Allostatic load in rat model: An efficient tool for evaluating and understanding aging.

AIM: Aging and age-related diseases are an ever-increasing social and public health problem. Allostatic load (AL) shows great potential as an interdisciplinary tool for assessing the aging of human beings but as yet lacks investigation in animal models which is our study focus at. METHODS: Here a continuous study of AL was conducted on naturally aging rats. Blood samples were collected from the rats at ages of 5, 8, 14, 18, and 21 months. Dozens of blood biochemical indicators, including serum corticosterone, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, C-reactive protein, interleukin-6, 25-hydroxyvitamin D, free fatty acid, CD3+ T cell count, CD4+/CD3+ T cell ratio, CD8+/CD3+ T cell ratio, and CD3/4/8+ T cell apoptosis, were determined. RESULTS: AL was scored from those indicators, and we found that AL score gradually increased with age. CONCLUSIONS: AL can reliably reveal the cumulative and systemic changes in aging. Geriatr Gerontol Int 2024; ••: ••-••.

Prognostic value of NT-proBNP and uric acid in acute ST-segment elevation myocardial infarction patients after complete revascularization.

OBJECTIVES: To explore the prognostic value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and uric acid (UA) in acute ST-segment elevation myocardial infarction (STEMI) patients after complete revascularization (CR). METHODS: The clinical and physical data from 125 acute STEMI patients (research group) who underwent CR between December 2017 and December 2020 and 60 healthy individuals (control group) who concurrently underwent physical examinations in the Affiliated Hospital of Guizhou Medical University were retrospectively analyzed in this study. Serum samples were collected from both groups to determine the levels of NT-proBNP and UA. The 3-year follow-up data of acute STEMI patients were collected, which were used to group the patients into a good and a poor prognosis group based on their prognoses to comparatively analyze NT-proBNP and UA levels. Receiver operating characteristic (ROC) curves were drawn to analyze the prognostic value of NT-proBNP and UA in STEMI patients following CR, and survival curves were plotted to observe their influences on patients' 3-year overall survival (OS). Meanwhile, a univariate analysis was conducted to identify factors associated with the 3-year OS of acute STEMI patients after CR. RESULTS: The data showed significantly higher expression levels of serum NT-proBNP and UA in acute STEMI patients than in the controls. Besides, the good prognosis group exhibited markedly lower serum NT-proBNP and UA levels than the poor prognosis group. The areas under the curve (AUCs) of NT-proBNP and UA in predicting the prognosis of acute STEMI patients after CR were all above 0.700, and the AUC of their combined detection reached over 0.800. In addition, high serum NT-proBNP and UA levels were strongly associated with lower 3-year OS rates. As indicated by the univariate analysis, a history of smoking and alcoholism as well as high NT-proBNP and UA levels were closely associated with 3-year OS in acute STEMI patients after CR. CONCLUSIONS: NT-proBNP and UA have promising prognostic value in acute STEMI after CR.

Equitable evaluation of supply-demand and layout optimization of urban park green space in high-density linear large city.

Equitable and effective planning of urban park green spaces (UPGSs) is an important way to promote green and healthy urban development and improve citizens' quality of life. However, under the background of rapid urbanization, linear large cities, with their unique spatial forms and high-density population agglomerations, have brought special challenges for the planning and management of urban public green spaces. This study takes Lanzhou, a typical representative of high-density linear large cities in China, as a case study. Based on the improvement of the traditional Gaussian Two-Step Floating Catchment Area method (G2SFCA), combined with the Gini coefficient and the Lorentz curve, the social equity and spatial equity of UPGS supply-demand in the central urban area of Lanzhou were evaluated at the city and district scales. Meanwhile, the areas with shortage of UPGS supply-demand were accurately identified as the key areas for future optimization. The results show that: (1) There are significant differences in the equity of UPGS supply-demand in the linear large Lanzhou at the social and spatial levels, and most UPGS resources are enjoyed by a few people; (2) The spatial accessibility of UPGSs has an obvious "string of beads" distribution Characteristics, and the areas with high accessibility are mainly concentrated along rivers; (3) The equity of UPGS supply-demand exhibits a spatial gradient effect, which is characterized by a circle distribution. From the inside to the outside, it is as follows: good supply-dense population, good supply-sparse population, supply shortage-dense population, supply shortage-sparse population. Finally, based on the concept of "progressive micro-regeneration" and the Location Allocation model (LA), the optimal sites for new UPGSs were determined, maximizing the equity of UPGS supply-demand. This provides a practical reference for relevant management departments to optimize park layouts in the future.

Study of symptom clusters in brain tumor patients 2 weeks after craniotomy.

BACKGROUND: This study aimed to identify potential symptom clusters among primary brain tumor patients using factor analysis. Understanding these clusters enables better-targeted interventions post-craniotomy. METHODS: A total of 211 participants visiting Department of Neurosurgery at Shanghai Tenth People's Hospital for proposed surgical treatment between January 2021 and March 2022 were enrolled. Two weeks after craniotomy, the patients' symptoms were measured using MDASI-BT (M.D. Anderson Symptom Inventory Brain Tumor Module), and factor analysis was performed to identify symptom clusters. RESULTS: A total of three symptom clusters, i.e., symptom cluster 1, symptom cluster 2, and symptom cluster 3, were identified. Among them, symptom cluster 1 represented the fatigue-related symptom cluster, including fatigue, lethargy, dry mouth, pain, and sleep disturbance (Cronbach's α = 0.742); symptom cluster 2 represented the gut-brain axis symptom cluster, including loss of appetite, weakness in one side of the body, and change in bowel habits (Cronbach's α = 0.532); and symptom cluster 3 represented the self-image symptom cluster, including change in appearance, sadness, and distress (Cronbach's α = 0.547). CONCLUSION: This study identified three potential symptom clusters among primary brain tumor patients. Understanding these clusters could well contribute to earlier interventions and improved quality of care.

Risk factors related to low-level viraemia in chronic hepatitis B patients receiving entecavir treatment.

Background: About 20% of on-treatment patients with chronic hepatitis B (CHB) experienced low-level viraemia (LLV), which is associated with persistent low-grade inflammation, fibrosis progression, and increased risk of hepatocellular carcinoma. We aimed to investigate the high-risk factors related to LLV. Methods: In this retrospective study, patients receiving entecavir (ETV) treatment from January 2018 to January 2023 were enrolled, and were divided into a LLV (HBV DNA 20-2000 IU/mL) cohort and a complete virological response (CVR) (HBV DNA < 20 IU/mL) cohort according to the virological response at week 48 posttreatment. Treatment baseline characteristics were retrieved from electronic medical records. Multivariate logistic regression was performed. Results: Totally, 1653 patients were enrolled, male patients accounted for 73.0%; the median age was 44 years; the mean HBV DNA level was 5.9 Log10 IU/ml. Among them, 472 (28.6%) experienced LLV. Multivariate analysis showed that HBeAg positivity (OR = 2.650, 95% CI: 2.000-3.511, p < 0.001), HBV DNA ≥ 6.0 Log10 IU/mL (OR = 1.370, 95% CI: 1.054-1.780, p = 0.019), qHBsAg ≥ 9000 IU/mL (OR = 4.472, 95% CI: 3.410-5.866, p < 0.001), cirrhosis (OR = 1.650, 95% CI: 1.234-2.207, P = 0.001), LSM ≥ 13.0 kPa (OR = 1.644, 95% CI: 1.203-2.246, p = 0.002), and PLT < 100×109/L (OR = 1.450, 95% CI: 1.094-1.922, p = 0.010) at baseline were related to the development of LLV. Conclusions: High HBV DNA/HBsAg quantification/LSM, low PLT, HBeAg positivity, and liver cirrhosis were high-risk factors associated with LLV in patients receiving entecavir treatment.

Pueraria lobata-Prunus mume Complex Alleviates Alcoholic Liver Disease by Regulating Lipid Metabolism and Inhibiting Inflammation: A Transcriptome and Gut Microbiota Analysis.

BACKGROUND: Lipid metabolism disorder appears to be one of the early features of alcoholic liver disease (ALD), which can be speculated via omics analysis including liver transcriptomics and gut microbiota. A complex consisting of the roots of Pueraria lobata and dried fruits of Prunus mume (PPC), which possesses hepatoprotective effects, could serve as a drug or functional food. The lack of non-polysaccharide compounds in PPC with their moderation effects on gut microbiota suggests the necessity for a relevant study. METHODS: Six groups of Kunming mice (control, Baijiu injury, silybin, low, medium, and high) were modelled by gavage with Baijiu (for 14 days) and PPC (equivalent to a maximum dose of 9 g/kg in humans). The liver transcriptome data were analyzed to predict gene annotation, followed by the verification of gut microbiota, serum, tissue staining, immunohistochemistry, and Western blotting. Liquid chromatography-mass spectrometry was used to detect the components. RESULTS: PPC normalized serum ALT (40 U/L), down-regulated TLR4-NF-κB signaling pathway to inhibit the release of TNF-α (90 pg/mL), improved the expression of occludin, claudin-4, and ZO-1, and restored the abundance of Muribaculaceae, Bacteroides and Streptococcus. CONCLUSION: PPC can alleviate ALD by regulating the gut microbiota with an anti-inflammatory and intestinal barrier, and has an application value in developing functional foods.

An Innovative Aggregation-Induced Emission-Based NIR Fluorescent Probe for Visualizing Carboxylesterases in Living Cells, Zebrafish, and Tumor-Bearing Mice.

In the human body, carboxylesterases (CEs) play crucial roles in xenobiotic metabolism and lipid homeostasis. But abnormal expression of CEs is highly associated with some diseases, such as hyperlipidemia, diabetes, and liver cancer. Therefore, it is of great importance to develop an efficient tool for the accurate detection of CEs in living organisms. Herein, an innovative near-infrared (NIR) fluorescent probe, TTAP-AB, was designed for CE detection based on the aggregation-induced emission (AIE) mechanism. This probe exhibits rapid response (2 min), excellent sensitivity (limit of detection = 8.14 × 10-6 U/mL), and high selectivity to CEs. Additionally, owing to its good biocompatibility, the TTAP-AB probe enables the monitoring of dynamic changes in CE levels under drug-induced modulation in living cells and zebrafish. More importantly, the TTAP-AB probe was successfully employed to image liver tumors and assist in tumor resection through the real-time monitoring of CEs, indicating that TTAP-AB is promising to guide liver cancer surgery. Therefore, the TTAP-AB probe can not only enrich the strategies for CE detection in biological systems but also has great potential for some clinical imaging applications, including medical diagnosis, preclinical research, and imaging-guided surgery.

Suicidal incidence and gender-based discrepancies in prolonged grief disorder: insights from a meta-analysis and systematic review.

Background: In the aftermath of bereavement, our research explores the subtleties of Prolonged Grief Disorder (PGD), focusing particularly on its correlation with suicidal behaviors and their variation across genders. This study seeks to elucidate the impact of gender on these behaviors among individuals suffering from PGD, thereby enhancing our understanding and facilitating the development of tailored therapeutic interventions. Methods: By November 24th, 2023, we had rigorously reviewed key databases such as PubMed, Web of Science, Cochrane Library, PsycINFO, and Embase. Independently, two researchers conducted detailed interviews and filled out questionnaires with participants to gather demographic information and record instances of prolonged grief disorder. The study also meticulously tracked occurrences of suicidal ideation, suicide attempts, suicide deaths, and self-injury among the participants. Results: The findings indicate that 22.34% of males reported suicidal ideation (95% CI: 21.33-23.35), a figure that rises to 26.84% among females (95% CI: 25.99-27.69). Notably, 12.11% of males attempted suicide (95% CI: 11.49-12.72), marginally surpassing the 9.60% observed in females (95% CI: 9.17-10.04). More striking disparities were observed in suicide deaths, with rates for males at 3.66% (95% CI: 3.32-4.00) compared to a notably higher 7.12% for females (95% CI: 6.44-7.81). Furthermore, the incidence of self-injury was lower among males, at 2.48% (95% CI: 2.03-2.94), than in females, who reported a rate of 5.09% (95% CI: 4.69-5.49). These patterns underscore the critical need for gender-specific interventions aimed at reducing these significant disparities. Conclusion: This study distinctly underscores the profound impact of gender on the manifestation of suicidal behaviors in individuals afflicted with prolonged grief disorder. It reveals that females are more prone to suicidal ideation, self-injury, and suicide deaths, while males predominantly exhibit a higher incidence of suicide attempts and risk-taking behaviors. These unmediated trends highlight the necessity for gender-specific clinical interventions tailored to address particular behaviors and modify prevalent patterns that typically resist conventional approaches. Systematic review registration: PROSPERO (york.ac.uk), identifier CRD42023480035.

Mendelian randomization study on causal association of TEF and circadian rhythm with pulmonary arterial hypertension.

BACKGROUND: Previous research has revealed the potential impact of circadian rhythms on pulmonary diseases; however, the connection between circadian rhythm-associated Thyrotroph Embryonic Factor (TEF) and Pulmonary Arterial Hypertension (PAH) remains unclear. We aim to assess the genetic causal relationship between TEF and PAH by utilizing two sets of genetic instrumental variables (IV) and publicly available Pulmonary Arterial Hypertension Genome-Wide Association Studies (GWAS). METHODS: Total of 23 independent TEF genetic IVs from recent MR reports and PAH GWAS including 162,962 European individuals were used to perform this two-sample MR study. Gain- and loss-of-function experiments were used to demonstrate the role of TEF in PAH. RESULTS: Our analysis revealed that as TEF levels increased genetically, there was a corresponding increase in the risk of PAH, as evidenced by IVW (OR = 1.233, 95% CI: 1.054-1.441; P = 0.00871) and weighted median (OR = 1.292, 95% CI for OR: 1.064-1.568; P = 0.00964) methods. Additionally, the up-regulation of TEF expression was associated with a significantly higher likelihood of abnormal circadian rhythm (IVW: P = 0.0024733, ß = 0.05239). However, we did not observe a significant positive correlation between circadian rhythm and PAH (IVW: P = 0.3454942, ß = 1.4980398). In addition, our in vitro experiments demonstrated that TEF is significantly overexpressed in pulmonary artery smooth muscle cells (PASMCs). And overexpression of TEF promotes PASMC viability and migratory capacity, as well as upregulates the levels of inflammatory cytokines. CONCLUSION: Our analysis suggests a causal relationship between genetically increased TEF levels and an elevated risk of both PAH and abnormal circadian rhythm. Consequently, higher TEF levels may represent a risk factor for individuals with PAH.

Noninvasive Monitoring of Severe Pulmonary Artery Hypertension in Atrial Septal Defect Patients: Role of Serum Bilirubin Combined with Uric Acid.

Background: Atrial septal defect (ASD) patients commonly experience severe pulmonary arterial hypertension (SPAH), which is frequently associated with a poor prognosis. While serum bilirubin levels, indicative of liver function, are known predictors of right heart failure (RHF), their potential to differentiate SPAH in ASD patients is yet to be ascertained. The purpose of this study was to discover the potential correlations between serum bilirubin levels and ASD patients with SPAH. Methods: In this cross-sectional study, 102 ASD patients admitted from December 2019 to November 2020 were enrolled and divided into two cohorts: those with SPAH and those without. Blood tests were conducted to measure serum direct bilirubin (DBIL), total bilirubin (TBIL), alanine aminotransferase (ALT), aspartate aminotransferase (AST), uric acid (UA) and N-terminal pro B-type natriuretic peptide (NT-proBNP). Additionally, all participants underwent transthoracic echocardiography, and invasive hemodynamic data were gathered through right heart catheterization. Results: ASD patients with SPAH exhibited significantly elevated serum DBIL (5.2 ± 3.0 vs. 2.4 ± 1.5 µmol/L, p < 0.001) and TBIL (24.6 ± 20.7 vs. 10.1 ± 4.8 µmol/L, p < 0.001) levels in comparison to those without SPAH. However, ALT and AST levels remained comparable between the cohorts. Additionally, the SPAH cohort displayed higher serum UA (403.5 ± 131.6 vs. 317.8 ± 67.9 µmol/L, p < 0.001) and NT-proBNP levels. Serum DBIL levels, when analyzed independently of other variables, correlated with an increased risk of mean pulmonary arterial pressure (mPAP) in ASD patients ( ß = 1.620, p = 0.010). A DBIL concentration of 2.15 mg/dL effectively differentiated ASD patients with SPAH from those without, with a sensitivity of 92.9% and a specificity of 51.4% (area under the curve [AUC]: 0.794, 95% confidence interval [CI]: 0.701-0.886, p < 0.001). Notably, the combination of DBIL and UA had a higher sensitivity of 92.9% and specificity of 71.6% (AUC: 0.874, 95% CI: 0.799-0.949, p < 0.001). Conclusions: Elevated serum DBIL and TBIL levels in ASD patients with SPAH were correlated with poor cardiac function and heightened pulmonary artery pressure. The combination of DBIL and UA has emerged as a strong noninvasive predictor for SPAH in ASD patients, presenting a potentially novel therapeutic biomarker.

Near-Barrierless CO Oxidation Using Phosphotungstic Acid-Supported Single-Atom Catalysts.

Efficient CO oxidation at ambient or low temperatures is essential for environmental purification and selective CO oxidation in H2, yet achieving this remains a challenge with current methodologies. In this research, we extensively evaluated the catalytic performance of phosphotungstic acid (PTA)-supported 11 M1/PTA single-atom catalysts (SACs) using density functional theory calculations across both gas phase and 12 common solvents. The Rh1/PTA, Pd1/PTA, and Pt1/PTA systems exhibit moderate CO adsorption energies, facilitating the feasibility of oxygen vacancy formation. Remarkably, the Pd1/PTA and Pt1/PTA catalysts exhibited negligible energy barriers and demonstrated exceptionally high catalytic rates, with values reaching up to (1 × 1010)11, markedly exceeding the threshold for room temperature reactions, set at 6.55 × 108. This phenomenon is attributed to a transition from the high-energy barrier processes of oxygen dissociation in O2 and N-O bond dissociation in N2O to the more efficient dissociation of H2O2. Orbital analysis and charge variations at metal sites throughout the reaction process provide deeper insights into the role of the three metal catalytic sites in CO activation. Our findings not only reveal key aspects of SACs in facilitating CO oxidation at low temperatures but also provide valuable insights for future catalytic reaction mechanism studies and environmental applications.

Homoharringtonine may help improve the outcomes of venetoclax and azacitidine in AML1-ETO positive acute myeloid leukemia.

PURPOSE: T(8;21)(q22;q22.1)/AML1-ETO positive acute myeloid leukemia (AE-AML) is sensitive to conventional chemotherapy with a favorable prognosis. However, recent small case reports suggest the limited effectiveness of venetoclax (VEN) and hypomethylating agents (HMA) in treating AE-AML. The aim of this retrospective study was to evaluate the effectiveness of VEN plus AZA (VA) in AE-AML and explore whether adding homoharringtonine (HHT) to VA (VAH) could improve the response. METHODS: Patients who received VEN plus AZA and HHT (VAH) or VEN plus AZA (VA) regimens were included in this retrospective study. The endpoints of this study were to evaluate the rate of composite complete remission (CRc), measurable residual disease (MRD), event-free survival (EFS), overall survival (OS), and relapse between VAH and VA groups. RESULTS: A total of 32 AE-AML patients who underwent VA or VAH treatments (newly diagnosed with VA, ND-VA, n = 8; relapsed/refractory with VA, R/R-VA, n = 10; relapsed/refractory with VAH, R/R-VAH, n = 14) were included. The CR (complete remission) /CRi (CR with incomplete count recovery) rate of ND-VA, R/R-VA and R/R-VAH were 25%, 10%, and 64.3%, respectively. Measurable residual disease (MRD) negative was observed in 66.7% of R/R-VAH and none of VA-R/R patients. Co-occurring methylation mutations are associated with poor outcomes with VA but exhibit a more favorable response with VAH treatment. Additionally, patients with c-kit mutation presented inferior outcomes with both VEN-based regimens. All regimens were tolerated well by all patients. CONCLUSION: Our data confirmed the poor response of VA in AE-AML, whether used as frontline or salvage therapy. Adding HHT to VA may improve outcomes and enhance the efficacy of VEN in this population.

The dual role of FSP1 in programmed cell death: resisting ferroptosis in the cell membrane and promoting necroptosis in the nucleus of THP-1 cells.

BACKGROUND: Acute monocytic leukemia-M5 (AML-M5) remains a challenging disease due to its high morbidity and poor prognosis. In addition to the evidence mentioned earlier, several studies have shown that programmed cell death (PCD) serves a critical function in treatment of AML-M5. However, the role and relationship between ferroptosis and necroptosis in AML-M5 remains unclear. METHODS: THP-1 cells were mainly treated with Erastin and IMP-366. The changes of ferroptosis and necroptosis levels were detected by CCK-8, western blot, quantitative real-time PCR, and electron microscopy. Flow cytometry was applied to detect the ROS and lipid ROS levels. MDA, 4-HNE, GSH and GSSG were assessed by ELISA kits. Intracellular distribution of FSP1 was studied by immunofluorescent staining and western blot. RESULTS: The addition of the myristoylation inhibitor IMP-366 to erastin-treated acute monocytic leukemia cell line THP-1 cell not only resulted in greater susceptibility to ferroptosis characterized by lipid peroxidation, glutathione (GSH) depletion and mitochondrial shrinkage, as the FSP1 position on membrane was inhibited, but also increased p-RIPK1 and p-MLKL protein expression, as well as a decrease in caspase-8 expression, and triggered the characteristic necroptosis phenomena, including cytoplasmic translucency, mitochondrial swelling, membranous fractures by FSP1 migration into the nucleus via binding importin α2. It is interesting to note that ferroptosis inhibitor fer-1 reversed necroptosis. CONCLUSION: We demonstrated that inhibition of myristoylation by IMP-366 is capable of switching ferroptosis and ferroptosis-dependent necroptosis in THP-1 cells. In these findings, FSP1-mediated ferroptosis and necroptosis are described as alternative mechanisms of PCD of THP-1 cells, providing potential therapeutic strategies and targets for AML-M5.

A pan-TE map highlights transposable elements underlying domestication and agronomic traits in Asian rice.

Transposable elements (TEs) are ubiquitous genomic components and hard to study due to being highly repetitive. Here we assembled 232 chromosome-level genomes based on long-read sequencing data. Coupling the 232 genomes with 15 existing assemblies, we developed a pan-TE map comprising both cultivated and wild Asian rice. We detected 177 084 high-quality TE variations and inferred their derived state using outgroups. We found TEs were one source of phenotypic variation during rice domestication and differentiation. We identified 1246 genes whose expression variation was associated with TEs but not single-nucleotide polymorphisms (SNPs), such as OsRbohB, and validated OsRbohB's relative expression activity using a dual-Luciferase (LUC) reporter assays system. Our pan-TE map allowed us to detect multiple novel loci associated with agronomic traits. Collectively, our findings highlight the contributions of TEs to domestication, differentiation and agronomic traits in rice, and there is massive potential for gene cloning and molecular breeding by the high-quality Asian pan-TE map we generated.

Pulmonary hypertension exacerbated by hereditary hemorrhagic telangiectasia combined with pulmonary arteriovenous fistula and pregnancy status: A case report.

Background: Hereditary hemorrhagic telangiectasia (HHT) is an uncommon autosomal dominant condition. The combination of pregnancy and HHT can exacerbate pulmonary hypertension (PH) and, in severe cases, lead to fatality. Case presentation: The case we presented is a 28-year-old multiparous woman. She developed chest tightness and dyspnea in the second trimester of pregnancy, which was not taken seriously at that time, and the symptoms worsened postpartum. Echocardiography showed elevated pulmonary artery pressure (PAP) and the computerized tomographic pulmonary angiogram revealed a significant pulmonary arteriovenous malformation. The patient's condition continued to deteriorate despite treatment to reduce pulmonary hypertension. We reviewed and updated the history of omission, recurrent epistaxis during pregnancy, and similar symptoms running in her family. Combined with the whole exon genetic testing report revealing the ACVRL1 gene mutation at chr12:52308295, the diagnosis of HHT was established. Four months later, a transcatheter closure of the pulmonary arteriovenous fistula was performed, with satisfying outcomes presenting a decrease of more than 15 mmHg in the pulmonary artery pressure. As of right now, the patient's status is stable during the outpatient follow-up. Conclusions: HHT is a rare condition that typically occurs alongside abnormal communication between pulmonary veins and arteries, leading to a high-flow state in the pulmonary circulation. A pulmonary hypertension crisis can also be triggered by the patient's pregnancy, which further increases blood volume. By reducinhttps://www.ecdc.europa.eu/sites/default/files/documents/Methods-for-the%20detection-and-characterisation-of-SARS-CoV-2-variants-first-update-WHO-20-Dec-2021.pdfg pulmonary vascular flow, catheter closure of the pulmonary arteriovenous fistula decreases pulmonary arterial pressure.

Porphyrin-Based Organic Nanoparticles with NIR-IIa Fluorescence for Orthotopic Glioblastoma Theranostics.

The development of efficient theranostic nanoagents for the precise diagnosis and targeted therapy of glioblastoma (GBM) remains a big challenge. Herein, we designed and developed porphyrin-based organic nanoparticles (PNP NPs) with strong emission in the near-infrared IIa window (NIR-IIa) for orthotopic GBM theranostics. PNP NPs possess favorable photoacoustic and photothermal properties, high photostability, and low toxicity. After modification with the RGD peptide, the obtained PNPD NPs exhibited enhanced blood-brain barrier (BBB) penetration capability and GBM targeting ability. NIR-IIa imaging was employed to monitor the in vivo biodistribution and accumulation of the nanoparticles, revealing a significant enhancement in penetration depth and signal-to-noise ratio. Both in vitro and in vivo results demonstrated that PNPD NPs effectively inhibited the proliferation of tumor cells and induced negligible side effects in normal brain tissues. In general, the work presented a kind of brain-targeted porphyrin-based NPs with NIR-IIa fluorescence for orthotopic glioblastoma theranostics, showing promising prospects for clinical translation.

A Mitochondria-Targeting Fluorescent Probe for the Dual Sensing of Hypochlorite and Viscosity without Signal Crosstalk in Living Cells and Zebrafish.

Hypochlorite (ClO-) and viscosity both affect the physiological state of mitochondria, and their abnormal levels are closely related to many common diseases. Therefore, it is vitally important to develop mitochondria-targeting fluorescent probes for the dual sensing of ClO- and viscosity. Herein, we have explored a new fluorescent probe, XTAP-Bn, which responds sensitively to ClO- and viscosity with off-on fluorescence changes at 558 and 765 nm, respectively. Because the emission wavelength gap is more than 200 nm, XTAP-Bn can effectively eliminate the signal crosstalk during the simultaneous detection of ClO- and viscosity. In addition, XTAP-Bn has several advantages, including high selectivity, rapid response, good water solubility, low cytotoxicity, and excellent mitochondrial-targeting ability. More importantly, probe XTAP-Bn is successfully employed to monitor the dynamic change in ClO- and viscosity levels in the mitochondria of living cells and zebrafish. This study not only provides a reliable tool for identifying mitochondrial dysfunction but also offers a potential approach for the early diagnosis of mitochondrial-related diseases.

Dicerandrol C Suppresses Proliferation and Induces Apoptosis of HepG2 and Hela Cancer Cells by Inhibiting Wnt/ß-Catenin Signaling Pathway.

Overwhelming evidence points to an aberrant Wnt/ß-catenin signaling as a critical factor in hepatocellular carcinoma (HCC) and cervical cancer (CC) pathogenesis. Dicerandrol C (DD-9), a dimeric tetrahydroxanthenone isolated from the endophytic fungus Phomopsis asparagi DHS-48 obtained from mangrove plant Rhizophora mangle via chemical epigenetic manipulation of the culture, has demonstrated effective anti-tumor properties, with an obscure action mechanism. The objective of the current study was to explore the efficacy of DD-9 on HepG2 and HeLa cancer cells and its functional mechanism amid the Wnt/ß catenin signaling cascade. Isolation of DD-9 was carried out using various column chromatographic methods, and its structure was elucidated with 1D NMR. The cytotoxicity of DD-9 on HepG2 and HeLa cells was observed with respect to the proliferation, clonality, migration, invasion, apoptosis, cell cycle, and Wnt/ß-catenin signaling cascade. We found that DD-9 treatment significantly reduced tumor cell proliferation in dose- and time-dependent manners in HepG2 and HeLa cells. The subsequent experiments in vitro implied that DD-63 could significantly suppress the tumor clonality, metastases, and induced apoptosis, and that it arrested the cell cycle at the G0/G1 phase of HepG2 and HeLa cells. Dual luciferase assay, Western blot, and immunofluorescence assay showed that DD-9 could dose-dependently attenuate the Wnt/ß-catenin signaling by inhibiting ß-catenin transcriptional activity and abrogating ß-catenin translocated to the nucleus; down-regulating the transcription level of ß-catenin-stimulated Wnt target gene and the expression of related proteins including p-GSK3-ß, ß-catenin, LEF1, Axin1, c-Myc, and CyclinD1; and up-regulating GSK3-ß expression, which indicates that DD-9 stabilized the ß-catenin degradation complex, thereby inducing ß-catenin degradation and inactivation of the Wnt/ß-catenin pathway. The possible interaction between DD-9 and ß-catenin and GSK3-ß protein was further confirmed by molecular docking studies. Collectively, DD-9 may suppress proliferation and induce apoptosis of liver and cervical cancer cells, possibly at least in part via GSK3-ß-mediated crosstalk with the Wnt/ß-catenin signaling axis, providing insights into the mechanism for the potency of DD-9 on hepatocellular and cervical cancer.

Influencing factors of delay in seeking medical attention of patients with obstructive sleep apnea based on the Model of Pathways to Treatment in China: a qualitative analysis.

BACKGROUND: There is the highest estimated number of patients with obstructive sleep apnea (OSA) in China. Early treatment could lead to fewer complications associated with OSA. This study aimed to analyze the factors influencing help-seeking from the first symptom discovery to treatment in OSA. METHODS: Semi-structured interview outline was designed to conduct face-to-face interview based on the analyses of a great number of related literatures on the delay in seeking medical attention of patients with OSA. 15 patients diagnosed were interviewed between June 2021 to September 2022 in general hospital of Shenyang, Northeastern of China. Qualitative data was analyzed by content analysis using the Model of Pathways to Treatment. RESULTS: Analyses identified factors contributing to elapsed time from first symptom discovery to received treatment that are linked to disease characteristic, patients, health system organization. Appraisal interval is most obvious for patients with OSA, but it is difficult to pinpoint precisely because the patients didn't remember exactly when the first symptom was detected. CONCLUSIONS: Patients diagnosed with OSA didn't initially interpret the snore as a warning sign and even thought it was a blessing. The findings provided guidance or avenues for reducing elapsed time between the first symptom and received treatment.

Population-level exploration of alternative splicing and its unique role in controlling agronomic traits of rice.

Alternative splicing (AS) plays crucial roles in regulating various biological processes in plants. However, the genetic mechanisms underlying AS and its role in controlling important agronomic traits in rice (Oryza sativa) remain poorly understood. In this study, we explored AS in rice leaves and panicles using the rice minicore collection. Our analysis revealed a high level of transcript isoform diversity, with approximately one fifth of potential isoforms acting as major transcripts in both tissues. Regarding the genetic mechanism of AS, we found that the splicing of 833 genes in the leaf and 1,230 genes in the panicle was affected by cis-genetic variation. Twenty-one percent of these AS events could only be explained by large structural variations. Approximately 77.5% of genes with significant splicing quantitative trait loci (sGenes) exhibited tissue-specific regulation, and AS can cause 26.9% (leaf) and 23.6% (panicle) of sGenes to have altered, lost or gained functional domains. Additionally, through splicing-phenotype association analysis, we identified phosphate-starvation induced RING-type E3 ligase (OsPIE1; LOC_Os01g72480), whose splicing ratio was significantly associated with plant height. In summary, this study provides an understanding of AS in rice and its contribution to the regulation of important agronomic traits.