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The enhancement of saltiness induced by odrants perceived from the retronasal cavity during Larou oral processing was analyzed. During the oral processing of Xiangtan Larou, the smoky attribute was the dominant when chewing 0-15 times, followed by the savory (15-24 times) and meaty (24-42 times). Partial least squares analysis predicted 33 aroma compounds from the retronasal cavity significantly (p < 0.05) contributing to the aroma perception. A total of 12 aroma compounds with saltiness-enhancement ability were confirmed by odorant-NaCl mixture model experiments. Results revealed that 2-methoxy-4-vinylphenol (1.00-1000.00 µg/L) had the strongest enhancing effect on saltiness at NaCl (2969.85 mg/L), followed by diallyl sulfide (0.156-2.50 µg/L), 2,5-dimethylthiophene (0.156-50.00 µg/L), 2,6-dimethylphenol (1.00-100.00 µg/L), 2,5-dimethylpyrazine (0.391-50.00 µg/L), and 2,3-butanedione (0.50-100.0 µg/L). The sulfur-containing, nitrogen-containing, and phenolic odorants with savory, roasty, sulfide, meaty or smoky, attributes showed the better ability in saltiness enhancement.

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The COVID-19 pandemic has driven substantial evolution of the SARS-CoV-2 virus, yielding subvariants that exhibit enhanced infectiousness in humans. However, this adaptive advantage may not universally extend to zoonotic transmission. In this work, we hypothesize that viral adaptations favoring animal hosts do not necessarily correlate with increased human infectivity. In addition, we consider the potential for gain-of-function mutations that could facilitate the virus's rapid evolution in humans following adaptation in animal hosts. Specifically, we identify the SARS-CoV-2 receptor-binding domain (RBD) mutations that enhance human-animal cross-transmission. To this end, we construct a multitask deep learning model, MT-TopLap trained on multiple deep mutational scanning datasets, to accurately predict the binding free energy changes upon mutation for the RBD to ACE2 of various species, including humans, cats, bats, deer, and hamsters. By analyzing these changes, we identified key RBD mutations such as Q498H in SARS-CoV-2 and R493K in the BA.2 variant that are likely to increase the potential for human-animal cross-transmission.

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PURPOSE: Multiple myeloma (MM) is characterized by the uncontrolled proliferation of monoclonal plasma cells (PC) in the bone marrow (BM). B-cell maturation antigen (BCMA) is predominantly expressed in malignant plasma cells, and associated with the proliferation, survival, and progression of various myeloma cells. Given these important roles, BCMA emerges as an ideal target antigen for MM therapy. However, effective stratification of patients who may benefit from targeted BCMA therapy and real-time monitoring the therapeutic efficacy poses significant clinical challenge. This study aims to develop a BCMA targeted diagnostic modality, and preliminarily explore its potential value in the radio-immunotherapy of MM. EXPERIMENTAL DESIGN: Using zirconium-89 (89Zr, t1/2 = 78.4 h) for labeling the BCMA-specific antibody, the BCMA-targeting PET tracer [89Zr]Zr-DFO-BCMAh230430 was prepared. The EC50 values of BCMAh230430 and DFO-BCMAh230430 were determined by ELISA assay. BCMA expression was assessed in four different tumor cell lines (MM.1S, RPMI 8226, BxPC-3, and KYSE520) through Western blot and flow cytometry. In vitro binding affinity was determined by cell uptake studies of [89Zr]Zr-DFO-BCMAh230430 in these tumor cell lines. For in vivo evaluation, PET imaging and ex vivo biodistribution studies were conducted in tumor-bearing mice to evaluate imaging performance and systemic distribution of [89Zr]Zr-DFO-BCMAh230430. Immunochemistry analysis was performed to detect BCMA expression in tumor tissues, confirming the specificity of our probe. Furthermore, we explored the anti-tumor efficacy of Lutetium-177 labeled BCMA antibody, [177Lu]Lu-DTPA-BCMAh230430, in tumor bearing-mice to validate its radioimmunotherapy potential. RESULTS: The radiolabeling of [89Zr]Zr-DFO-BCMAh230430 and [177Lu]Lu-DTPA-BCMAh230430 showed satisfactory radiocharacteristics, with a radiochemical purity exceeding 99%. ELISA assay results revealed closely aligned EC50 values for BCMAh230430 and DFO-BCMAh230430, which are 57 pM and 67 pM, respectively. Western blot and flow cytometry analyses confirmed the highest BCMA expression level. Cell uptake data indicated that MM.1S cells had a total cellular uptake (the sum of internalization and surface binding) of 38.3% ± 1.53% for [89Zr]Zr-DFO-BCMAh230430 at 12 h. PET imaging of [89Zr]Zr-DFO-BCMAh230430 displayed radioactive uptake of 7.71 ± 0.67%ID/g in MM.1S tumors and 4.13 ± 1.21%ID/g in KYSE520 tumors at 168 h post-injection (n = 4) (P < 0.05), consistent with ex vivo biodistribution studies. Immunohistochemical analysis of tumor tissues confirmed higher BCMA expression in MM.1S tumors xenograft compared to KYSE520 tumors. Notably, [177Lu]Lu-DTPA-BCMAh230430 showed some anti-tumor efficacy, evidenced by slowed tumor growth. Furthermore, no significant difference in body weight was observed in MM.1S tumor-bearing mice over 14 days of administration with or without [177Lu]Lu-DTPA-BCMAh230430. CONCLUSIONS: Our study has successfully validated the essential role of [89Zr]Zr-DFO-BCMAh230430 in non-invasively monitoring BCMA status in MM tumors, showing favorable tumor uptake and specific binding affinity to MM tumors. Furthermore, our research revealed, as a proof-of-concept, the effectiveness of [177Lu]Lu-DTPA-BCMAh230430 in radioimmunotherapy for MM tumors. In conclusion, we present a novel BCMA antibody-based radiotheranostic modality that holds promise for achieving efficient and precise MM diagnostic and therapy.

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BACKGROUND AND AIMS: Previous phylogenetic studies on the pharmaceutically significant genus Paris (Melanthiaceae) have consistently revealed substantial cytonuclear discordance, yet the underlying mechanism responsible for this phenomenon remains elusive. This study aims to reconstruct a robust nuclear backbone phylogeny and elucidate the potential evolutionarily complex events contributing to previously observed cytonuclear discordance within Paris. METHODS: Based on a comprehensive set of nuclear low-copy orthologous genes obtained from transcriptomic data, the intrageneric phylogeny of Paris, along with its phylogenetic relationships to allied genera were inferred, using coalescent and concatenated approaches. The analysis of gene tree discordance and reticulate evolution, in conjunction with an incomplete lineage sorting (ILS) simulation, was conducted to explore potential hybridization and ILS events in the evolutionary history of Paris and assess their contribution to the discordance of gene trees. KEY RESULTS: The nuclear phylogeny unequivocally confirmed the monophyly of Paris and its sister relationship with Trillium, while widespread incongruences in gene trees were observed at the majority of internal nodes within Paris. The reticulate evolution analysis identified five instances of hybridization events in Paris, indicating that hybridization events might have recurrently occurred throughout the evolutionary history of Paris. In contrast, the ILS simulations revealed that only two internal nodes within sect. Euthyra experienced ILS events. CONCLUSIONS: Our data suggest that the previously observed cytonuclear discordance in the phylogeny of Paris can primarily be attributed to recurrent hybridization events, with secondary contributions from infrequent ILS events. The recurrent hybridization events in the evolutionary history of Paris not only drove lineage diversification and speciation but also facilitated morphological innovation, and enhanced ecological adaptability. Therefore, artificial hybridization has great potential for breeding medicinal Paris species. These findings significantly contribute to our comprehensive understanding of the evolutionary complexity of this pharmaceutically significant plant lineage, thereby facilitating effective exploration and conservation efforts.

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The increasing demand for high-performance electrode materials in lithium-ion batteries has driven significant attention towards Nb2O5 due to its high working voltage, large theoretical capacity, environmental friendliness, and cost-effectiveness. However, inherent drawbacks such as poor electrical conductivity and sluggish electrochemical reaction kinetics have hindered its lithium storage performance. In this study, we introduced KCa2Nb3O10 into Nb2O5 to form a heterojunction, creating a built-in electric field to enhance the migration and diffusion of Li+, effectively promoting electrochemical reaction kinetics. Under the regulation of the built-in electric field, the charge transfer resistance of the KCa2Nb3O10/Nb2O5 anode decreased by 3.4 times compared to pure Nb2O5, and the Li+ diffusion coefficient improved by two orders of magnitude. Specifically, the KCa2Nb3O10/Nb2O5 anode exhibited a high capacity of 276 mAh g-1 under 1 C, retaining a capacity of 128 mAh g-1 even at 100 C. After 3000 cycles at 25 C, the capacity degradation was only 0.012% per cycle. Through combined theoretical calculations and experimental validation, it was found that the built-in electric field induced by the heterojunction interface contributed to an asymmetric charge distribution, thereby improving the rates of charge and ion migration within the electrode, ultimately enhancing the electrochemical performance of the electrode material. This study provides an effective approach for the rational design of high-performance electrode materials.

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Strategies beyond hormone-related therapy need to be developed to improve prostate cancer mortality. Here, we show that FUBP1 and its methylation were essential for prostate cancer progression, and a competitive peptide interfering with FUBP1 methylation suppressed the development of prostate cancer. FUBP1 accelerated prostate cancer development in various preclinical models. PRMT5-mediated FUBP1 methylation, regulated by BRD4, was crucial for its oncogenic effect and correlated with earlier biochemical recurrence in our patient cohort. Suppressed prostate cancer progression was observed in various genetic mouse models expressing the FUBP1 mutant deficient in PRMT5-mediated methylation. A competitive peptide, which was delivered through nanocomplexes, disrupted the interaction of FUBP1 with PRMT5, blocked FUBP1 methylation, and inhibited prostate cancer development in various preclinical models. Overall, our findings suggest that targeting FUBP1 methylation provides a potential therapeutic strategy for prostate cancer management.

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Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by unpredictable progression and limited therapeutic options. Current diagnosis relies on high resolution computed tomography (HRCT), which may not adequately capture early signs of deterioration. The enzyme autotaxin (ATX) emerges as a prominently expressed extracellular secretory enzyme in the lungs of IPF patients. The objective of this study was to evaluate the effectiveness of 18F-labeled ATX-targeted tracer [18F]ATX-1905, in comparison with [18F]FDG, for early fibrosis diagnosis, disease evolution monitoring, and treatment efficacy assessment in bleomycin-induced pulmonary fibrosis (BPF) models. To assess treatment efficacy, mice were treated with two commonly used drugs for IPF, pirfenidone or nintedanib, from Day 9 to Day 23 postbleomycin administration. Lung tissue assessments encompassed inflammation severity via H&E staining, and Ashcroft scoring via Masson staining, alongside quantification of ATX expression through ELISA. Positron emission tomography (PET) imaging employing [18F]FDG and [18F]ATX-1905 tracked disease progression pre- and post-treatment. The extent of pulmonary fibrosis corresponded to changes in ATX expression levels in the BPF mouse model. Notably, [18F]ATX-1905 exhibited elevated uptake in BPF lungs during the progression of the disease, particularly evident at the early stage (Day 9). This uptake was inhibited by an ATX inhibitor, PF-8380, underscoring the specificity of the radiotracer. Conversely, [18F]FDG uptake, peaking at Day 15, decreased subsequently, likely reflective of diminished inflammation. A 2-week treatment regimen using either pirfenidone or nintedanib resulted in notable reductions of ATX expression levels and fibrosis degrees within lung tissues, based on ELISA and Masson staining, as evidenced by PET imaging with [18F]ATX-1905. [18F]FDG uptake also decreased following the treatment period. Additionally, PET/CT imaging extended to a nonhuman primate (NHP) BPF model. The uptake of [18F]ATX-1905 (SUVmax = 2.2) was significantly higher than that of [18F]FDG (SUVmax = 0.7) in fibrotic lung tissue. Using our novel ATX-specific radiotracer [18F]ATX-1905 and PET/CT imaging, we demonstrated excellent ability in early fibrosis detection, disease monitoring, and treatment assessment within lungs of the BPF mouse models. [18F]ATX-1905 displayed remarkable specificity for ATX expression and high sensitivity for ATX alterations, suggesting its potential for monitoring varying ATX expression in lungs of IPF patients.

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Positron emission tomography (PET) targeting translocator protein 18 kDa (TSPO) can be used for the noninvasive detection of neuroinflammation. Improved in vivo stability of a TSPO tracer is beneficial for minimizing the potential confounding effects of radiometabolites. Deuteration represents an important strategy for improving the pharmacokinetics and stability of existing drug molecules in the plasma. This study developed a novel tracer via the deuteration of [18F]LW223 and evaluated its in vivo stability and specific binding in neuroinflammatory rodent models and nonhuman primate (NHP) brains. Compared with LW223, D2-LW223 exhibited improved binding affinity to TSPO. Compared with [18F]LW223, [18F]D2-LW223 has superior physicochemical properties and favorable brain kinetics, with enhanced metabolic stability and reduced defluorination. Preclinical investigations in rodent models of LPS-induced neuroinflammation and cerebral ischemia revealed specific [18F]D2-LW223 binding to TSPO in regions affected by neuroinflammation. Two-tissue compartment model analyses provided excellent model fits and allowed the quantitative mapping of TSPO across the NHP brain. These results indicate that [18F]D2-LW223 holds significant promise for the precise quantification of TSPO expression in neuroinflammatory pathologies of the brain.

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Molnupiravir (MO) is a pyrimidine nucleoside anti-SARS-CoV-2 drug. MO treatment could cause mild liver injury. However, the underlying mechanism of MO-induced liver injury and the metabolic pathway of MO in vivo are unclear. In this study, metabolomics analysis and molecular biology methods were used to explore these issues. Through metabolomics analysis, it was found that the homeostasis of pyrimidine, purine, lysophosphatidylcholine (LPC), and amino acids in mice was destroyed after MO treatment. A total of 80 changed metabolites were detected. Among these changed metabolites, 4-ethylphenyl sulfate, dihydrouracil, and LPC 20:0 was related to the elevation of alkaline phosphatase (ALP), interleukin-6 (IL6), and nuclear factor kappa-B (NF-κB). The levels of 4-ethylphenyl sulfate, dihydrouracil, and LPC 20:0 in plasma were positively correlated with their levels in the liver, suggesting that these metabolites were associated with MO-induced liver injury. MO treatment could increase NHC and cytidine levels, activate cytidine deaminase (CDA), and increase LPC levels. CDA and LPC could increase the mRNA expression level of toll-like receptor (TLR). The current study indicated that the elevation of hepatic TLR may be an important reason for MO leading to the liver injury.

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The metabotropic glutamate receptor 2 (mGluR2) has emerged as a potential therapeutic target for the treatment of various neurological diseases, prompting substantial interest in the development of mGluR2-targeted drug candidates. As part of our medicinal chemistry program, we synthesized a series of isoindolone derivatives and assessed their potential as mGluR2 positive allosteric modulators (PAMs). Notably, AZ12559322 exhibited high affinity (K i mGluR2 = 1.31 nM) and an excellent in vitro binding specificity of 89% while demonstrating selectivity over other mGluR subtypes (>4000-fold). Autoradiography with the radiolabeled counterpart, [3H]AZ12559322, revealed a heterogeneous accumulation with the highest binding in mGluR2-rich brain regions. Radioligand binding was significantly reduced by pretreatment with nonradioactive mGluR2 PAMs in brains of rats and nonhuman primates. Although positron emission tomography imaging of [11C]AZ12559322 (6a) revealed low brain uptake in a nonhuman primate, this study provides valuable guidance to further design novel isoindolone-based mGluR2 PAMs with improved brain exposure.

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The Shitou goose, the largest meat-type goose breed, is an ideal model for offering insights into enhancing meat production efficiency through understanding its genetic regulation of muscle development. Here, through whole-transcriptomic analysis of embryonic leg muscles, we identified 847 differentially expressed genes (DEG), 244 differentially expressed lncRNAs (DEL), 37 differentially expressed circRNAs (DEC), and 84 differentially expressed miRNAs (DEM). Gene ontology (GO) analysis highlighted the significant enrichment of differentially expressed RNAs in muscle structure development, actin filament-based processes, and the actin cytoskeleton pathway. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis identified pathways associated with the FoxO signaling pathway, AMPK signaling pathway, Wnt signaling pathway and calcium signaling pathway. Furthermore, we utilized Miranda, TargetScan, and miRDB to identify regulatory networks that involve interactions between lncRNA-mRNA, circRNA-mRNA, miRNA-mRNA, lncRNA-miRNA-mRNA, and circRNA-miRNA-mRNA, which regulated the growth and development of skeletal muscle. Notably, differentially expressed genes within the ceRNA network were most significantly enriched in the regulation of actin cytoskeletal organization. Additionally, a lncRNA/circRNA-miRNA-mRNA ceRNA network related to muscle growth and development was constructed based on protein-protein interaction (PPI) analysis and hub genes selection using Cytoscape. This further elucidated the regulatory roles of noncoding RNAs (ncRNA) in the formation of muscle fibers in Shitou goose. In summary, this study provides a valuable transcriptional regulatory network for goose muscle development laying the groundwork for further exploration of the molecular regulatory mechanisms underlying the excellent meat production performance of Shitou goose.

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The Coptidis Rhizoma and Bovis Calculus herb pair possesses clearing heat and detoxifying effects. The aim of this study was to reveal the effects and mechanisms of the herb pair in the treatment of NASH by network pharmacology and experimental verification. A network pharmacology-based approach was employed to predict the putative mechanism of the herb pair against NASH. The high-fat diet (HFD) and methionine/choline deficient (MCD) diet induced NASH models were used to evaluate efficacy and mechanism of the herb pair. Network pharmacological analysis showed that the herb pair modulated NOD-like receptor pathway. In the HFD mice, herb pair reduced body weight, blood sugar, serum ALT, AST, TBA, TC, TG and LDL-C contents, also improved the general morphology and pathological manifestations. Hepatic transcriptomics study showed that herb pair attenuated NASH by regulating NOD-like receptor signaling pathway. Western blotting showed that herb pair reduced the protein expression levels of NLRP3, cleaved Caspase-1 and cleaved IL-1ß. In the MCD mice, herb pair also reduced serum ALT, ALT and TBA levels, improved liver pathological manifestations, inhibited the protein expression levels of NLRP3, cleaved Caspase-1 and cleaved IL-1ß. Our findings proved that the Coptidis Rhizoma and Bovis Calculus herb pair attenuates NASH through suppression of NLRP3 inflammasome activation. This will demonstrate effective pharmacological evidence for the clinical application of herb pair.

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Background: Diaphragmatic dysfunction escalates the susceptibility to postoperative pulmonary complications (PPCs). Currently, no study reports the occurrence of diaphragmatic dysfunction correlated with PPCs following radical resection of esophageal cancer in aged patients. We aimed to diagnose diaphragmatic dysfunction via ultrasonography and analyze diaphragmatic dysfunction's relation with PPCs after radical resection of esophageal cancer surgery in aged patients. Methods: This prospective observational study comprised 86 aged patients undergoing radical resection of esophageal cancer. Patient characteristics data and intraoperative details were collected. Ultrasonography was performed before (preoperative) and after (first, third, and fifth day postoperatively) surgery. Outcome measures included PPCs within seven days postoperative, occurrence of diaphragmatic dysfunction, and short-term prognosis. Results: After excluding 14 patients, we finally analyzed clinical data from 72 patients. The prevalence of PPCs was higher in the patients with diaphragmatic dysfunction than those without (19 of 23, 83% vs. 21 of 49, 43%, P=0.004). Postoperative diaphragmatic dysfunction was positively correlated with PPCs in patients who underwent elective radical esophageal cancer surgery (r=0.37, P=0.001). Persistent diaphragmatic dysfunction, furthermore, was positively correlated with the development of multiple PPCs (r=0.43, P<0.001). The logistic regression analysis revealed that age, total open procedure, and postoperative diaphragmatic dysfunction were identified as significant risk factors for PPCs, while total open procedure was an independent risk factor for diaphragmatic dysfunction. Conclusions: Postoperative diaphragmatic dysfunction positively correlates with developing PPCs. Continuous monitoring of postoperative diaphragmatic function can screen high-risk patients with PPCs, which has specific clinical significance. Age, total open procedure, and diaphragmatic dysfunction are identified as risk factors for developing PPCs, while total open procedure specifically increases the risk for postoperative diaphragmatic dysfunction.

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In order to analyze the stability of the bridge above the goaf, the disturbance influence of goaf residual deformation on the bridge is studied. Firstly, an equivalent numerical simulation method of goaf residual deformation evolution process is studied by quantitative analysis the sensitivity of residual subsidence to the rock parameters using the OAT (one-variable-at-a-time). Then, the collaborative deformation of ground, pile, and bridge floor is studied under the condition of a simply-supported beam bridge above the goaf center. Finally, the mechanism of collaborative deformation of ground, pile, and bridge floor is revealed. The results show that the goaf residual deformation process can be obtained by weakening the elastic modulus of fractured rock in the caving zone. At the final residual deformation stage, the subsidence ratio of ground to pile is about 10, and the subsidence ratio of pile to bridge floor is about 2, while the ground horizontal movement ratio of ground to pile is about 7, and the bridge floor horizontal movement can be ignored. The bridge floor is always in the positive curvature influence zone, and the pile has an inhibitory effect on the curvature deformation of the bridge floor. The compression deformation occurs between the piles locations, while the tensile deformation occurs at the pile location. The evolution of negative frictional resistance derived from goaf residual deformation is the main reason for the change in the collaborative deformation law among the ground, pile and bridge floor. This research can provide scientific support and theoretical basis for the design, construction, and protection of the bridge above the goaf center, and can also provide reference for the stability evaluation of bridge above goaf under other conditions.

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Surgical resection is a primary treatment option for triple-negative breast cancer (TNBC) patients, but it is associated with a high rate of postoperative local and metastatic relapse. Although chimeric antigen receptor-engineered natural killer (CAR-NK) cell therapy can specifically recognize and eradicate tumor cells, its therapeutic potency toward TNBCs is markedly suppressed by the hostile tumor microenvironment, which restricts the infiltration, survival and effector functions of CAR-NK cells inside the tumor masses. Herein, HER1-overexpressing TNBC-targeted CAR-NK (HER1-CAR-NK) cells were genetically engineered with catalase to endow them with tolerance toward the high levels of oxidative stress and hypoxia inside TNBC tumors through the catalytic decomposition of hydrogen peroxide, which is a principle reactive oxygen species inside tumors, into O2. We refer to these cells as HER1-CAR-CAT-NK cells. Upon intratumoral fixation with an injectable alginate hydrogel, HER1-CAR-CAT-NK cells enabled sustained tumor hypoxia attenuation and exhibited markedly enhanced persistence and effector functions inside TNBC tumors. As a result, locoregional HER1-CAR-CAT-NK cell therapy not only inhibited the growth of local primary residual tumors, but also elicited systemic antitumor activity to suppress the growth of distant tumors. This study highlights that genetic engineering of HER1-CAR-NK cells with catalase is a promising strategy to suppress the postoperative local and distant relapse of TNBC tumors.

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Aim: To investigate the characteristics of 4 Chinese patients with Bartter syndrome type 3 (BS Type 3). Methods: The clinical data, genetic analysis, and outcome of four cases with Bartter syndrome type 3 were retrospectively summarised. Results: Gene sequencing analysis showed that all children carried a compound heterozygous mutation in the CLCNKB gene and were diagnosed with BS type 3. All types of mutations were detected, including two missense mutations, one nonsense mutation, one small fragment deletion mutation, two large deletion mutations and one splice-site mutation. The splice-site mutation c.100 + 1 (IVS2) C > T was novel. Two cases carried large deletion mutations. The patients presented as classic BS with modest manifestations. The most common sign was growth retardation. There was no polyhydramnios or preterm delivery. All cases were treated with potassium chloride supplementation and indomethacin. During long-term follow-up, clinical symptoms and growth retardation improved significantly. Nephrocalcinosis or renal dysfunction was not observed. Conclusion: The clinical manifestations of BS type 3 are mostly presented as cBS. Growth retardation is a common sign. BS type 3 had a good long-term prognosis. There were various types of mutations in the CLCNKB gene. Large deletions were the most common.

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The drugs extending healthspan in clinic have always been searched. Nitazoxanide is an FDA-approved clinical antiprotozoal drug. Nitazoxanide is rapidly metabolized to tizoxanide after absorption in vivo. Our previous studies find that nitazoxanide and its metabolite tizoxanide induce mild mitochondrial uncoupling and activate cellular AMPK, oral nitazoxanide protects against experimental hyperlipidemia, hepatic steatosis, and atherosclerosis. Here, we demonstrate that both nitazoxanide and tizoxanide extend the lifespan and healthspan of Caenorhabditis elegans through Akt/AMPK/sir 2.1/daf16 pathway. Additionally, both nitazoxanide and tizoxanide improve high glucose-induced shortening of C. elegans lifespan. Nitazoxanide has been a clinical drug with a good safety profile, we suggest that it is a novel anti-aging drug.

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In recent decades, hypoxic areas have rapidly expanded worldwide in estuaries and coastal zones. The Pearl River Estuary (PRE), one of China's largest estuaries, experiences frequent seasonal hypoxia due to intense human activities and eutrophication. However, the ecological effects of hypoxia in the PRE, particularly on fish communities, remain unclear. To explore these effects, we collected fish community and environmental data in July 2021 during the summer hypoxia development period. The results revealed that bottom-layer dissolved oxygen (DO) in the PRE ranged from 0.08 to 5.71 mg/L, with extensive hypoxic zones (DO ≤ 2 mg/L) observed. Hypoxia has varied effects on fish community composition, distribution, species, and functional diversity in the PRE. A total of 104 fish species were collected in this study, with approximately 30 species (28.6%) exclusively found in hypoxic areas. Species responses to hypoxia varied: species such as Sardinella zunasi, Coilia mystus, and Nuchequula nuchalis were sensitive, while Decapterus maruadsi, Siganus fuscescens, and Lagocephalus spadiceus showed higher tolerance. Within the hypoxia area, dissolved oxygen was the main limiting factor for fish community diversity. Functional diversity (FDiv) decreased with higher dissolved oxygen levels, indicating a potential shift in the functional traits and ecological roles of fish species in response to changing oxygen conditions. Further analysis demonstrated that dissolved oxygen had a significantly stronger effect on fish community structure at hypoxic sites than in the whole PRE. Moreover, other environmental variables also had significant effects on the fish community structure and interacted with dissolved oxygen in the hypoxia area. These findings suggest that maintaining sufficient dissolved oxygen levels is essential for sustaining fish communities and ecosystem health in the PRE. This study provides novel insights into the effects of hypoxia on fish communities in estuarine ecosystems and has significant implications for the ecological health and management of the PRE.

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OBJECTIVES: Alveolar echinococcosis (AE) represents one of the deadliest helminthic infections, characterized by an insidious onset and high lethality. METHODS: This study utilized the Gene Expression Omnibus (GEO) database, applied Weighted Correlation Network Analysis (WGCNA) and Differential Expression Analysis (DEA), and employed the Matthews Correlation Coefficient (MCC) to identify CCL17 and CCL19 as key genes in AE. Immunohistochemistry and immunofluorescence co-localization techniques were used to examine the expression of CCL17 and CCL19 in liver tissue lesions of AE patients. Additionally, a mouse model of multilocular echinococcus larvae infection was developed to study the temporal expression patterns of these genes, along with liver fibrosis and inflammatory responses. RESULTS: The in vitro model simulating echinococcal larva infection mirrored the hepatic microenvironment post-infection with multilocular echinococcal tapeworms. Quantitative RT-PCR analysis showed that liver fibrosis occurred in AE patients, with proximal activation and increased expression of CCL17 and CCL19 over time post-infection. Notably, expression peaked during the late stages of infection. Similarly, F4/80, a macrophage marker, exhibited corresponding trends in expression. Upon stimulation of normal hepatocytes by vesicular larvae in cellular experiments, there was a significant increase in CCL17 and CCL19 expression at 12 h post-infection, mirroring the upregulation observed with F4/80. CONCLUSION: CCL17 and CCL19 facilitate macrophage aggregation via the chemokine pathway and their increased expression correlates with the progression of infection, suggesting their potential as biomarkers for AE progression.

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Alterations in telomeres constitute some of the earliest occurrences in the tumourigenesis of prostate adenocarcinoma (PRAD) and persist throughout the progression of the tumour. While the activity of telomerase and the length of telomeres have been demonstrated to correlate with the prognosis of PRAD, the prognostic potential of telomere-related genes (TRGs) in this disease remains unexplored. Utilising mRNA expression data from the Cancer Genome Atlas (TCGA), we devised a risk model and a nomogram to predict the survival outcomes of patients with PRAD. Subsequently, our investigations extended to the relationship between the risk model and immune cell infiltration, sensitivity to chemotherapeutic drugs, and specific signalling pathways. The risk model we developed is predicated on seven key TRGs, and immunohistochemistry results revealed significant differential expression of three TRGs in tumours and paracancerous tissues. Based on the risk scores, PRAD patients were stratified into high-risk and low-risk cohorts. The Receiver operating characteristics (ROC) and Kaplan-Meier survival analyses corroborated the exceptional predictive performance of our novel risk model. Multivariate Cox regression analysis indicated that the risk score was an independent risk factor associated with Overall Survival (OS) and was significantly associated with T and N stages of PRAD patients. Notably, the high-risk group exhibited a greater response to chemotherapy and immunosuppression compared to the low-risk group, offering potential guidance for treatment strategies for high-risk patients. In conclusion, our new risk model, based on TRGs, serves as a reliable prognostic indicator for PRAD. The model holds significant value in guiding the selection of immunotherapy and chemotherapy in the clinical management of PRAD patients.