. Here, we evaluated the efficacy and molecular mechanism of BMSC-derived NVs carrying the curcumin analog H8 (H8-BMSCs-NVs) on hepatic glucose and lipid metabolism in type 2 diabetes (T2D). Subjects and Methods: Mouse BMSCs were isolated by collagenase digestion and H8-BMSCs-NVs were prepared by microvesicle extrusion. The effects of H8-BMSCs-NVs on hepatic glucose and lipid metabolism were observed in a T2D mouse model and a HepG2 cell insulin resistance model. To evaluate changes in potential signaling pathways, the PI3K/AKT/AMPK signaling pathway and expression levels of G6P and PEPCK were assessed by Western blotting. Results: H8-BMSCs-NVs effectively improved lipid accumulation in liver tissues and restored liver dysfunction in T2D mice. Meanwhile, H8-BMSCs-NVs effectively inhibited intracellular lipid accumulation in the insulin resistance models of HepG2 cells. Mechanistic studies showed that H8-BMSCs-NVs activated the PI3K/AKT/AMPK signaling pathway and decreased the expression levels of G6P and PEPCK. Conclusion: These findings demonstrate that H8-BMSCs-NVs improved hepatic glucose and lipid metabolism in T2D mice by activating the PI3K/AKT/AMPK signaling pathway, which provides novel evidence suggesting the potential of H8-BMSCs-NVs in the clinically treatment of T2D patients.

A Latent Dirichlet Allocation approach to understanding students' perceptions of Automated Writing Evaluation.

Automated writing evaluation (AWE) has shown promise in enhancing students' writing outcomes. However, further research is needed to understand how AWE is perceived by middle school students in the United States, as they have received less attention in this field. This study investigated U.S. middle school students' perceptions of the MI Write AWE system. Students reported their perceptions of MI Write's usefulness using Likert-scale items and an open-ended survey question. We used Latent Dirichlet Allocation (LDA) to identify latent topics in students' comments, followed by qualitative analysis to interpret the themes related to those topics. We then examined whether these themes differed among students who agreed or disagreed that MI Write was a useful learning tool. The LDA analysis revealed four latent topics: (1) students desire more in-depth feedback, (2) students desire an enhanced user experience, (3) students value MI Write as a learning tool but desire greater personalization, and (4) students desire increased fairness in automated scoring. The distribution of these topics varied based on students' ratings of MI Write's usefulness, with Topic 1 more prevalent among students who generally did not find MI Write useful and Topic 3 more prominent among those who found MI Write useful. Our findings contribute to the enhancement and implementation of AWE systems, guide future AWE technology development, and highlight the efficacy of LDA in uncovering latent topics and patterns within textual data to explore students' perspectives of AWE.

Permafrost carbon cycle and its dynamics on the Tibetan Plateau.

Our knowledge on permafrost carbon (C) cycle is crucial for understanding its feedback to climate warming and developing nature-based solutions for mitigating climate change. To understand the characteristics of permafrost C cycle on the Tibetan Plateau, the largest alpine permafrost region around the world, we summarized recent advances including the stocks and fluxes of permafrost C and their responses to thawing, and depicted permafrost C dynamics within this century. We find that this alpine permafrost region stores approximately 14.1 Pg (1 Pg=1015 g) of soil organic C (SOC) in the top 3 m. Both substantial gaseous emissions and lateral C transport occur across this permafrost region. Moreover, the mobilization of frozen C is expedited by permafrost thaw, especially by the formation of thermokarst landscapes, which could release significant amounts of C into the atmosphere and surrounding water bodies. This alpine permafrost region nevertheless remains an important C sink, and its capacity to sequester C will continue to increase by 2100. For future perspectives, we would suggest developing long-term in situ observation networks of C stocks and fluxes with improved temporal and spatial coverage, and exploring the mechanisms underlying the response of ecosystem C cycle to permafrost thaw. In addition, it is essential to improve the projection of permafrost C dynamics through in-depth model-data fusion on the Tibetan Plateau.

Assessment of the migration characteristics and source-oriented health risks of heavy metals in the soil and groundwater of a legacy contaminated by the chlor-alkali industry in central China.

The chlor-alkali industry (CAI) is crucial for global chemical production; however, its operation has led to widespread heavy metal (HM) contamination at numerous sites, which has not been thoroughly investigated. This study analysed 122 soil and groundwater samples from a typical CAI site in Kaifeng, China. Our aim was to assess the ecological and health risks, identify the sources, and examine the migration characteristics of HMs at this site using Monte Carlo simulation, absolute principal component score-multiple linear regression (APCS-MLR), and the potential environmental risk index (Ei). Our findings revealed that the exceedance rates for Cd, Pb, Hg, and Ni were 71.96%, 45.79%, 49.59%, and 65.42%, respectively. Mercury (Hg) displayed the greatest coefficient of variation across all the soil layers, indicating a significant anthropogenic influence. Cd and Hg were identified as having high and extremely high potential environmental risk levels, respectively. The spatial distributions of the improved Nemerow index (INI), total ecological risk (Ri), and HM content varied considerably, with the most contaminated areas typically associated with the storage of raw and auxiliary materials. Surface aggregation and significant vertical transport were noted for HMs; As and Ni showed substantial accumulation in subsoil layers, severely contaminating the groundwater. Self-organizing maps categorized the samples into two different groups, showing strong positive correlations between Cd, Pb, and Hg. The APCS-MLR model suggested that industrial emissions were the main contributors, accounting for 60.3% of the total HM input. Elevated hazard quotient values for Hg posed significant noncarcinogenic risks, whereas acceptable levels of carcinogenic risk were observed for both adults (96.60%) and children (97.83%). This study significantly enhances historical CAI pollution data and offers valuable insights into ongoing environmental and health challenges.

Unraveling the H19/GAS1 axis in recurrent implantation failure: A potential biomarker for diagnosis and insight into immune microenvironment alteration.

Recurrent implantation failure (RIF) presents a significant clinical challenge due to the lack of established diagnostic and therapeutic guidelines. Emerging evidence underscores the crucial role of competitive endogenous RNA (ceRNA) regulatory networks in non-cancerous female reproductive disorders, yet the intricacies and operational characteristics of these networks in RIF are not fully understood. This study aims to demystify the ceRNA regulatory network and identify potential biomarkers for its diagnosis. We analyzed expression profiles of three RNA types (long noncoding RNAs [lncRNAs], microRNAs [miRNAs], and mRNAs) sourced from the GEO database, leading to the identification of the H19-hsa-miR-301a-3p-GAS1 ceRNA network. This network demonstrates significant diagnostic relevance for RIF. Notably, the H19/GAS1 axis within this ceRNA network, identified through correlation analysis, emerged as a promising diagnostic marker, as evidenced by operating receiver operator characteristic (ROC) curve analysis. Further investigation into the binding potential of miR-301a-3p with H19 and GAS1 revealed a close association of these genes with endometrial disorders and embryo loss, as per the Comparative Toxicogenomics Database. Additionally, our immune infiltration analysis revealed a lower proportion of T cells gamma delta (γδ) in RIF, along with distinct differences in the expression of immune cell type-specific markers between fertile patients and those with RIF. We also observed a correlation between aberrant expression of H19/GAS1 and these immune markers, suggesting that the H19/GAS1 axis might play a role in modifying the immune microenvironment, contributing to the pathogenesis of RIF. In conclusion, the ceRNA-based H19/GAS1 axis holds promise as a novel diagnostic biomarker for RIF, potentially enhancing our understanding of its underlying mechanisms and improving the success rates of implantation.

Detectability of intracranial vessel wall atherosclerosis using black-blood spectral CT: a phantom and clinical study.

BACKGROUND: Computed tomography (CT) is the usual modality for diagnosing stroke, but conventional CT angiography reconstructions have limitations. METHODS: A phantom with tubes of known diameters and wall thickness was scanned for wall detectability, wall thickness, and contrast-to-noise ratio (CNR) on conventional and spectral black-blood (SBB) images. The clinical study included 34 stroke patients. Diagnostic certainty and conspicuity of normal/abnormal intracranial vessels using SBB were compared to conventional. Sensitivity/specificity/accuracy of SBB and conventional were compared for plaque detectability. CNR of the wall/lumen and quantitative comparison of remodeling index, plaque burden, and eccentricity were obtained for SBB imaging and high-resolution magnetic resonance imaging (hrMRI). RESULTS: The phantom study showed improved detectability of tube walls using SBB (108/108, 100% versus conventional 81/108, 75%, p < 0.001). CNRs were 75.9 ± 62.6 (mean ± standard deviation) for wall/lumen and 22.0 ± 17.1 for wall/water using SBB and 26.4 ± 15.3 and 101.6 ± 62.5 using conventional. Clinical study demonstrated (i) improved certainty and conspicuity of the vessels using SBB versus conventional (certainty, median score 3 versus 0; conspicuity, median score 3 versus 1 (p < 0.001)), (ii) improved sensitivity/specificity/accuracy of plaque (≥ 1.0 mm) detectability (0.944/0.981/0.962 versus 0.239/0.743/0.495) (p < 0.001), (iii) higher wall/lumen CNR of SBB of (78.3 ± 50.4/79.3 ± 96.7) versus hrMRI (18.9 ± 8.4/24.1 ± 14.1) (p < 0.001), and (iv) excellent reproducibility of remodeling index, plaque burden, and eccentricity using SBB versus hrMRI (intraclass correlation coefficient 0.85-0.94). CONCLUSIONS: SBB can enhance the detectability of intracranial plaques with an accuracy similar to that of hrMRI. RELEVANCE STATEMENT: This new spectral black-blood technique for the detection and characterization of intracranial vessel atherosclerotic disease could be a time-saving and cost-effective diagnostic step for clinical stroke patients. It may also facilitate prevention strategies for atherosclerosis. KEY POINTS: • Blooming artifacts can blur vessel wall morphology on conventional CT angiography. • Spectral black-blood (SBB) images are generated from material decomposition from spectral CT. • SBB images reduce blooming artifacts and noise and accurately detect small plaques.

Sirenian genomes illuminate the evolution of fully aquatic species within the mammalian superorder afrotheria.

Sirenians of the superorder Afrotheria were the first mammals to transition from land to water and are the only herbivorous marine mammals. Here, we generated a chromosome-level dugong (Dugong dugon) genome. A comparison of our assembly with other afrotherian genomes reveals possible molecular adaptations to aquatic life by sirenians, including a shift in daily activity patterns (circadian clock) and tolerance to a high-iodine plant diet mediated through changes in the iodide transporter NIS (SLC5A5) and its co-transporters. Functional in vitro assays confirm that sirenian amino acid substitutions alter the properties of the circadian clock protein PER2 and NIS. Sirenians show evidence of convergent regression of integumentary system (skin and its appendages) genes with cetaceans. Our analysis also uncovers gene losses that may be maladaptive in a modern environment, including a candidate gene (KCNK18) for sirenian cold stress syndrome likely lost during their evolutionary shift in daily activity patterns. Genomes from nine Australian locations and the functionally extinct Okinawan population confirm and date a genetic break ~10.7 thousand years ago on the Australian east coast and provide evidence of an associated ecotype, and highlight the need for whole-genome resequencing data from dugong populations worldwide for conservation and genetic management.

Marangoni-driven deterministic formation of softer, hollow microstructures for sensitivity-enhanced tactile system.

Microengineering the dielectric layers with three-dimensional microstructures has proven effective in enhancing the sensitivity of flexible pressure sensors. However, the widely employed geometrical designs of solid microstructures exhibit limited sensitivity over a wide range of pressures due to their inherent but undesired structural compressibility. Here, a Marangoni-driven deterministic formation approach is proposed for fabricating hollow microstructures, allowing for greater deformation while retarding structural stiffening during compression. Fluid convective deposition enables solute particles to reassemble in template microstructures, controlling the interior cavity with a void ratio exceeding 90%. The hollow micro-pyramid sensor exhibits a 10-fold sensitivity improvement across wider pressure ranges over the pressure sensor utilizing solid micro-pyramids, and an ultra-low detect limit of 0.21 Pa. With the advantages of facilitation, scalability, and large-area compatibility, such an approach for hollow microstructures can be expanded to other sensor types for superior performance and has considerable potential in robotic tactile and epidermal devices.

Association between estimated plasma volume status and acute kidney injury in patients who underwent coronary revascularization: A retrospective cohort study from the MIMIC-IV database.

BACKGROUND: Acute kidney injury (AKI) remains a common complication of coronary revascularization and increases poor outcomes in critically ill surgical patients. Compared to the plasma volume status (PVS), estimated plasma volume status (ePVS) has the advantages of being noninvasive and simple and has been shown to be associated with worse prognosis in patients undergoing coronary revascularization. This study was to evaluate the association of ePVS with the risk of AKI in patients who underwent coronary revascularization. METHODS: In this retrospective cohort study, data of patients who underwent coronary revascularization were extracted from the Medical Information Mart for Intensive Care (MIMIC)-IV database (2008-2019). The outcome was the occurrence of AKI after ICU admission. The covariates were screened via the LASSO regression method. Univariate and multivariate Logistic regression models were performed to assess the association of ePVS and PVS and the odds of AKI in patients who underwent coronary revascularization, with results shown as odds ratios (ORs) and 95% confidence intervals (CIs). Subgroup analyses of age, surgery, and anticoagulation agents and sequential organ failure assessment (SOFA) score were performed to further explore the association of ePVS with AKI. RESULTS: A total of 3,961 patients who underwent coronary revascularization were included in this study, of whom 2,863 (72.28%) had AKI. The high ePVS was associated with the higher odds of AKI in patients who received coronary revascularization (OR = 1.06, 95%CI: 1.02-1.10), after adjusting for the covariates such as age, race, SAPS-II score, SOFA score, CCI, weight, heart rate, WBC, RDW-CV, PT, BUN, glucose, calcium, PH, PaO2, mechanical ventilation, vasopressors, and diuretic. Similar results were found in patients who underwent the CABG (OR = 1.07, 95%CI: 1.02-1.11), without anticoagulation agents use (OR = 1.07, 95%CI: 1.03-1.12) and with high SOFA score (OR = 1.10, 95%CI: 1.04-1.17). No relationship was found between PVS and the odds of AKI in patients who underwent the coronary revascularization. CONCLUSION: The ePVS may be a promising parameter to evaluate the risk of AKI in patients undergoing coronary revascularization, which provides a certain reference for the risk stratification management of ICU patients who underwent coronary revascularization.

Cavitation is the determining mechanism for the atomization of high-viscosity liquid.

Piezoelectric atomization is becoming mainstream in the field of inhalation therapy due to its significant advantages. With the rapid development of high-viscosity gene therapy drugs, the demand for piezoelectric atomization devices is increasing. However, conventional piezoelectric atomizers with a single-dimensional energy supply are unable to provide the energy required to atomize high-viscosity liquids. To address this problem, our team has designed a flow tube internal cavitation atomizer (FTICA). This study focuses on dissecting the atomization mechanism of FTICA. In contrast to the widely supported capillary wave hypothesis, our study provides evidence in favor of the cavitation hypothesis, proving that cavitation is the key to atomizing high-viscosity liquids with FTICA. In order to prove that the cavitation is the key to atomizing in the structure of FTICA, the performance of atomization is experimented after changing the cavitation conditions by heating and stirring of the liquids.

Quantification of multiple microRNAs by microchip electrophoresis assisted by strand displacement amplification.

MicroRNAs (miRNAs) are increasingly recognized as potential biomarkers for the early diagnosis of cancer. However, the concurrent detection of multiple miRNAs in biological samples presents a significant challenge due to their high homogeneity and low abundance. This study introduced a novel approach combining strand displacement amplification (SDA) with microchip electrophoresis (MCE) for the simultaneous quantitation of trace levels of three miRNAs associated with cancer: miRNA-21, miRNA-145, and miRNA-221. Specifically designed probes were utilized to selectively capture the target miRNAs, thereby initiating the SDA process in a single solution without cross-interference. Under optimized conditions, the SDA-MCE method achieved the limit of detection (LOD) as low as 0.02 fM (S/N = 3) and the limit of quantitation (LOQ) as low as 0.1 fM across a broad linear range spanning from 0.1 fM to 1 pM. The SDA reaction was completed in approximately 1.5 h, and all target products were separated within 135 s through MCE. Application of this method for the simultaneous detection of these three miRNAs in human lung cancer cell samples yielded satisfactory results. Featuring high sensitivity, rapid analysis, minimal reagent consumption, and straightforward operation, the proposed MCE-SDA strategy holds considerable promise for multi-miRNAs detection applications.

Predicting Abrocitinib Efficacy at Week 12 Based on Clinical Response at Week 4: A Post Hoc Analysis of Four Randomized Studies in Moderate-to-Severe Atopic Dermatitis.

INTRODUCTION: Early prediction of abrocitinib efficacy in atopic dermatitis (AD) could help identify candidates for an early dose increase. A predictive model determined week 12 efficacy based on week 4 responses in patients receiving abrocitinib 100 mg/day and assessed the effect of an abrocitinib dose increase on platelet counts. METHODS: Analysis included the phase 3 trials JADE MONO-1 (NCT03349060), MONO-2 (NCT03575871), COMPARE (NCT03720470), and TEEN (NCT03796676). For platelet counts and simulations, a phase 2 psoriasis trial (NCT02201524) and phase 2b (NCT02780167) and phase 3 (MONO-1, MONO-2, and REGIMEN (NCT03627767)) abrocitinib trials were pooled. A training-and-validation framework assessed potential predictors of response at week 4: score and score change from baseline in the Eczema Area and Severity Index (EASI), Investigator's Global Assessment (IGA), and Peak Pruritus Numerical Rating Scale (PP-NRS), and percentage change from baseline in EASI. The dependent variables at week 12 were ≥ 75% improvement in EASI (EASI-75) and IGA score of 0 (clear) or 1 (almost clear) and ≥ 2-point improvement from baseline. The probability of each variable to predict week 12 EASI-75 and IGA responses was calculated. RESULTS: In the training cohort (n = 453), 72% of the ≥ 50% improvement in EASI (EASI-50) at week 4 responders and 16% of the nonresponders with abrocitinib 100 mg achieved EASI-75 at week 12; 48% and 6% of the week 4 EASI-50 responders and nonresponders, respectively, achieved week 12 IGA response. Similar results occurred with week 4 IGA = 2, ≥ 4-point improvement from baseline in PP-NRS, or EASI = 8 responders/nonresponders. Platelet counts after an abrocitinib dose increase from 100 to 200 mg were similar to those seen with continuous dosing with abrocitinib 100 mg or 200 mg. CONCLUSION: Achieving week 4 clinical responses with abrocitinib 100 mg may be useful in predicting week 12 responses. Week 4 nonresponders may benefit from a dose increase to abrocitinib 200 mg, and those that receive this dose increase are likely to achieve treatment success at week 12, with no significant impact on platelet count recovery. Video abstract available for this article. CLINICAL TRIAL REGISTRATION: NCT03349060, NCT03575871, NCT03720470, NCT03796676, NCT02201524, NCT02780167 and NCT03627767.

Abrocitinib is an approved treatment for people with moderate or severe atopic dermatitis. Abrocitinib tablets are available in two doses (100 and 200 mg) and are taken by mouth once daily. Some people with atopic dermatitis who are taking abrocitinib 100 mg may need to increase the dose to 200 mg to get adequate symptom relief. We studied whether people with atopic dermatitis who did or did not experience clear skin or itch relief after taking abrocitinib 100 mg for 4 weeks are likely or not likely to experience relief after 12 weeks of treatment. We also defined the level of response after 4 weeks of treatment that best differentiates people who did or did not experience symptom relief, and we identified who might benefit from increasing the abrocitinib dose from 100 to 200 mg. We found that people with atopic dermatitis who had symptom relief after 4 weeks of abrocitinib 100 mg treatment were much more likely to have greater relief after 12 weeks, and people who did not achieve symptom relief after 4 weeks may benefit from a dose increase at week 4. Some people who receive abrocitinib 200 mg may have a temporary decrease in the number of certain blood cells called platelets at week 4, but platelets return to near-normal levels by week 12. This analysis showed that increasing the abrocitinib dose from 100 to 200 mg at week 4 did not seem to affect the platelet numbers after week 4. Video abstract (MP4 174529 KB).

A genome-wide association study reveals novel loci and candidate genes associated with plant height variation in Medicago sativa.

BACKGROUND: Plant height (PH) is an important agronomic trait influenced by a complex genetic network. However, the genetic basis for the variation in PH in Medicago sativa remains largely unknown. In this study, a comprehensive genome-wide association analysis was performed to identify genomic regions associated with PH using a diverse panel of 220 accessions of M. sativa worldwide. RESULTS: Our study identified eight novel single nucleotide polymorphisms (SNPs) significantly associated with PH evaluated in five environments, explaining 8.59-12.27% of the phenotypic variance. Among these SNPs, the favorable genotype of chr6__31716285 had a low frequency of 16.4%. Msa0882400, located proximal to this SNP, was annotated as phosphate transporter 3;1, and its role in regulating alfalfa PH was supported by transcriptome and candidate gene association analysis. In addition, 21 candidate genes were annotated within the associated regions that are involved in various biological processes related to plant growth and development. CONCLUSIONS: Our findings provide new molecular markers for marker-assisted selection in M. sativa breeding programs. Furthermore, this study enhances our understanding of the underlying genetic and molecular mechanisms governing PH variations in M. sativa.

Pathogenic fungi synergistically cooperate with Serratia marcescens to increase cockroach mortality.

The abuse of chemical insecticides has led to strong resistance in cockroaches, and biopesticides with active ingredients based on insect pathogens have good development prospects; however, their slow effect has limited their practical application, and improving their effectiveness has become an urgent problem. In this study, the interaction between Serratia marcescens and Metarhizium anisopliae enhanced their virulence against Blattella germanica and exhibited a synergistic effect. The combination of S. marcescens and M. anisopliae caused more severe tissue damage and accelerated the proliferation of the insect pathogen. The results of high-throughput sequencing demonstrated that the gut microbiota was dysbiotic, the abundance of the opportunistic pathogen Weissella cibaria increased, and entry into the hemocoel accelerated the death of the German cockroaches. In addition, the combination of these two agents strongly downregulated the expression of Imd and Akirin in the IMD pathway and ultimately inhibited the expression of antimicrobial peptides (AMPs). S. marcescens released prodigiosin to disrupted the gut homeostasis and structure, M. anisopliae released destruxin to damaged crucial organs, opportunistic pathogen Weissella cibaria overproliferated, broke the gut epithelium and entered the hemocoel, leading to the death of pests. These findings will allow us to optimize the use of insect pathogens for the management of pests and produce more effective biopesticides.

Disturbance of fetal growth by azithromycin through induction of ER stress in the placenta.

AIM: Azithromycin (AZM) is widely used to treat mycoplasma infection in pregnancy. However, there is no adequate evaluation of its side effect on the placenta. Here, by using human placental syncytiotrophoblasts and a mouse model, we investigated whether AZM use in pregnancy might adversely affect placental function and pregnancy outcome. RESULTS: Transcriptomic analysis of AZM-treated human placental syncytiotrophoblasts showed increased expression of ER stress-related genes and decreased expression of genes for hormone production and growth factor processing. Verification studies showed that AZM increased the abundance of ER stress mediators (phosphorylated eIF2α, ATF4 and CHOP), and decreased the abundance of enzymes involved in progesterone and estradiol synthesis (STS, CYP11A1 and CYP19A1) and IGFBP cleavage (PAPPA and ADAM12) in human placental syncytiotrophoblasts. Inhibition of ER stress blocked AZM-induced decreases in the expression of CYP19A1, CYP11A1, PAPPA and ADAM12, suggesting that the inhibition of AZM on those genes' expression was secondary to AZM-induced ER stress. Further mechanism study showed that increased ATF4 in ER stress might repressively interact with C/EBPα to suppresstheexpression ofthose genes including CEBPAitself. Mouse studies showed that AZM administration decreased fetal weights along with increased ER stress mediators and decreased levels of insulin-like growth factor, estrogen and progesterone in the maternal blood, which could be alleviated by inhibition of ER stress. INNOVATION AND CONCLUSION: These findings firstly support AZM, often used during pregnancy, may affect fetal growth by inhibiting crucial enzymes for estrogen and progesterone synthesis and disrupting crucial proteases for IGFBP cleavage via inducing ER stress in placental syncytiotrophoblasts.

Recanalization of a long segment occluded superior vena cava by puncturing the remnant calcified fibrin sheath of the internal jugular vein: A case report.

A fibrin sheath with central venous occlusion is a common complication after central venous catheterization, and these patients often experience catheter dysfunction. A calcified fibrin sheath can cause a catheter to be stuck, and typically necessitates catheter removal or replacement. From another point of view, a calcified fibrin sheath can be seen in ultrasound and computed tomography, and the original fibrin sheath channel between the internal jugular vein and the atrium is unusually strong. When central vein occlusion occurs, the remnant calcified fibrin sheath of the internal jugular vein can be punctured under ultrasound guidance, allowing the guidewire to enter the atrium directly through the fibrin sheath. Here, we report a case in which we achieved easy recanalization of a long segment occluded superior vena cava by puncturing the remnant calcified fibrin sheath of the internal jugular vein.

Genome-wide identification, characterization, molecular evolution and expression profiling analysis of scavenger receptors in black rockfish (Sebastes schlegelii).

The scavenger receptors (SRs) gene family is considered as the membrane-associated pattern recognition receptors that plays important roles in the immune responses of organisms. However, there is currently limited research on the systematic identification of the SRs gene family in teleost and their role in the innate immunity of S. schegelii. In this study, we identified and annotated 15 SRs genes in S. schegelii. Through phylogenetic analysis, analysis of conserved domains, gene structure, and motif composition, we found that SRs gene family within different classes were relatively conserved. Additionally, we used qRT-PCR to analyze the expression patterns of SRs genes in immune-related tissues from healthy and Acinetobacter johnsonii-infected S. schegelii. The results showed that SRs genes exhibited different tissue expression patterns and the expression of SRs genes significantly changed after A. johnsonii infection. These results provided a valuable basis for further understanding of the functions of SRs in the innate immune response of S. schegelii.

ALKBH5-mediated m6A demethylation of Runx2 mRNA promotes extracellular matrix degradation and intervertebral disc degeneration.

BACKGROUND: N6-methyladenosine (m6A) methylation is a prevalent RNA modification implicated in various diseases. However, its role in intervertebral disc degeneration (IDD), a common cause of low back pain, remains unclear. RESULTS: In this investigation, we explored the involvement of m6A demethylation in the pathogenesis of IDD. Our findings revealed that ALKBH5 (alkylated DNA repair protein AlkB homolog 5), an m6A demethylase, exhibited upregulation in degenerative discs upon mild inflammatory stimulation. ALKBH5 facilitated m6A demethylation within the three prime untranslated region (3'-UTR) of Runx2 mRNA, consequently enhancing its mRNA stability in a YTHDF1 (YTH N6-methyladenosine RNA binding protein F1)-dependent manner. The subsequent elevation in Runx2 expression instigated the upregulation of ADAMTSs and MMPs, pivotal proteases implicated in extracellular matrix (ECM) degradation and IDD progression. In murine models, subcutaneous administration of recombinant Runx2 protein proximal to the lumbar disc in mice elicited complete degradation of intervertebral discs (IVDs). Injection of recombinant MMP1a and ADAMTS10 proteins individually induced mild to moderate degeneration of the IVDs, while co-administration of MMP1a and ADAMTS10 resulted in moderate to severe degeneration. Notably, concurrent injection of the Runx2 inhibitor CADD522 with recombinant Runx2 protein did not result in IVD degeneration in mice. Furthermore, genetic knockout of ALKBH5 and overexpression of YTHDF1 in mice, along with lipopolysaccharide (LPS) treatment to induce inflammation, did not alter the expression of Runx2, MMPs, and ADAMTSs, and no degeneration of the IVDs was observed. CONCLUSION: Our study elucidates the role of ALKBH5-mediated m6A demethylation of Runx2 mRNA in activating MMPs and ADAMTSs, thereby facilitating ECM degradation and promoting the occurrence of IDD. Our findings suggest that targeting the ALKBH5/Runx2/MMPs/ADAMTSs axis may represent a promising therapeutic strategy for preventing IDD.