Risk factors for bloodstream infection among patients admitted to an intensive care unit of a tertiary hospital of Shanghai, China.

Blood flow infections (BSIs) is common occurrences in intensive care units (ICUs) and are associated with poor prognosis. The study aims to identify risk factors and assess mortality among BSI patients admitted to the ICU at Shanghai Ruijin hospital north from January 2022 to June 2023. Additionally, it seeks to present the latest microbiological isolates and their antimicrobial susceptibility. Independent risk factors for BSI and mortality were determined using the multivariable logistic regression model. The study found that the latest incidence rate of BSI was 10.11%, the mortality rate was 35.21% and the mean age of patients with BSI was 74 years old. Klebsiella pneumoniae was the predominant bacterial isolate. Logistic multiple regression revealed that tracheotomy, tigecycline, gastrointestinal bleeding, shock, length of hospital stay, age and laboratory indicators (such as procalcitonine and hemoglobin) were independent risk factors for BSI. Given the elevated risk associated with use of tracheotomy and tigecycline, it underscores the importance of the importance of cautious application of tracheostomy and empirical antibiotic management strategies. Meanwhile, the independent risk factors of mortality included cardiovascular disease, length of hospital stay, mean platelet volume (MPV), uric acid levels and ventilator. BSI patients exhibited a significant decrease in platelet count, and MPV emerged as an independent factor of mortality among them. Therefore, continuous monitoring of platelet-related parameters may aid in promptly identifying high-risk patients and assessing prognosis. Moreover, monitoring changes in uric acid levels may serve as an additional tool for prognostic evaluation in BSI patients.

Depressive symptoms and associated factors among older patients with arthritis: evidence from a community-based study in eastern China.

Introduction: Depressive symptoms are often experienced by patients with arthritis and are correlated with poor health outcomes. However, the association between depressive symptoms and multidimensional factors (sociodemographic characteristics, health conditions, health behaviors, and social support) among older patients with arthritis in China remains poorly understood. This study aimed to explore the prevalence of depressive symptoms in older patients with arthritis in eastern China and identify the associated factors. Methods: We analyzed data of 1,081 older patients with arthritis using secondary data from 2014 to 2020 from a community-based ongoing study initiated in 2014 in eastern China. The prevalence of depressive symptoms was calculated, and univariate and multilevel logistic regression analyses were used to identify the associated factors. Results: The mean age of older patients with arthritis was 69.16 ± 7.13 years; 42.92% were men and 57.08% were women. The prevalence of depressive symptoms in older patients with arthritis was 14.99% (95% confidence interval: 12.91-17.26%), about 1.8 times higher than that in older adults without arthritis (8.49%, p < 0.001). Multilevel logistic regression identified perception of poor economic status (odds ratio [OR] = 5.52, p < 0.001), multimorbidity (OR = 1.96, p = 0.001), limitations in activities of daily living (OR = 2.36, p = 0.004), and living alone (OR = 3.13, p = 0.026) as factors positively associated with depressive symptoms. Patients diagnosed with arthritis at an older age had lower odds of experiencing depressive symptoms (OR = 0.67, p = 0.046). Conclusion: Screening for depressive symptoms is essential among older patients with arthritis, especially those who perceive themselves as having a poor economic status, are diagnosed at an earlier age, have multimorbidity, have limitations in activities of daily living, and live alone. The associations of age at arthritis diagnosis and dietary behaviors with depressive symptoms require further research.

Circumvention of Topoisomerase IIα Intron 19 Intronic Polyadenylation (IPA) in Acquired Etoposide Resistant Human Leukemia K562 Cells.

DNA topoisomerase IIα (TOP2α, 170kDa, TOP2α/170) is an essential enzyme for proper chromosome dysjunction by producing transient DNA double-stranded breaks and is a significant target for DNA damage stabilizing anti-cancer agents such as etoposide. Therapeutic effects of TOP2α poisons can be limited due to acquired drug resistance. We previously demonstrated decreased TOP2α/170 levels in an etoposide-resistant human leukemia K562 subline, designated K/VP.5, accompanied by increased expression of a C-terminal truncated TOP2α isoform (90 kDa, TOP2α/90) which heterodimerized with TOP2α/170 and was a determinant of resistance by exhibiting dominant-negative effects against etoposide activity. Based on 3'-Rapid Amplification of cDNA Ends (3'-RACE), we confirmed TOP2α/90 as the translation product of a TOP2α mRNA in which a cryptic polyadenylation site (PAS) harbored in intron 19 (I19) was utilized. We hypothesized that resultant intronic polyadenylation (IPA) can would be attenuated by blocking or mutating the I19 PAS thereby circumventing acquired drug resistance. An antisense morpholino oligonucleotide (AMO) was used to hybridize/block the PAS in TOP2α pre-mRNA in K/VP.5 cells, resulting in decreased TOP2α/90 mRNA/protein levels in K/VP.5 cells and partially circumventing drug resistance. Subsequently, CRISPR/Cas9 homology-directed repair (HDR) was used to mutate the cryptic I19 PAS (AATAAA-->ACCCAA) to prevent IPA. Gene-edited clones exhibited increased TOP2α/170 and decreased TOP2α/90 mRNA/protein and demonstrated restored sensitivity to etoposide and other TOP2α-targeted drugs. Together, results indicated that blocking/mutating a cryptic I19 PAS in K/VP.5 cells reduced IPA and restored sensitivity to TOP2α-targeting drugs. Significance Statement Results presented here indicate that CRISPR/Cas9 gene editing of a cryptic polyadenylation site (PAS) within I19 of the TOP2α gene results in reversal of acquired resistance to etoposide and other TOP2-targeted drugs. An antisense morpholino oligonucleotide (AMO) targeting the PAS also partially circumvented resistance. Results demonstrate the importance of intronic polyadenylation (IPA) in acquired drug resistance and points to tractable strategies to overcome this form of resistance to TOP2-targeted agents.

Correlation of NAT10 expression with clinical data and survival profiles in esophageal squamous cell carcinoma patients, and its impact on cell proliferation and apoptosis.

BACKGROUND: This study investigates the association between NAT10 expression and clinical parameters while assessing prognostic outcomes in esophageal squamous cell carcinoma (ESCC) patients. Furthermore, the study seeks to elucidate the functional role of NAT10 in neoplastic cell proliferation and apoptosis. MATERIALS AND METHODS: NAT10 expression was assessed in ESCC tissue microarrays through immunohistochemistry (IHC) tests. We employed SPSS software to analyze the correlation between NAT10 staining data, clinical indicators, and their implications for patient prognosis. Small interference RNA (siRNA) was utilized to inhibit NAT10 expression in two esophageal cancer cell lines, TE-1 and KYSE150. Subsequently, we meticulously quantified and compared cellular proliferation and apoptotic ratios among experimental groups. NAT10, Ki67, and Caspase3 expression levels in different groups were evaluated using quantitative polymerase chain reaction (qPCR) and Western blot (WB) assays. Statistical analyses were conducted using GraphPad Prism software, with significance at p<0.05. RESULTS: Our findings indicate that NAT10 is overexpressed in ESCC tissues and exhibits a significant correlation with tumor diameter and overall patient survival. Decreasing NAT10 expression led to the inhibition of tumor cell proliferation and the promotion of apoptosis. Furthermore, siRNA-mediated NAT10 inhibition resulted in the downregulation of Ki67 expression and the concomitant upregulation of Caspase3. CONCLUSION: The observed overexpression of NAT10 in ESCC tissues is associated with larger tumor diameters and reduced patient survival. NAT10 appears to play a pivotal role in the progression of esophageal cancer by influencing cell proliferation and apoptosis. These findings suggest potential clinical implications, with Ki67 and Caspase3 potentially participating in this intricate molecular biological process.

Electric Double Layer Regulator Design through a Functional Group Assembly Strategy towards Long-lasting Zinc Metal Batteries.

Regulating the electric double layer (EDL) structure of the zinc metal anode by using electrolyte additives is an efficient way to suppress interface side reactions and facilitate uniform zinc deposition. Nevertheless, there are no reports investigating the proactive design of EDL-regulating additives before the start of experiments. Herein, a functional group assembly strategy is proposed to design electrolyte additives for modulating the EDL, thereby realizing a long-lasting zinc metal anode. Specifically, by screening ten common functional groups, N, N-dimethyl-1H-imidazole-1-sulfonamide (IS) is designed by assembling an imidazole group, characterized by its high adsorption capability on the zinc anode, and a sulfone group, which exhibits strong binding with Zn2+ ions. Benefiting from the adsorption functionalization of the imidazole group, the IS molecules occupy the position of H2O in the inner Helmholtz layer of the EDL, forming a molecular protective layer to inhibit H2O-induced side reactions. Meanwhile, the sulfone group in IS, acting as a binding site to Zn2+, promotes the de-solvation of Zn2+ ions, facilitating compact zinc deposition. Consequently, the utilization of IS significantly extending the cycling stability of Zn||Zn and Zn||NaV3O8·1.5H2O full cell. This study offers an innovative approach to the design of EDL regulators for high-performance zinc metal batteries.

Degradation mechanism and decomposition of sulfamethoxazole aqueous solution with persulfate activated by dielectric barrier discharge.

The present study focused on the degradation of sulfamethoxazole (SMX) aqueous solution and the toxicity of processing aqueous by the dielectric barrier discharge (DBD) activated persulfate (PS). The effects of input voltage, input frequency, duty cycle, and PS dosage ratio on the SMX degradation efficiency were measured. Based on the results of the Response Surface Methodology (RSM), SMX degradation efficiency reached 83.21% which is 10.54% higher than that without PS, and the kinetic constant was 0.067 min-1 in 30 min when the input voltage at 204 V (input power at 110.6 W), the input frequency at 186 Hz, the duty cycle at 63%, and the PS dosage ratio at 5.1:1. The addition of PS can produce more active particles reached 1.756 mg/L (O3), 0.118 mg/L (H2O2), 0.154 mmol/L (·OH) in 30 min. Furthermore, the DBD plasma system effectively activated an optimal amount of PS, leading to improved removal efficiency of COD, and TOC to 30.21% and 47.21%, respectively. Subsequently, eight primary by-products were pinpointed, alongside the observation of three distinct pathways of transformation. Predictions from the ECOSAR software indicated that most of the degradation intermediates were less toxic than SMX. The biological toxicity experiments elucidated that the treatment with the DBD/PS system effectively reduced the mortality of zebrafish larvae caused by SMX from 100% to 20.13% and improved the hatching rate from 55.69% to 80.86%. In particular, it is important to note that the degradation intermediates exhibit teratogenic effects on zebrafish larvae.

Spin Crossover in [Fe(qsal-5-Brq)2]+ Complexes with a Quinoline-Substituted Qsal Ligand.

Using a quinoline substituted Qsal ligand, Hqsal-5-Brq (Hqsal-5-Brq = N-(5-bromo-8-quinolyl)salicylaldimine), four FeIII complexes, [Fe(qsal-5-Brq)2]A·CH3OH (Y = NO3- (1NO3), BF4- (2BF4), PF6- (3PF6), OTf- (4OTf), were prepared and characterized. Structure analysis revealed that complex 2BF4 contained two species (2BF4(P1̅) and 2BF4(C2/c)). In these compounds except 3PF6, the [Fe(qsal-5-Brq)2]+ cations form 1D chains through π-π interactions and other weak interactions. Adjacent chains are connected to form the 2D "Chain Layer" structures and 3D structures through various supramolecular interactions. For 3PF6, a "Dimer Chain" structure is formed from the loosely connected dimers. Magnetic studies revealed that compounds 1NO3 and 2BF4(P1̅) displayed abrupt hysteretic SCO with the transition temperature T1/2↓ = 235 K, T1/2↑ = 240 K for 1NO3 and T1/2↓ = 230 K, T1/2↑ = 235 K for 2BF4(P1̅), while compounds 3PF6 and 4OTf are in the HS state. Desolvation of the complexes significantly modifies their SCO properties: the desolvated 1NO3 and 2BF4 show a gradual SCO, desolvated 3PF6 undergoes a two-step SCO, and desolvated 4OTf exhibits a hysteretic transition. Overall, this work reported the FeIII-SCO complexes of the quinoline-substituted Hqsal ligand and highlighted the potential of these ligands for the development of interesting FeIII-SCO materials.

Composite Aerogel Scaffolds Containing Flexible Silica Nanofiber and Tricalcium Phosphate Enable Skin Regeneration.

Poor hemostatic ability and less vascularization at the injury site could hinder wound healing as well as adversely affect the quality of life (QOL). An ideal wound dressing should exhibit certain characteristics: (a) good hemostatic ability, (b) rapid wound healing, and (c) skin appendage formation. This necessitates the advent of innovative dressings to facilitate skin regeneration. Therapeutic ions, such as silicon ions (Si4+) and calcium ions (Ca2+), have been shown to assist in wound repair. The Si4+ released from silica (SiO2) can upregulate the expression of proteins, including the vascular endothelial growth factor (VEGF) and alpha smooth muscle actin (α-SMA), which is conducive to vascularization; Ca2+ released from tricalcium phosphate (TCP) can promote the coagulation alongside upregulating the expression of cell migration and cell differentiation related proteins, thereby facilitating the wound repair. The overarching objective of this study was to exploit short SiO2 nanofibers along with the TCP to prepare TCPx@SSF aerogels and assess their wound healing ability. Short SiO2 nanofibers were prepared by electrospinning and blended with varying proportions of TCP to afford TCPx@SSF aerogel scaffolds. The TCPx@SSF aerogels exhibited good cytocompatibility in a subcutaneous implantation model and manifested a rapid hemostatic effect (hemostatic time 75 s) in a liver trauma model in the rabbit. These aerogel scaffolds also promoted skin regeneration and exhibited rapid wound closure, epithelial tissue regeneration, and collagen deposition. Taken together, TCPx@SSF aerogels may be valuable for wound healing.

Molecularly imprinted polymer-based SERS sensing of transferrin in human serum.

Specific detection of glycoproteins such as transferrin (TRF) related to neurological diseases, hepatoma and other diseases always plays an important role in the field of disease diagnosis. We designed an antibody-free immunoassay sensing method based on molecularly imprinted polymers (MIPs) formed by the polymerization of multiple functional monomers for the sensitive and selective detection of TRF in human serum. In the sandwich surface-enhanced Raman spectroscopy (SERS) sensor, the TRF-oriented magnetic MIP nanoparticles (Fe3O4@SiO2-MIPs) served as capture units to specifically recognize TRF and 4-mercaptophenylboronic acid-functionalized gold nanorods (MPBA-Au NRs) served as SERS probes to label the targets. In order to achieve stronger interaction between the recognition cavities of the prepared MIPs and the different amino acid fragments that make up TRF, Fe3O4@SiO2-MIPs were obtained through polycondensation reactions between more silylating reagents, enhancing the specific recognition of the entire TRF protein and achieving high IF. This sensing method exhibited a good linear response to TRF within the TRF concentration range of 0.01 ng mL-1 to 1 mg mL-1 (R2 = 0.9974), and the LOD was 0.00407 ng mL-1 (S/N = 3). The good stability, reproducibility and specificity of the resulting MIP based SERS sensor were demonstrated. The determination of TRF in human serum confirmed the feasibility of the method in practical applications.

Emerging role of gut microbiota in autoimmune diseases.

Accumulating studies have indicated that the gut microbiota plays a pivotal role in the onset of autoimmune diseases by engaging in complex interactions with the host. This review aims to provide a comprehensive overview of the existing literatures concerning the relationship between the gut microbiota and autoimmune diseases, shedding light on the complex interplay between the gut microbiota, the host and the immune system. Furthermore, we aim to summarize the impacts and potential mechanisms that underlie the interactions between the gut microbiota and the host in autoimmune diseases, primarily focusing on systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, type 1 diabetes mellitus, ulcerative colitis and psoriasis. The present review will emphasize the clinical significance and potential applications of interventions based on the gut microbiota as innovative adjunctive therapies for autoimmune diseases.

Margin quality analysis for wedge resection of lung cancer and construction of a predictive model.

Background: Insufficient pulmonary wedge resection margin is associated with malignant positive margins and high local recurrence risk for lung cancer. This study aimed to identify the risk factors of insufficient or guideline discordant resection margin distance and establish a predictive model to preoperatively estimate the risk of discordant margin for individual patient. Methods: Guideline discordant resection margin was defined as ratio of resection margin distance to tumor size less than one. Patients who had pulmonary malignancies and underwent wedge resection between April 2014 and February 2023 were enrolled and stratified by quality of resection margin. Multivariable logistic regression analysis was employed to identify risk factors of guideline discordant margin and a predictive model was developed. Data from March 2023 to January 2024 were collected for internal validation. Results: A total of 530 patients were included. The incidence of guideline discordant wedge resection margin was 37.2%. Longer tumor's max distance to pleura and larger tumor size were variables associated with increased risk and included in the final model. Preoperative localization and right-side surgery were protective variables in the predictive model. A nomogram was built based on the predictive model. The model showed satisfying predictive performance with a concordance index of 0.720 for the predictive model, and 0.761 for internal validation. The goodness-if-fit tests were non-significant for both model development and internal validation data set. Conclusions: The preoperative predictive model and nomogram show good predictive performance to estimate the risk of guideline discordant wedge resection margin. Individualized surgical plans or preoperative nodule localization can be made for high-risk patients.

A study on the treatment effects of Crataegus pinnatifida polysaccharide on non-alcoholic fatty liver in mice by modulating gut microbiota.

The objective of this study was to investigate the protective effect of Crataegus pinnatifida polysaccharide (CPP) on non-alcoholic fatty liver disease (NAFLD) induced by a high-fat diet (HFD) in mice. The findings demonstrated that CPP improved free fatty acid (FFA)-induced lipid accumulation in HepG2 cells and effectively reduced liver steatosis and epididymal fat weight in NAFLD mice, as well as decreased serum levels of TG, TC, AST, ALT, and LDL-C. Furthermore, CPP exhibited inhibitory effects on the expression of fatty acid synthesis genes FASN and ACC while activating the expression of fatty acid oxidation genes CPT1A and PPARα. Additionally, CPP reversed disturbances in intestinal microbiota composition caused by HFD consumption. CPP decreased the firmicutes/Bacteroidetes ratio, increased Akkermansia abundance, and elevated levels of total short-chain fatty acid (SCFA) content specifically butyric acid and acetic acid. Our results concluded that CPP may intervene in the development of NAFLD by regulating of intes-tinal microbiota imbalance and SCFAs production. Our study highlights that CPP has a potential to modulate lipid-related pathways via alterations to gut microbiome composition thereby ex-erting inhibitory effects on obesity and NAFLD development.

Home care needs assessment among caregivers of children and adolescents with osteogenesis imperfecta: a cross-sectional study.

BACKGROUND: Children and adolescents with complex medical issues need home care services; however, few studies have provided insight into the unmet home care needs of the families of patients with osteogenesis imperfecta (OI). In this study, we aimed to assess the home care needs of caregivers of children and adolescents with OI and the associated factors. METHODS: A self-administered questionnaire was administered online to 142 caregivers of patients with OI aged 3-17 years between May and October 2022 from 25 provinces in China. The questionnaire comprised 15 questions on demographic variables and 14 questions on home care needs. Chi-square analysis was used to compare group differences for categorical variables. Multivariate binary logistic regression analysis was conducted to examine predictors of caregivers' home care needs. RESULTS: The study findings indicated that 81.5% of caregivers had high home care needs. The three leading types of home care needs were helping the child carry out physical fitness recovery exercises at home (72.5%), understanding precautions regarding treatment drugs (72.5%), and relieving the child's pain (70.4%). OI patients' poor self-care ability (adjusted odds ratio = 5.9, 95% confidence interval = 1.8-19.0) was related to caregivers' high level of home care needs. CONCLUSIONS: The findings of this study suggest that future scientific research and nursing guidance should focus on OI patients' physical training, medication management, pain relief, fracture prevention, and treatment. In addition, caregivers of patients with poor self-care ability should receive special attention in the development of interventions. This study can help with addressing the unmet home care needs of caregivers of children and adolescents with OI. It is vital to develop a personalized intervention plan based on patients' self-care ability.

Development of a smartphone screening test for preclinical Alzheimer's disease and validation across the dementia continuum.

BACKGROUND: Dementia prevalence is predicted to triple to 152 million globally by 2050. Alzheimer's disease (AD) constitutes 70% of cases. There is an urgent need to identify individuals with preclinical AD, a 10-20-year period of progressive brain pathology without noticeable cognitive symptoms, for targeted risk reduction. Current tests of AD pathology are either too invasive, specialised or expensive for population-level assessments. Cognitive tests are normal in preclinical AD. Emerging evidence demonstrates that movement analysis is sensitive to AD across the disease continuum, including preclinical AD. Our new smartphone test, TapTalk, combines analysis of hand and speech-like movements to detect AD risk. This study aims to [1] determine which combinations of hand-speech movement data most accurately predict preclinical AD [2], determine usability, reliability, and validity of TapTalk in cognitively asymptomatic older adults and [3], prospectively validate TapTalk in older adults who have cognitive symptoms against cognitive tests and clinical diagnoses of Mild Cognitive Impairment and AD dementia. METHODS: Aim 1 will be addressed in a cross-sectional study of at least 500 cognitively asymptomatic older adults who will complete computerised tests comprising measures of hand motor control (finger tapping) and oro-motor control (syllabic diadochokinesis). So far, 1382 adults, mean (SD) age 66.20 (7.65) years, range 50-92 (72.07% female) have been recruited. Motor measures will be compared to a blood-based AD biomarker, phosphorylated tau 181 to develop an algorithm that classifies preclinical AD risk. Aim 2 comprises three sub-studies in cognitively asymptomatic adults: (i) a cross-sectional study of 30-40 adults to determine the validity of data collection from different types of smartphones, (ii) a prospective cohort study of 50-100 adults ≥ 50 years old to determine usability and test-retest reliability, and (iii) a prospective cohort study of ~1,000 adults ≥ 50 years old to validate against cognitive measures. Aim 3 will be addressed in a cross-sectional study of ~200 participants with cognitive symptoms to validate TapTalk against Montreal Cognitive Assessment and interdisciplinary consensus diagnosis. DISCUSSION: This study will establish the precision of TapTalk to identify preclinical AD and estimate risk of cognitive decline. If accurate, this innovative smartphone app will enable low-cost, accessible screening of individuals for AD risk. This will have wide applications in public health initiatives and clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT06114914, 29 October 2023. Retrospectively registered.

Structure-function coupling and hierarchy-specific antidepressant response in major depressive disorder.

BACKGROUND: Extensive research has explored altered structural and functional networks in major depressive disorder (MDD). However, studies examining the relationships between structure and function yielded heterogeneous and inconclusive results. Recent work has suggested that the structure-function relationship is not uniform throughout the brain but varies across different levels of functional hierarchy. This study aims to investigate changes in structure-function couplings (SFC) and their relevance to antidepressant response in MDD from a functional hierarchical perspective. METHODS: We compared regional SFC between individuals with MDD (n = 258) and healthy controls (HC, n = 99) using resting-state functional magnetic resonance imaging and diffusion tensor imaging. We also compared antidepressant non-responders (n = 55) and responders (n = 68, defined by a reduction in depressive severity of >50%). To evaluate variations in altered and response-associated SFC across the functional hierarchy, we ranked significantly different regions by their principal gradient values and assessed patterns of increase or decrease along the gradient axis. The principal gradient value, calculated from 219 healthy individuals in the Human Connectome Project, represents a region's position along the principal gradient axis. RESULTS: Compared to HC, MDD patients exhibited increased SFC in unimodal regions (lower principal gradient) and decreased SFC in transmodal regions (higher principal gradient) (p < 0.001). Responders primarily had higher SFC in unimodal regions and lower SFC in attentional networks (median principal gradient) (p < 0.001). CONCLUSIONS: Our findings reveal opposing SFC alterations in low-level unimodal and high-level transmodal networks, underscoring spatial variability in MDD pathology. Moreover, hierarchy-specific antidepressant effects provide valuable insights into predicting treatment outcomes.

Radioactive iodine therapy improves overall survival outcome in oncocytic carcinoma of the thyroid by reducing death risks from noncancer causes: A competing risk analysis of 4641 patients.

BACKGROUND: Oncocytic carcinoma of the thyroid (OCA) is an independent type of thyroid cancer. Radioactive iodine (RAI) therapy was frequently administered to OCA patients, but its contribution to improving survival is indefinite. METHODS: 4641 OCA patients from 2000 to 2018 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Cox proportional hazard regression and competing risk analysis were applied. RESULTS: Tumor size, SEER stage, primary surgery, and neck dissection were prognostic factors for cancer-specific survival. The results of competing risk analysis demonstrated that age over 55 years dramatically increased non-OCA death risks. Treatments that improve non-OCA survival (including total thyroidectomy, RAI therapy, and systemic therapy) should be recommended in OCA patients older than 55 years of age. Neck lymphadenectomy should not be recommended for OCA, since the metastatic lymph node ratio was low (about 3%). CONCLUSIONS: RAI therapy can improve survival in OCA by reducing noncancer death risks.

Identification of potential biomarkers of gout through weighted gene correlation network analysis.

Background: Although hyperuricemia is not always associated with acute gouty arthritis, uric acid is a significant risk factor for gout. Therefore, we investigated the specific mechanism of uric acid activity. Methods: Using the gout-associated transcriptome dataset GSE160170, we conducted differential expression analysis to identify differentially expressed genes (DEGs). Moreover, we discovered highly linked gene modules using weighted gene coexpression network analysis (WGCNA) and evaluated their intersection. Subsequently, we screened for relevant biomarkers using the cytoHubba and Mcode algorithms in the STRING database, investigated their connection to immune cells and constructed a competitive endogenous RNA (ceRNA) network to identify upstream miRNAs and lncRNAs. We also collected PBMCs from acute gouty arthritis patients and healthy individuals and constructed a THP-1 cell gout inflammatory model, RT-qPCR and western blotting (WB) were used to detect the expression of C-X-C motif ligand 8 (CXCL8), C-X-C motif ligand 2 (CXCL2), and C-X-C motif ligand 1 (CXCL1). Finally, we predicted relevant drug targets through hub genes, hoping to find better treatments. Results: According to differential expression analysis, there were 76 upregulated and 28 downregulated mRNAs in GSE160170. Additionally, WGCNA showed that the turquoise module was most strongly correlated with primary gout; 86 hub genes were eventually obtained upon intersection. IL1ß, IL6, CXCL8, CXCL1, and CXCL2 are the principal hub genes of the protein-protein interaction (PPI) network. Using RT-qPCR and WB, we found that there were significant differences in the expression levels of CXCL8, CXCL1, and CXCL2 between the gouty group and the healthy group, and we also predicted 10 chemicals related to these proteins. Conclusion: In this study, we screened and validated essential genes using a variety of bioinformatics tools to generate novel ideas for the diagnosis and treatment of gout.

Rectifying METTL4-Mediated N6-Methyladenine Excess in Mitochondrial DNA Alleviates Heart Failure.

BACKGROUND: Myocardial mitochondrial dysfunction underpins the pathogenesis of heart failure (HF), yet therapeutic options to restore myocardial mitochondrial function are scarce. Epigenetic modifications of mitochondrial DNA (mtDNA), such as methylation, play a pivotal role in modulating mitochondrial homeostasis. However, their involvement in HF remains unclear. METHODS: Experimental HF models were established through continuous angiotensin II and phenylephrine (AngII/PE) infusion or prolonged myocardial ischemia/reperfusion injury. The landscape of N6-methyladenine (6mA) methylation within failing cardiomyocyte mtDNA was characterized using high-resolution mass spectrometry and methylated DNA immunoprecipitation sequencing. A tamoxifen-inducible cardiomyocyte-specific Mettl4 knockout mouse model and adeno-associated virus vectors designed for cardiomyocyte-targeted manipulation of METTL4 (methyltransferase-like protein 4) expression were used to ascertain the role of mtDNA 6mA and its methyltransferase METTL4 in HF. RESULTS: METTL4 was predominantly localized within adult cardiomyocyte mitochondria. 6mA modifications were significantly more abundant in mtDNA than in nuclear DNA. Postnatal cardiomyocyte maturation presented with a reduction in 6mA levels within mtDNA, coinciding with a decrease in METTL4 expression. However, an increase in both mtDNA 6mA level and METTL4 expression was observed in failing adult cardiomyocytes, suggesting a shift toward a neonatal-like state. METTL4 preferentially targeted mtDNA promoter regions, which resulted in interference with transcription initiation complex assembly, mtDNA transcriptional stalling, and ultimately mitochondrial dysfunction. Amplifying cardiomyocyte mtDNA 6mA through METTL4 overexpression led to spontaneous mitochondrial dysfunction and HF phenotypes. The transcription factor p53 was identified as a direct regulator of METTL4 transcription in response to HF-provoking stress, thereby revealing a stress-responsive mechanism that controls METTL4 expression and mtDNA 6mA. Cardiomyocyte-specific deletion of the Mettl4 gene eliminated mtDNA 6mA excess, preserved mitochondrial function, and mitigated the development of HF upon continuous infusion of AngII/PE. In addition, specific silencing of METTL4 in cardiomyocytes restored mitochondrial function and offered therapeutic relief in mice with preexisting HF, irrespective of whether the condition was induced by AngII/PE infusion or myocardial ischemia/reperfusion injury. CONCLUSIONS: Our findings identify a pivotal role of cardiomyocyte mtDNA 6mA and the corresponding methyltransferase, METTL4, in the pathogenesis of mitochondrial dysfunction and HF. Targeted suppression of METTL4 to rectify mtDNA 6mA excess emerges as a promising strategy for developing mitochondria-focused HF interventions.

Effects of Long-Term Cryopreservation on the Transcriptomes of Giant Grouper Sperm.

The giant grouper fish (Epinephelus lanceolatus), one of the largest and rarest groupers, is a fast-growing economic fish. Grouper sperm is often used for cross-breeding with other fish and therefore sperm cryopreservation is important. However, freezing damage cannot be avoided. Herein, we performed a transcriptome analysis to compare fresh and frozen sperm of the giant grouper with frozen storage times of 0, 23, 49, and 61 months. In total, 1911 differentially expressed genes (DEGs), including 91 in El-0-vs-El-23 (40 upregulated and 51 downregulated), 251 in El-0-vs-El-49 (152 upregulated and 69 downregulated), and 1569 in El-0-vs-El-61 (984 upregulated and 585 downregulated), were obtained in the giant grouper sperm. DEGs were significantly increased at 61 months of cryopreservation (p < 0.05). GO and KEGG enrichment analyses of the DEGs revealed significant enrichment in the pilus assembly, metabolic process, MAPK signaling pathway, apoptosis, and P53 signaling pathway. Time-series expression profiling of the DEGs showed that consistently upregulated modules were also significantly enriched in signaling pathways associated with apoptosis. Four genes, scarb1, odf3, exoc8, and atp5f1d, were associated with mitochondria and flagella in a weighted correlation network analysis. These genes may play an important role in the response to sperm freezing. The experimental results show that long-term cryopreservation results in freezing damage to the giant grouper sperm. This study provides rich data for studies of the mechanism underlying frozen fish sperm damage as well as a technical reference and evaluation index for the long-term cryopreservation of fish sperm.

M2 Macrophage-Derived Extracellular Vesicles Encapsulated in Hyaluronic Acid Alleviate Osteoarthritis by Modulating Macrophage Polarization.

An imbalance between M1 and M2 macrophage polarization is critical in osteoarthritis (OA) development. We investigated the effect of M2 macrophage-derived extracellular vesicles (M2-EVs) to reprogramme macrophages from the M1 to M2 phenotype for OA treatment. M1 macrophages and mouse OA models were treated with M2-EVs. Proteomic analysis was performed to evaluate macrophage polarization in vitro. The OA models were as follows: destabilization of the medial meniscus (DMM) surgery-induced OA and collagenase-induced OA (CIOA). Hyaluronic acid (HA) was used to deliver M2-EVs. M2-EVs decreased macrophage accumulation, repolarized macrophages from the M1 to M2 phenotype, mitigated synovitis, reduced cartilage degradation, alleviated subchondral bone damage, and improved gait abnormalities in the CIOA and DMM models. Moreover, HA increased the retention time of M2-EVs and enhanced the efficiency of M2-EVs in OA treatment. Furthermore, proteomic analysis demonstrated that M2-EVs exhibited a macrophage reprogramming ability similar to IL-4, and the pathways might be the NOD-like receptor (NLR), TNF, NF-κB, and Toll-like receptor (TLR) signaling pathways. M2-EVs reprogrammed macrophages from the M1 to M2 phenotype, which resulted in beneficial effects on cartilage and attenuation of OA severity. In summary, our study indicated that M2-EV-guided reprogramming of macrophages is a promising treatment strategy for OA.