An Open-Label Phase II Study Assessing the Safety of Bilateral, Sequential Administration of Retinal Gene Therapy in Participants with Choroideremia: The GEMINI Study.

Choroideremia, an incurable, progressive retinal degeneration primarily affecting young men, leads to sight loss. GEMINI was a multicenter, open-label, prospective, two-period, interventional Phase II study assessing the safety of bilateral sequential administration of timrepigene emparvovec, a gene therapy, in adult males with genetically confirmed choroideremia (NCT03507686, ClinicalTrials.gov). Timrepigene emparvovec is an adeno-associated virus serotype 2 vector encoding the cDNA of Rab escort protein 1, augmented by a downstream woodchuck hepatitis virus post-transcriptional regulatory element. Up to 0.1 mL of timrepigene emparvovec, containing 1 × 1011 vector genomes, was administered by subretinal injection following vitrectomy and retinal detachment. The second eye was treated after an intrasurgery window of <6, 6-12, or >12 months. Each eye was followed at up to nine visits over 12 months. Overall, 66 participants received timrepigene emparvovec, and 53 completed the study. Visual acuity (VA) was generally maintained in both eyes, independent of intrasurgery window duration, even after bilateral retinal detachment and subretinal injection. Bilateral treatment was well tolerated, with predominantly mild or moderate treatment-emergent adverse events (TEAEs) and a low rate of serious surgical complications (7.6%). Retinal inflammation TEAEs were reported in 45.5% of participants, with similar rates in both eyes; post hoc analyses found that these were not associated with clinically significant vision loss at month 12 versus baseline. Two participants (3.0%) reported serious noninfective retinitis. Prior timrepigene emparvovec exposure did not increase the risk of serious TEAEs or serious ocular TEAEs upon injection of the second eye; furthermore, no systemic immune reaction or inoculation effect was observed. Presence of antivector neutralizing antibodies at baseline was potentially associated with a higher percentage of TEAEs related to ocular inflammation or reduced VA after injection of the first eye. The GEMINI study results may inform decisions regarding bilateral sequential administration of other gene therapies for retinal diseases.

3-Hydroxyneocryptolepine, a new indoloquinoline alkaloid from the roots of Cryptolepis sanguinolenta (Lindl.) Schltr.

Phytochemical investigations of the African ethnomedicinal plant Cryptolepis sanguinolenta (Lindl.) Schltr. (Apocynaceae) have yielded only a small number of rare naturally occurring indoloquinoline alkaloids. Our recent work has resulted in the isolation of a new indoloquinoline named 3-hydroxyneocryptolepine, which was obtained from an ethanolic extract of the roots. The structure of the compound was elucidated based on 1D and 2D NMR as well as HRESIMS spectral evidence. LDL uptake promotion activity of the compound in HepG2 cells was not significant.

Real-world effectiveness and safety of macitentan in patients with pulmonary artery hypertension: a multicenter, retrospective, observational study in China.

Background: Macitentan, either as monotherapy or part of combination therapy, improved clinical outcomes in patients with pulmonary artery hypertension (PAH) in clinical trials. Evidence on the effectiveness and safety of macitentan administered in real-world clinical practice in China is limited. Methods: This real-world, retrospective, multicenter chart review study was conducted at seven hospitals in China. Adult patients with a diagnosis of PAH who initiated macitentan and had medical assessments at 3-7 months after macitentan initiation were included. The primary outcomes were changes in the World Health Organization functional class (WHO-FC), 6-minute walk distance (6MWD), and N-terminal pro-B-type natriuretic peptide/B-type natriuretic peptide (NT-proBNP/BNP) from baseline to first follow-up visit (months 3-7). Serious adverse events (SAEs) and adverse drug reactions (ADRs) of macitentan were collected. Results: From 30 August 2021 to 31 March 2022, 214 eligible patients were included in the safety analysis set and 105 patients were included in the analysis of effectiveness. At the first follow-up visit compared with baseline, significant changes in WHO-FC were observed (p = .04), 93.5% patients had their WHO-FC improved (25.8%) or maintained (67.7%). 6MWD changed by a mean (standard deviation [SD]) of 45.0 (81.4) meters (p < .001), with 94.7% having their 6MWD improved (34.7%) or maintained (60.0%). The mean (SD) of NT-proBNP decreased from 1667.4 (3233.0) ng/L to 1090.0 (2230.1) ng/L (p < .001). In the safety analysis set, 24 (11.2%) patients experienced at least one ADR and/or SAE. ADRs and SAEs were reported in 11 (5.1%) and 18 (8.4%), respectively. No deaths or unexpected safety events were observed. Conclusion: This study provided real-world evidence on the clinical benefits and good tolerance of macitentan in Chinese patients with PAH treated in routine clinical practice.

Isolation of a methyl-reducing methanogen outside the Euryarchaeota.

Methanogenic archaea are main contributors to methane emissions, and have a crucial role in carbon cycling and global warming. Until recently, methanogens were confined to Euryarchaeota, but metagenomic studies revealed the presence of genes encoding the methyl coenzyme M reductase complex in other archaeal clades1-4, thereby opening up the premise that methanogenesis is taxonomically more widespread. Nevertheless, laboratory cultivation of these non-euryarchaeal methanogens was lacking to corroborate their potential methanogenic ability and physiology. Here we report the isolation of a thermophilic archaeon LWZ-6 from an oil field. This archaeon belongs to the class Methanosuratincolia (originally affiliated with 'Candidatus Verstraetearchaeota') in the phylum Thermoproteota. Methanosuratincola petrocarbonis LWZ-6 is a strict hydrogen-dependent methylotrophic methanogen. Although previous metagenomic studies speculated on the fermentative potential of Methanosuratincolia members, strain LWZ-6 does not ferment sugars, peptides or amino acids. Its energy metabolism is linked only to methanogenesis, with methanol and monomethylamine as electron acceptors and hydrogen as an electron donor. Comparative (meta)genome analysis confirmed that hydrogen-dependent methylotrophic methanogenesis is a widespread trait among Methanosuratincolia. Our findings confirm that the diversity of methanogens expands beyond the classical Euryarchaeota and imply the importance of hydrogen-dependent methylotrophic methanogenesis in global methane emissions and carbon cycle.

AutoDock and molecular dynamics-based therapeutic potential prediction of flavonoids for primary Sjögren's syndrome.

Primary Sjögren's Syndrome (pSS) is a systemic autoimmune disease that leads to reduced saliva production, primarily affecting women due to estrogen deficiency. The estrogen receptor α (ERα) plays a crucial role in mediating the expression of the aquaporin 5 (AQP5) gene through the estrogen response element-dependent signaling pathway, making ERα a key drug target for pSS. Several flavonoids have been reported to have the potential to treat pSS. This study aimed to screen and compare flavonoids binding to ERα using AutoDock, providing a basis for treating pSS with flavonoids. The estrogenic potential of six representative flavonoids was examined in this study. Molecular docking revealed that the binding energy of all six flavonoids to ERα was less than -5.6 kcal/mol. Apigenin, naringenin, and daidzein were the top three flavonoids with even lower binding energies of -7.8, -8.09, and -8.59 kcal/mol, respectively. Similar to the positive control estradiol, apigenin, naringenin, and daidzein showed hydrogen bond interactions with GLU353, GLY521, and HIS524 at the active site. The results of luciferase reporter assays demonstrated that apigenin, naringenin, and daidzein significantly enhanced the transcription of estrogen receptor element (ERE) in the PGL3/AQP5 promoter. Furthermore, molecular dynamics simulations using GROMACS for a time scale of 100 ns revealed relatively stable binding of apigenin-ERα, naringenin-ERα, and daidzein-ERα. Mechanistically, homology modeling indicated that GLU353, GLY521, and HIS524 were the key residues of ERα exerting an estrogenic effect. The therapeutic effect of apigenin on dry mouth in pSS models was further validated. In conclusion, these results indicate the estrogenic and pSS therapeutic potential of apigenin, naringenin, and daidzein.

Benzo(a)pyrene promotes the malignant progression of malignant-transformed BEAS-2B cells by regulating YTH N6-methyladenosine RNA binding protein 1 to inhibit ferroptosis.

Benzo[a]pyrene (BaP) is associated with the development of lung cancer, but the underlying mechanism has not been completely clarified. Here, we used 10 µM BaP to induce malignant transformation of human bronchial epithelial BEAS-2B cells, named BEAS-2B-T. Results indicated that BaP (6.25, 12.5 and 25 µM) treatment significantly promoted the migration and invasion of BEAS-2B-T cells. Meanwhile, BaP exposure inhibited ferroptosis in BEAS-2B-T, ferroptosis-related indexes Fe2+, malondialdehyde (MDA), lipid peroxidation (LPO) and reactive oxygen species (ROS) decreased significantly. The protein level of ferroptosis-related molecule transferrin receptor (TFRC) decreased significantly, while solute carrier family 7 membrane 11 (SLC7A11), ferritin heavy chain 1 (FTH1) and glutathione peroxidase 4 (GPX4) increased significantly. The intervention of ferroptosis dramatically effected the migration and invasion of BEAS-2B-T induced by BaP. Furthermore, the expression of YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) was markedly increased after BaP exposure. YTHDF1 knockdown inhibited BEAS-2B-T migration and invasion by promoting ferroptosis. In the meantime, the contents of Fe2+, MDA, LPO and ROS increased significantly, TFRC was markedly increased, and SLC7A11, FTH1, and GPX4 were markedly decreased. Moreover, overexpression of YTHDF1 promoted BEAS-2B-T migration and invasion by inhibiting ferroptosis. Importantly, knockdown of YTHDF1 promoted ferroptosis and reduced BEAS-2B-T migration and invasion during BaP exposure, and overexpression of YTHDF1 increased migration and invasion of BEAS-2B-T by inhibiting ferroptosis during BaP exposure. RNA immunoprecipitation assays indicated that the binding of YTHDF1 to SLC7A11 and FTH1 markedly increased after YTHDF1 overexpression. Therefore, we concluded that BaP promotes the malignant progression of BEAS-2B-T cells through YTHDF1 upregulating SLC7A11 and FTH1 to inhibit ferroptosis. This study reveals new epigenetic and ferroptosis markers for preventing and treating lung cancer induced by environmental carcinogens.

FTO mediates bisphenol F-induced blood-testis barrier impairment through regulating ferroptosis via YTHDF1/TfRc and YTHDF2/SLC7A11 signal axis.

Bisphenol F (BPF) has been extensively utilized in daily life, which brings new hazards to male reproductive health. However, the specific functional mechanism is still unclear. Both cell and animal models were utilized for exploring the role of RNA methylation and ferroptosis and its underlying mechanisms in male reproductive injury induced by BPF. In animal model, BPF severely destroyed the integrity of the blood-testis barrier (BTB) and induced ferroptosis. Furthermore, BPF significantly affected the barrier function of TM4 cells and promoted ferroptosis. Importantly, ChIP assays revealed that BPF inhibited AR transcriptional regulation of FTO and FTO expression was downregulated in TM4 cells. Overexpression of FTO prevented the impairment of BTB by inhibiting ferroptosis in TM4 cells. Mechanistically, FTO could significantly down-regulate the m6A modification level of TfRc and SLC7A11 mRNA through MeRIP experiment. RIP experiments showed that YTHDF1 can bind to TfRc mRNA and promote its translation while YTHDF2 could bind to SLC7A11 mRNA and reduce its mRNA stability. Therefore, our results suggest that FTO plays a key role in BPF induced male reproductive toxicity through YTHDF1-TfRc axis and YTHDF2-SLC7A11 axis and may provide new ideas and methods for the prevention and treatment of male reproductive diseases associated with environmental pollutants.

Sesquiterpene lactones from Tithonia diversifolia with ferroptosis-inducing activities.

Eight previously undescribed sesquiterpene lactones (1-8), together with six known ones (9-14) were isolated from the aerial parts of Tithonia diversifolia (Hemsl.) A. Gray. The absolute configurations of these compounds were elucidated using HRMS, NMR spectroscopy, optical rotation measurements, X-ray crystallography, and ECD. Among them, sesquiterpene lactones 2-4 share a unique carbon skeleton with a rare C-3/C-4 ring-opened structure. Compounds 1 and 8 showed moderate inhibitory effects toward CT26 murine colon carcinoma cells by promoting lipid ROS production, highlighting their potential as ferroptosis inducers.

Welded Gold Nanoparticle Assemblies Defined Plasmonic Coupling.

Nanoparticle assemblies with interparticle ohmic contacts are crucial for nanodevice fabrication. Despite tremendous progress in DNA-programmable nanoparticle assemblies, seamlessly welding discrete components into welded continuous three-dimensional (3D) configurations remains challenging. Here, we introduce a single-stranded DNA-encoded strategy to customize welded metal nanostructures with tunable morphologies and plasmonic properties. We demonstrate the precise welding of gold nanoparticle assemblies into continuous metal nanostructures with interparticle ohmic contacts through chemical welding in solution. We find that the welded gold nanoparticle assemblies show a consistent morphology with welded efficiency over 90%, such as the rod-like, triangular, and tetrahedral metal nanostructures. Next, we show the versatility of this strategy by welding gold nanoparticle assemblies of varied sizes and shapes. Furthermore, the experiment and simulation show that the welded gold nanoparticle assemblies exhibit defined plasmonic coupling. This single-stranded DNA encoded welding system may provide a new route for accurately building functional plasmonic nanomaterials and devices.

Association patterns of ketone bodies with the risk of adverse outcomes according to diabetes status.

AIM: To investigate the associations between ketone bodies (KB) and multiple adverse outcomes including cardiovascular disease (CVD), chronic kidney disease (CKD) and all-cause mortality according to diabetes status. METHODS: This prospective study included 222 824 participants free from CVD and CKD at baseline from the UK Biobank. Total KB including ß-hydroxybutyrate, acetoacetate and acetone were measured by nuclear magnetic resonance. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between KB and adverse outcomes among participants with normoglycaemia, prediabetes and type 2 diabetes, respectively. RESULTS: During a mean follow-up of 14.1 years, 24 088 incident CVD events (including 17 303 coronary heart disease events, 5172 stroke events and 5881 heart failure [HF] events), 8605 CKD events and 15 813 deaths, were documented. Higher total KB significantly increased the risk of HF among participants with normoglycaemia (HR, 1.32 [95% CI, 1.17-1.49], per 10-fold increase in total KB) and prediabetes (1.35 [1.04-1.76]), and increased the risk of CKD among those with normoglycaemia (1.20 [1.09-1.33]). Elevated KB levels were associated with an increased risk of all-cause mortality across the glycaemic spectrum (1.32 [1.23-1.42] for normoglycaemia, 1.45 [1.24-1.71] for prediabetes and 1.47 [1.11-1.94] for diabetes). Moreover, a significant additive interaction between KB and diabetes status was observed on the risk of death (P = .009), with 4.9% of deaths attributed to the interactive effects. CONCLUSIONS: Our study underscored the variation in association patterns between KB and adverse outcomes according to diabetes status and suggested that KB could interact with diabetes status in an additive manner to increase the risk of mortality.

Ultrafast Super-Resolution Imaging Exploiting Spontaneous Blinking of Static Excimer Aggregates.

Single-molecule localization methods have been popularly exploited to obtain super-resolved images of biological structures. However, the low blinking frequency of randomly switching emission states of individual fluorophores greatly limits the imaging speed of single-molecule localization microscopy (SMLM). Here we present an ultrafast SMLM technique exploiting spontaneous fluorescence blinking of cyanine dye aggregates confined to DNA framework nanostructures. The DNA template guides the formation of static excimer aggregates as a "light-harvesting nanoantenna", whereas intermolecular excitation energy transfer (EET) between static excimers causes collective ultrafast fluorescence blinking of fluorophore aggregates. This DNA framework-based strategy enables the imaging of DNA nanostructures with 12.5-fold improvement in speed compared to conventional SMLM. Further, we demonstrate the use of this strategy to track the movement of super-resolved DNA nanostructures for over 20 min in a microfluidic system. Thus, this ultrafast SMLM holds great potential for revealing the dynamic processes of biomacromolecules in living cells.

Characterization and analysis of dynamic changes of microbial community associated with grape decay during storage.

The rot caused by pathogens during the storage of table grapes is an important factor that affects the development of the grape industry and food safety, and it cannot be ignored. The development of innovative methods for pathogen control should be based on a comprehensive understanding of the overall microbial community changes that occur during grape storage. The study aims to investigate the relationship between the native microbiota (including beneficial, pathogenic and spoilage microorganisms) on grape surfaces and the development of disease during grape storage. In this study, the bacteria and fungi present on grape surfaces were analyzed during storage under room temperature conditions using high-throughput sequencing. During the storage of grapes at room temperature, observable diseases and a noticeable decrease in quality were observed at 8 days. Microbial community analysis showed that 4996 bacterial amplicon sequence variants (ASVs) and 488 fungal ASVs were determined. The bacterial richness exhibited an initial increase followed by a subsequent decrease. However, the diversity exhibited a distinct pattern of gradual decrease. The fungal richness and community diversity both exhibit a gradual decrease during the storage of grapes. Fungal ß-diversity analysis showed that despite the absence of rot and the healthy state of grapes on the first and fourth days, the fungal ß-diversity exhibited a significant difference. The analysis of changes in genera abundances suggested that Candidatus Profftella and Aspergillus exhibited dominance in the rotting grape at 16 days, which are the main pathogens that caused disease in the present study. The co-occurrence networks among the microbial showed that the Candidatus proftella genera has a positive correlation with Aspergillus niger, indicating that they work together to cause disease and promote growth in grapes. Predicting the function of bacterial communities found that the microorganisms associated with lipid metabolism at 4 days play an important role in the process of postharvest decay of grapes.

Decoding ecosystem heterogeneity and transcriptional regulation characteristics of multi-subtype renal cell carcinoma.

Background: Renal cell carcinoma (RCC) is characterized by its heterogeneity and the complexity of its tumor microenvironment. This study addresses the need to understand RCC at a cellular level, with a focus on its three main subtypes: clear cell (ccRCC), chromophobe (chRCC), and papillary renal cell carcinoma (pRCC). Objective: This study aims to comprehensively characterize the cellular diversity and intercellular communication networks of RCC subtypes using scRNA-seq technology. By focusing on macrophages and cancer-associated fibroblasts (CAFs), we seek to reveal their functional states, developmental trajectories, and signaling pathways. Methodology: We utilized single-cell RNA sequencing (scRNA-seq) data from various kidney cancer subtypes. Advanced analytical techniques, including Uniform Manifold Approximation and Projection (UMAP) and Reactome Gene Set Variation Analysis (ReactomeGSA), were employed to assess cellular heterogeneity and pathway activities. The developmental dynamics of macrophages were studied using CytoTRACE, and cell-to-cell communication was analyzed to identify subtype-specific interaction networks. Results: Our comprehensive analysis revealed significant cellular diversity within RCC. Distinct macrophage and CAF subpopulations were identified, each exhibiting unique gene expression profiles and pathway activities. Notably, ccRCC showed prominent bidirectional communication between macrophages and CAFs, while chRCC and pRCC displayed disrupted signaling pathways. Metabolic pathway analysis reflected the adaptability of macrophages and CAFs to the tumor microenvironment, and the MIF signaling pathway was identified as a key mediator of cellular interactions. Conclusion: The study highlights the cellular heterogeneity and the intricate communication networks within RCC subtypes, underscoring the complexity of the tumor microenvironment. Our findings suggest that targeting specific cellular interactions and pathways may offer new avenues for therapeutic intervention in RCC. The unique macrophage and CAF profiles across RCC subtypes provide valuable insights for the development of personalized and targeted treatment strategies.

[Sivelestat sodium inhibits neutrophil elastase to regulate intrahepatic biliary mucin 5AC expression].

OBJECTIVE: To explore whether sivelestat sodium could reduce the expression of mucin 5AC (MUC5AC) in intrahepatic bile duct epithelial cells by inhibiting neutrophil elastase (NE) and thus provide new potential therapeutic ideas for the treatment of intrahepatic bile duct stone (IBDS). METHODS: (1) Bioinformatics analysis: differential gene analysis was performed on gallbladder stone cholecystitis sequencing data based on the gene expression omnibus (GEO) to screen for significantly different genes related to neutrophils and mucins. The search tool for the retrieval of interacting genes database (STRING) was used for protein interaction analysis to predict whether there was an interaction between NE and MUC5AC genes. (2) Animal experiment: a total of 18 male SD rats were divided into the sham-operated group, cholangitis model group and sivelestat sodium treatment group according to the random number table method, with 6 rats in each group. The cholangitis rat model was established by a one-time injection of 1.25 mg/kg lipopolysaccharide (LPS) into the right anterior lobe of the liver of rats in combination with the pre-experiment; the liver of the sham-operated group was injected with an equal volume of saline. After the modelling, 100 mg/kg of sivelestat sodium was injected into the tail vein of the cevalexin treatment group once a day for 5 days, and an equal volume of saline was injected into the tail vein of the sham-operated group and the cholangitis model group. Two weeks later, the rats were euthanized and their liver and bile duct tissues were taken. The pathological changes in the liver and bile duct tissues were observed under the light microscope. Immunohistochemical staining was used to detect the expressions of NE and MUC5AC in liver and bile duct tissues. The protein expressions of NE, MUC5AC and Toll-like receptor 4 (TLR4) were detected by Western blotting. (3) Cell experiment: primary human intrahepatic biliary epithelial cell line (HiBEpiC) was divided into blank control group, NE group (10 nmol/L NE), NE+sivelestat sodium low dose group (10 nmol/L NE+1×10-8 g/L sivelestat sodium 1 mL), NE+sivelestat sodium medium dose group (10 nmol/L NE+1×10-7 g/L sivelestat sodium 1 mL), NE+sivelestat sodium high dose group (10 nmol/L NE+1×10-6 g/L sivelestat sodium 1 mL). Cells were collected after 48 hours of culture, and EdU was performed to detect the proliferative activity of cells; enzyme linked immunosorbent assay (ELISA) and Western blotting were performed to detect the expression of MUC5AC in cells. RESULTS: (1) Bioinformatics analysis: the NE gene (ELANE) had a reciprocal relationship with MUC5AC. (2) Animal experiment: light microscopy showed that hepatocyte edema, hepatocyte diffuse point and focal necrosis, confluent area fibrous tissue and intrahepatic bile ducts hyperplasia and inflammatory cell infiltration in the cholangitis model group; hepatic lobule structure of sivelestat sodium treatment group was clear, and the degree of peripheral inflammatory cell infiltration was reduced compared with the cholangitis model group. Immunohistochemical staining showed that the expressions of NE and MUC5AC were increased in the cholangitis model group compared with the sham-operated group, and the expressions of NE and MUC5AC were decreased in the sivelestat sodium group compared with the cholangitis model group [NE (A value): 5.23±2.02 vs. 116.67±23.06, MUC5AC (A value): 5.40±3.09 vs. 23.81±7.09, both P < 0.05]. Western blotting showed that the protein expressions of NE, MUC5AC, and TLR4 in the hepatic biliary tissues of the cholangitis model group were significantly higher than those of the sham-operated group; and the protein expressions of NE, MUC5AC, and TLR4 in the liver biliary tissues of the sivelestat sodium treatment group were significantly higher than those of the sham-operated group (NE/ß-actin: 0.38±0.04 vs. 0.70±0.10, MUC5AC/ß-actin: 0.37±0.03 vs. 0.61±0.05, TLR4/ß-actin: 0.39±0.10 vs. 0.93±0.15, all P < 0.05). (3) Cell experiment: fluorescence microscopy showed that the proliferation of HiBEpiC cells in each group was good, and there was no significant difference in the proportion of positive cells. ELISA and Western blotting showed that the expressions of MUC5AC in cells of the NE group were significantly higher than those of the blank control group. The expressions of MUC5AC in the NE+different dose of sivelestat sodium group were significantly lower than those in the NE group, and showed a decreasing trend with the increase of sevastatin sodium concentration, especially in the highest dose group [MUC5AC (µg/L): 3.46±0.20 vs. 6.33±0.52, MUC5AC/ß-actin: 0.45±0.07 vs. 1.75±0.10, both P < 0.05]. CONCLUSIONS: LPS can upregulate the expression of NE and MUC5AC in rats with cholangitis, while sodium sivelestat can reduce the expression of MUC5AC in in intrahepatic biliary epithelial cells by inhibiting NE, providing a new direction for the treatment of IBDS.

Microbial community structure in an uranium-rich acid mine drainage site: implication for the biogeochemical release of uranium.

The generation of acid mine drainage (AMD) characterized by high acidity and elevated levels of toxic metals primarily results from the oxidation and dissolution of sulfide minerals facilitated by microbial catalysis. Although there has been significant research on microbial diversity and community composition in AMD, as well as the relationship between microbes and heavy metals, there remains a gap in understanding the microbial community structure in uranium-enriched AMD sites. In this paper, water samples with varying levels of uranium pollution were collected from an abandoned stone coal mine in Jiangxi Province, China during summer and winter, respectively. Geochemical and high-throughput sequencing analyses were conducted to characterize spatiotemporal variations in bacterial diversity and community composition along pollution groups. The results indicated that uranium was predominantly concentrated in the AMD of new pits with strong acid production capacity, reaching a peak concentration of 9,370 µg/L. This was accompanied by elevated acidity and concentrations of iron and total phosphorus, which were identified as significant drivers shaping the composition of bacterial communities, rather than fluctuations in seasonal conditions. In an extremely polluted environment (pH < 3), bacterial diversity was lowest, with a predominant presence of acidophilic iron-oxidizing bacteria (such as Ferrovum), and a portion of acidophilic heterotrophic bacteria synergistically coexisting. As pollution levels decreased, the microbial community gradually evolved to cohabitation of various pH-neutral heterotrophic species, ultimately reverting back to background level. The pH was the dominant factor determining biogeochemical release of uranium in AMD. Acidophilic and uranium-tolerant bacteria, including Ferrovum, Leptospirillum, Acidiphilium, and Metallibacterium, were identified as playing key roles in this process through mechanisms such as enhancing acid production rate and facilitating organic matter biodegradation.

Characteristics and clinical significance of tertiary lymphoid structures in OSCC.

OBJECTIVES: This study aimed to investigate the characteristics of tertiary lymphoid structures (TLSs) in oral squamous cell carcinoma (OSCC) and their association with clinical and pathological features. MATERIALS AND METHODS: 12 TLS-related chemokines in TCGA database were analyzed to investigate the TLSs in OSCC. The density, maturity, and location of TLSs in a large cohort of 189 OSCC patients (114 of which had clinical and prognostic information) were assessed. And the significance between TLSs and clinicopathologic characteristics was analyzed. RESULTS: Bioinformatics and analysis showed that TLSs were associated with better clinical outcomes in OSCC. Histological staining and analysis showed that the overall survival rate of the high-density group (71/112, 63.4%) was significantly higher (p < 0.0001) than that of the low-density group (41/112, 36.6%), and the high-density group had fewer lymph node metastases (50.0%/68.3%, p = 0.021). And TLSs were divided into 4 types according to the maturity and location. Different types of TLSs are associated with prognosis (OS, p < 0.0001), clinical features (T stage, p = 0.028; degree of differentiation, p = 0.043), and precancerous lesion types (OSF, p = 0.049) of OSCC patients. CONCLUSION: TLSs were closely associated with better OSCC prognosis, and a more systematic classification may better guide the formulation of further treatment options.

Aptamer-Modified Nb2C Multifunctional Nanomedicine for Targeted Photothermal/Chemotherapy Combined Therapy of Tumor.

The poor delivery efficiency of nanotherapeutic drugs and their potential off-target toxicity significantly limit their effectiveness and extensive application. An active targeting system with high efficiency and few side effects is a promising strategy for tumor therapy. Herein, a multifunctional nanomedicine Nb2C-PAA-DOX@Apt-M (NDA-M) was constructed for targeted photothermal/chemotherapy (PTT/CHT) combined tumor therapy. The specific targeting ability of aptamer could effectively enhance the absorption of nanomedicine by the MCF-7 cell. By employing Apt-M, the NDA-M nanosheets demonstrated targeted delivery to MCF-7 cells, resulting in enhanced intracellular drug concentration. Under 1060 nm laser irradiation, a rapid temperature increase of the NDA-M was observed within the tumor region to achieve PTT. Meanwhile, CHT was triggered when DOX release was induced by photothermal/acid stimulation. The experimental results demonstrated that aptamer-mediated targeting achieved enhanced PTT/CHT efficacy both in vitro and in vivo. Notably, NDA-M induced complete ablation of solid tumors without any adverse side effects in mice. This study demonstrated new and promising tactics for the development of nanomaterials for targeted tumor therapy.

Tenecteplase versus alteplase before stroke thrombectomy: outcomes after system-wide transitions in Pennsylvania.

INTRODUCTION: United States stroke systems are increasingly transitioning from alteplase (TPA) to tenecteplase (TNK). Real-world data on the safety and effectiveness of replacing TPA with TNK before large vessel occlusion (LVO) stroke endovascular treatment (EVT) are lacking. METHODS: Four Pennsylvania stroke systems transitioned from TPA to TNK during the study period 01/2020-06/2023. LVO stroke patients who received intravenous thrombolysis with TPA or TNK before EVT were reviewed. Multivariate logistic analysis was conducted adjusting for age, sex, National Institute of Health Stroke Scale (NIHSS), occlusion site, last-known-well-to-intravenous thrombolysis time, interhospital-transfer and stroke system. RESULTS: Of 635 patients, 309 (48.7%) received TNK and 326 (51.3%) TPA prior to EVT. The site of occlusion was the M1 middle cerebral artery (MCA) (47.7%), M2 MCA (25.4%), internal carotid artery (14.0%), tandem carotid with M1 or M2 MCA (9.8%) and basilar artery (3.1%). A favorable functional outcome (90-day mRS ≤ 2) was observed in 47.6% of TNK and 49.7% of TPA patients (p = 0.132). TNK versus TPA groups had similar rates of early recanalization (11.9% vs. 8.4%, p = 0.259), successful endovascular reperfusion (93.5% vs. 89.3%, p = 0.627), symptomatic intracranial hemorrhage (3.2% vs. 3.4%, p = 0.218) and 90-day all-cause mortality (23.1% vs. 21.5%, p = 0.491). CONCLUSIONS: This U.S. multicenter real-world clinical experience demonstrated that switching from TPA to TNK before EVT for LVO stroke resulted in similar endovascular reperfusion, safety, and functional outcomes.

Multiple stochastic and inverse stochastic resonances with transition phenomena in complex corporate financial systems.

This study examines the role of periodic information, the mechanism of influence, stochastic resonance, and its controllable analysis in complex corporate financial systems. A stochastic predator-prey complex corporate financial system model driven by periodic information is proposed. Additionally, we introduce signal power amplification to quantify the stochastic resonance phenomenon and develop a method for analyzing stochastic resonance in financial predator-prey dynamics within complex corporate financial systems. We optimize a simplified integral calculation method to enhance the proposed model's performance, which demonstrates superiority over benchmark models based on empirical evidence. Based on stochastic simulations and numerical calculations, we can observe multiple stochastic and multiple inverse stochastic resonances. Furthermore, variations in initial financial information, periodic information frequency, and corporate growth capacity induced stochastic resonance and inverse stochastic resonance. These variations also led to state transitions between the two resonance behaviors, indicating transition phenomena. These findings suggest the potential for regulating and controlling stochastic and inverse stochastic resonance in complex corporate finance, enabling controllable stochastic resonance behaviors.

Noise induces intercellular Ca 2+ signaling waves and the unfolded protein response in the hearing cochlea.

Exposure to loud noise is a common cause of acquired hearing loss. Disruption of subcellular calcium homeostasis and downstream stress pathways in the endoplasmic reticulum and mitochondria, including the unfolded protein response, have been implicated in the pathophysiology of noise-induced hearing loss. However, studies on the association between calcium homeostasis and stress pathways has been limited due to limited ability to measure calcium dynamics in mature-hearing, noise-exposed mice. We used a genetically encoded calcium indicator mouse model in which GcAMP is expressed specifically in hair cells or supporting cells under control of Myo15Cre or Sox2Cre, respectively. We performed live calcium imaging and UPR gene expression analysis in 8-week-old mice exposed to levels of noise that cause cochlear synaptopathy (98 db SPL) or permanent hearing loss (106 dB SPL). UPR activation occurred immediately after noise exposure and was noise dose-dependent, with the pro-apoptotic pathway upregulated only after 106 dB noise exposure. Spontaneous calcium transients in hair cells and intercellular calcium waves in supporting cells, which are present in neonatal cochleae, were quiescent in mature-hearing cochleae, but re-activated upon noise exposure. 106 dB noise exposure was associated with more persistent and expansive ICS wave activity. These findings demonstrate a strong and dose-dependent association between noise exposure, UPR activation, and changes in calcium homeostasis in hair cells and supporting cells, suggesting that targeting these pathways may be effective to develop treatments for noise-induced hearing loss.