Rational design of self-amplifying virus-like vesicles with Ebola virus glycoprotein as vaccines.

As emerging and re-emerging pathogens, filoviruses, especially Ebola virus (EBOV), pose a great threat to public health and require sustained attention and ongoing surveillance. More vaccines and antiviral drugs are imperative to be developed and stockpiled to respond to unpredictable outbreaks. Virus-like vesicles, generated by alphavirus replicons expressing homogeneous or heterogeneous glycoproteins, have demonstrated the capacity of self-propagation and shown great potential in vaccine development. Here, we describe a novel class of Ebola virus-like vesicles (eVLVs) incorporating both EBOV GP and VP40. The eVLVs exhibited similar antigenicity as EBOV. In murine models, eVLVs were highly attenuated and elicited robust GP-specific antibodies with neutralizing activities. Importantly, a single dose of eVLVs conferred complete protection in a surrogate EBOV lethal mouse model. Furthermore, our VLVs strategy was also successfully applied to Marburg virus (MARV), the representative member of the genus Marburgvirus. Taken together, our findings indicate the feasibility of alphavirus-derived VLVs strategy in combating infection of filoviruses represented by EBOV and MARV, which provides further evidence of the potential of this platform for universal live-attenuated vaccine development.

Lysosomal TFEB-TRPML1 Axis in Astrocytes Modulates Depressive-like Behaviors.

Lysosomes are important cellular structures for human health as centers for recycling, signaling, metabolism and stress adaptation. However, the potential role of lysosomes in stress-related emotions has long been overlooked. Here, it is found that lysosomal morphology in astrocytes is altered in the medial prefrontal cortex (mPFC) of susceptible mice after chronic social defeat stress. A screen of lysosome-related genes revealed that the expression of the mucolipin 1 gene (Mcoln1; protein: mucolipin TRP channel 1) is decreased in susceptible mice and depressed patients. Astrocyte-specific knockout of mucolipin TRP channel 1 (TRPML1) induced depressive-like behaviors by inhibiting lysosomal exocytosis-mediated adenosine 5'-triphosphate (ATP) release. Furthermore, this stress response of astrocytic lysosomes is mediated by the transcription factor EB (TFEB), and overexpression of TRPML1 rescued depressive-like behaviors induced by astrocyte-specific knockout of TFEB. Collectively, these findings reveal a lysosomal stress-sensing signaling pathway contributing to the development of depression and identify the lysosome as a potential target organelle for antidepressants.

Acute-phase plasma proteomics of rabbit lung VX2 tumors treated by image-guided microwave ablation.

Purpose: To explore the plasma proteomic changes of rabbit lung VX2 tumors treated by microwave ablation, and to explore the molecular pathway mechanisms that may be involved. Methods: New Zealand white rabbits were inoculated with VX2 tumor cell suspension in the right lower lung and treated with microwave ablation after 2-3 weeks of tumor formation. Blood was collected at 5 time points (TP1~TP5) before and after ablation by cardiac blood sampling and pre-treated before proteomic analysis. The plasma proteome was analyzed by Data-Independent Acquisition (DIA). Results: Different molecular pathways were activated at different time points:(i) TP1vsTP2: more proteins were down-regulated and enrichment analysis showed that the proteasome pathway was activated. The abnormal protein folding process involved in this pathway is closely related to the process of tumor development. (ii) TP2vsTP3: more proteins were up-regulated although the number of differentially differentiated proteins was lower and enrichment analysis showed that the phagosome pathway was activated. After microwave ablation inactivates tumor cells, it activates the phagosomal pathway for immune clearance of necrotic tumor tissue. (iii) TP3vsTP4: more down-regulated proteins, enrichment analysis showed that cysteine and methionine metabolism pathway was activated. Decreased metabolism of these amino acids suggests that cancer progression may be blocked after microwave ablation therapy. (iv) TP4vsTP5: the number of differential proteins was less and more down-regulated proteins, enrichment analysis showed that glutathione metabolism and metabolism of xenobiotics by cytochrome P450 pathway were activated. The down-regulated proteins in this pathway may suggest that microwave ablation may have reduced resistance to certain chemotherapeutic agents following. Conclusions: In the process of lung cancer treatment by microwave ablation, the changes of proteins on the possible molecular pathways at each time point are related to lung cancer, and not only involve some simple inflammatory reactions, and some of the proteins released by destroying the tumor cells can be used as possible drug binding sites and reduce drug resistance.

Clinical and pathogen features of COVID-19-associated infections during an Omicron strain outbreak in Guangzhou, China.

Although the Omicron variant has been associated with greater transmissibility and tropism of the upper respiratory tract, the clinical and pathogenic features of patients infected with the Omicron variant during an outbreak in China have been unclear. Adults with COVID-19 were retrospectively enrolled from seven medical centers in Guangzhou, China, and clinical information and specimens ( BALF, sputum, and throat swabs) from participants were collected. Conventional detection methods, metagenomics next-generation sequencing (mNGS), and other methods were used to detect pathogens in lower respiratory tract samples. From December 2022 to January 2023, we enrolled 836 patients with COVID-19, among which 56.7% patients had severe/critical illness. About 91.4% of patients were infected with the Omicron strain (BA.5.2). The detection rate of possible co-infection pathogens was 53.4% by mNGS, including Klebsiella pneumoniae (16.3%), Aspergillus fumigatus (12.2%), and Pseudomonas aeruginosa (11.8%). The co-infection rate was 19.5%, with common pathogens being Streptococcus pneumoniae (11.5%), Haemophilus influenzae (9.2%), and Adenovirus (6.9%). The superinfection rate was 75.4%, with common pathogens such as Klebsiella pneumoniae (26.1%) and Pseudomonas aeruginosa (19.4%). Klebsiella pneumoniae (27.1%% vs 6.1%, P < 0.001), Aspergillus fumigatus (19.6% vs 5.3%, P = 0.001), Acinetobacter baumannii (18.7% vs 4.4%, P = 0.001), Pseudomonas aeruginosa (16.8% vs 7.0%, P = 0.024), Staphylococcus aureus (14.0% vs 5.3%, P = 0.027), and Streptococcus pneumoniae (0.9% vs 10.5%, P = 0.002) were more common in severe cases. Co-infection and superinfection of bacteria and fungi are common in patients with severe pneumonia associated with Omicron variant infection. Sequencing methods may aid in the diagnosis and differential diagnosis of pathogens. IMPORTANCE: Our study has analyzed the clinical characteristics and pathogen spectrum of the lower respiratory tract associated with co-infection or superinfection in Guangzhou during the outbreak of the Omicron strain, particularly after the relaxation of the epidemic prevention and control strategy in China. This study will likely prompt further research into the specific issue, which will benefit clinical practice.

Amlexanox targeted inhibition of TBK1 regulates immune cell function to exacerbate DSS-induced inflammatory bowel disease.

Amlexanox (ALX) is a small molecule drug for the treatment of inflammatory, autoimmune, metabolic and tumor diseases. At present, there are no studies on whether ALX has a therapeutic effect on inflammatory bowel disease (IBD). In this study, we used a mouse model of dextran sulfate sodium (DSS)-induced colitis to investigate the effect of ALX targeted inhibition of TBK1 on colitis. We found that the severity of colitis in mice was correlated with TBK1 expression. Notably, although ALX inhibited the activation of the TBK1-NF-κB/TBK1-IRF3 pro-inflammatory signaling pathway, it exacerbated colitis and reduced survival in mice. The results of drug safety experiments ruled out a relationship between this exacerbating effect and drug toxicity. In addition, ELISA results showed that ALX promoted the secretion of IL-1ß and IFN-α, and inhibited the production of cytokines IL-6, TNF-α, IL-10, TGF-ß and secretory IgA. Flow cytometry results further showed that ALX promoted T cell proliferation, activation and differentiation, and thus played a pro-inflammatory role; Also, ALX inhibited the generation of dendritic cells and the polarization of macrophages to M1 type, thus exerting anti-inflammatory effect. These data suggest that the regulation of ALX on the function of different immune cells is different, so the effect on the inflammatory response is bidirectional. In conclusion, our study demonstrates that simply inhibiting TBK1 in all immune cells is not effective for the treatment of colitis. Further investigation the anti-inflammatory mechanism of ALX on dendritic cells and macrophages may provide a new strategy for the treatment of IBD.

Luteipulveratus flavus sp. nov. isolated from two lichen species.

Two novel strains, YIM 133132T and YIM 133296, were isolated from lichen samples collected from Yunnan Province, Southwest PR China. YIM 133132T and YIM 133296 are aerobic, Gram-staining-positive, non-motile actinomycetes. They are also catalase-positive and oxidase-negative, and YIM 133132T formed flat yellowish colonies that were relatively dry on YIM38 agar medium. Flat yellowish colonies of YIM 133296 were also observed on YIM38 agar medium. YIM 133132T grew at 25-35 °C (optimum 25-30 °C), pH 6.0-9.0 (optimum pH 7.0) and in the presence of 0-8% (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strains YIM 133132T and YIM 133296 represented members of the genus Luteipulveratus and exhibited high sequence similarity (96.93%) with Luteipulveratus halotolerans C296001T. The genomic DNA G+C content of both strains was 71.8%. The DNA-DNA hybridisation (dDDH) values between YIM 133132T and YIM 133296 were 85.1%, and the DNA-DNA hybridisation value between YIM 133132T and YIM 133296 and L. halotolerans C296001T was 23.4%. On the basis of the draft genome sequences, the average nucleotide identity (ANI) between strains YIM 133132T and YIM 133296 and L. halotolerans C296001T was 80.8%. The major menaquinones that were identified were MK-8(H4), MK-9 and MK-8(H2). The polar lipids were diphosphatidylglycerol and phosphatidylinositol. On the basis of the morphological, physiological, biochemical, genomic, phylogenetic and chemotaxonomic characteristics, strains YIM 133132T and YIM 133296 can be clearly distinguished from L. halotolerans C296001T, and the two strains represent a novel species for which the name L. flavus sp. nov. is proposed. The type strain is YIM 133132T (CGMCC= 1.61357T and KCTC= 49824T).

Three new species of the genus Clavulina (Hydnaceae, Cantharellales) from North China based on morphological and phylogenetic analysis.

Clavulina possesses important ecological and economic value and has attracted extensive attention from mycologists. Macrofungal diversity is high in China, but Clavulina species have not been thoroughly studied. In this study, based on morphological evidence and phylogenetic analyses of the nucleotide sequences of three loci (nrITS, nrLSU, and rpb2), three new species of Clavulina from North China were identified. Morphologically, Clavulinachengdeensis is characterized by its white to dirty white basidiomata with somewhat pale orange tips and somewhat wrinkled hymenium. Clavulinagriseoviolacea is characterized by its gray to dark grayish violet basidiomata, with a sometimes-white stipe base, monopodial or irregularly polychotomous toward branch apices. Clavulinapallida is characterized by its white to pale cream white basidiomata with somewhat orange tips. Phylogenetically, the three new species form three independent branches with high support values in the phylogenetic tree.

Spying with a pilot's eye: Using eye tracking to investigate pilots' attention allocation and workload during helicopter autorotative gliding.

Flight safety in helicopters is a critical aspect of overall aircraft operational safety management, particularly during engine failures requiring autorotative glide, which makes it extremely challenging for the pilot to land the helicopter successfully. In this study, we evaluated the workload and attention allocation of helicopter pilots under such circumstances. In the experiment, a helicopter flight simulator was used to simulate level flight followed by autorotative glide, with the two phases divided into time segments for data collection. First, the data were visualized using heat maps and saccade sequence diagrams, while changes in eye movement metrics (such as peak value and standard deviation) were statistically analyzed. Finally, the criteria through the inter-criteria correlation (CRITIC) method was used to calculate the weight coefficient for each area of interest. This evaluation system was further applied to analyze and compare the changes in eye-movement data and attention to areas of interest during the two phases. The results revealed a shorter fixation duration, but a greater fixation number during the autorotative glide phase. Further, the mean pupil diameter changed over a larger range than during level flight (in level flight, the mean was 5.229 mm, while the standard deviation was 0.059 mm; in autorotative glide the corresponding values were 5.326 mm and 0.126 mm, respectively). For the tachometer, the weight coefficient matched the color of the heat map (2.7 % and colorless during level flight, but 23.8 % and red during autorotative glide), while those for the airspeed indicator and forward view differed significantly between the two phases. This discrepancy stemmed from the fact that during autorotative glide, the pilots prioritized monitoring aircraft rotation speed and attitude, with a particular focus on the forward view, rotor speed, and airspeed, resulting in a more concentrated attention distribution compared to that achieved during level flight. These results confirmed a significant increase in pilot workload during autorotative glide landing, while a shift was observed from low-frequency long gaze time during level flight to high-frequency short gaze time during autorotative glide. Furthermore, the pilots allocated 81 % of their attention to the tachometer, airspeed indicator, and forward views. Adopting this strategy can improve pilots' landing success and provide flight students with valuable training advice to prevent landing failures when helicopters lose power.

Alteration of lncRNA RHPN1-AS1 predicts clinical prognosis and regulates the progression of bladder cancer via modulating miR-485-5p.

BACKGROUND: Exploring effect biomarkers that monitor tumor progression and predict the prognosis could benefit the clinical management of bladder cancer and improve the postoperative life of patients. This study aimed to estimate the function of long non-coding (lnc)RNA RHPN1-AS1 (RHPN1-AS1) in bladder cancer and the potential molecular mechanism. METHODS: The expression of RHPN1-AS1 was evaluated in bladder cancer tissues from 115 patients and cells by polymerase chain reaction. The clinical significance of RHPN1-AS1 was assessed and its effect was also estimated in cell proliferation, migration, and invasion. The underlying molecular mechanism was explored by the dual-luciferase reporter assay. RESULTS: The expression of RHPN1-AS1 was 2.91-fold elevated in bladder cancer, which showed a close correlation with advanced tumor node metastasis stage (P = 0.013) and the presence of lymph node metastasis (P = 0.018). RHPN1-AS1 also served as a poor prognostic indicator (hazard ratio = 2.563) for bladder cancer. The knockdown of RHPN1-AS1 significantly suppressed the proliferation and metastasis ability of bladder cancer cells. Moreover, miR-485-5p was found to mediate the function of RHPN1-AS1 in bladder cancer, which was considered the underlying regulatory mechanism. CONCLUSIONS: RHPN1-AS1 serves as a prognostic biomarker and tumor promoter in bladder cancer via modulating miR-485-5p, which might be a reliable target of bladder cancer therapy.

G-Protein-Coupled Receptor Kinase 2 Inhibition Induces Meiotic Arrest by Disturbing Ca2+ Release in Porcine Oocytes.

G-protein-coupled receptor kinase 2 (GRK2) interacts with Gßγ and Gαq, subunits of G-protein alpha, to regulate cell signalling. The second messenger inositol trisphosphate, produced by activated Gαq, promotes calcium release from the endoplasmic reticulum (ER) and regulates maturation-promoting factor (MPF) activity. This study aimed to investigate the role of GRK2 in MPF activity during the meiotic maturation of porcine oocytes. A specific inhibitor of GRK2 (ßi) was used in this study. The present study showed that GRK2 inhibition increased the percentage of oocyte arrest at the metaphase I (MI) stage (control: 13.84 ± 0.95%; ßi: 31.30 ± 4.18%), which resulted in the reduction of the maturation rate (control: 80.36 ± 1.94%; ßi: 65.40 ± 1.14%). The level of phospho-GRK2 decreased in the treated group, suggesting that GRK2 activity was reduced upon GRK2 inhibition. Furthermore, the addition of ßi decreased Ca2+ release from the ER. The protein levels of cyclin B and cyclin-dependent kinase 1 were higher in the treatment group than those in the control group, indicating that GRK2 inhibition prevented a decrease in MPF activity. Collectively, GRK2 inhibition induced meiotic arrest at the MI stage in porcine oocytes by preventing a decrease in MPF activity, suggesting that GRK2 is essential for oocyte meiotic maturation in pigs.

The Role of Plasma Trough Concentration of Voriconazole and Voriconazole N-Oxide in Its Hepatotoxicity in Adult Patients.

Objective: Hepatotoxicity is an important cause of early withdrawal of voriconazole (VCZ). The role of the plasma trough concentration of VCZ (C0) in hepatotoxicity is confusion. VCZ N-oxide is the primary metabolite of VCZ in plasma. We investigated the role of VCZ C0 and plasma trough concentration of VCZ N-oxide (CN) in hepatotoxicity in adult patients. Materials and Methods: This was a prospective study. VCZ C0 and CN were measured using liquid chromatography-tandem mass spectrometry. Results: In total, 601 VCZ C0 and CN from 376 adult patients were included. The percentage of grade 1 or higher adverse events for ALP, ALT, AST, γ-GT, and TBIL were 35.4%, 21.0%, 30.1%, 56.2%, and 22.2%, respectively. Compared with younger adult patients, elderly patients (≥65 years) had a higher rate of grade 1 or higher adverse events of ALP. In the multivariate analysis, VCZ C0 was a risk factor for grade 1 or higher adverse events of AST in elderly patients and TBIL in younger adult patients, and VCZ CN was a risk factor for grade 1 or higher adverse events of ALT, AST, and TBIL. Results of the receiver operating characteristic curve analysis indicated that when the VCZ C0 was higher than 4.0 µg/mL, or the VCZ CN was lower than 1.7 µg/mL, the incidence of grade 1 or higher adverse events of AST and TBIL increased. Conclusion: VCZ C0 and CN were associated with liver function-related adverse events. Measurement of VCZ CN should be considered for VCZ therapeutic drug monitoring.

A new species of the newt genus Hypselotriton (Amphibia, Urodela, Salamandridae) from Jiangxi Province, southeastern China.

A new newt species, Hypselotritonhuanggangensis sp. nov., is described based on nine specimens collected from Huanggangshan Mountains, Yanshan County, Jiangxi, China. Morphologically, the new species is characterized by the combination of nine external characters: (1) obvious black patches with clear boundaries on the whole body; (2) ground color of the dorsal body tan; (3) ground color of venter bright orange; (4) skin rough; (5) vertebral ridge weak; (6) fingers and toes overlapping when forelimb and hindlimb adpressed towards each other along body; (7) postocular orange spot absent; (8) small white warty glands around the eye; (9) two discontinuous longitudinal lines formed by white warty glands from neck to lateral parts of tail. Molecularly, the new species forms an independent clade with strong support in the phylogenetic trees of the genus based on the mitochondrial locus of NADH dehydrogenase subunit 2 (ND2) gene fragments. The new species distinctly differs from H.fudingensis by differences in its body measurements, vertebral ridge, dorsal black patches, and ventral black patches. Furthermore, the new species and H.fudingensis are geographically isolated by a series of high mountain ranges, including the Wuyishan and Jiufengshan Mountains. The number of Hypselotriton species is now 11.

Photoinduced Decarboxylative Thioacylation of N-Hydroxyphthalimide Esters with Tetraalkylthiuram Disulfides.

Dithiocarbamate is a key structural sequence in pharmaceuticals and agrochemicals, and its synthesis is crucial in organic chemistry. Although significant progress has been made in related synthesis research, developing a practical and universal synthesis method remains fascinating. Herein, we report a new visible-light-induced decarboxylation coupling reaction between N-hydroxyphthalimide esters and tetraalkylthiuram disulfides, which uses Ir(ppy)3 as a photocatalyst to promote the generation of corresponding decarboxylation thioacylation product-dithiocarbamates in high yields. This redox-neutral protocol uses inexpensive and readily available starting material under mild reaction conditions, exhibiting broad substrate scope and wide functional group compatibility. This method can be further used for post modification of complex natural products and bioactive drugs.

First Report of Powdery mildew caused by Golovinomyces ambrosiae on Bidens pilosa in Guangdong Province, China.

Bidens pilosa L., an annual herbaceous plant with a wide distribution, possesses novel medicinal properties. In January 2021, a powdery mildew disease outbreak was documented on B. pilosa plants located in the roadside areas in Shenzhen, Guangdong Province, China, with 60 to 80% disease incidence. Initial symptoms manifested as small, irregular white powdery patches, primarily on the adaxial surfaces of leaves. Subsequently, the colonies expanded, forming coalescent colonies that spread across the leaves, petioles, and stems, eventually leading to the distortion and senescence of leaves. Hyphae are hyaline, flexuous to straight, septate, with thin walls and a width ranging from 2 to 8 µm. Hyphal appressoria are nipple-shaped. Conidophores are erect or slightly flexuous, ranging from 80 to 150 µm in length and 12 to 18 µm in width (n = 30). Typically, these conidophores bear chains of 2 to 5 immature conidia, displaying a sinuate outline. Foot-cells, located at the base of conidophores, are cylindrical and erect, approximately 33 to 100 µm in length and 6 to 10 µm in width (n = 30). Conidia are hyaline, ellipsoid-ovoid to barrel-shaped, and lack fibrosin bodies. Primary conidia are ellipsoid-ovoid in shape, characterized by a rounded apex and a subtruncate base, 25 to 40 µm × 15 to 22 µm in width. Secondary conidia are barrel-shaped with truncate or subtruncate ends, 27 to 35 µm × 15 to 20 µm in width. Germ tubes exhibit a longitubus pattern and are prominently produced at the perihilar or apical region of the conidia. No chasmothecia were observed in the collected samples. In order to conduct a molecular-level identification, mycelium and conidia were collected from B. pilosa leaves. Genomic DNA was subsequently extracted from these samples. The internal transcribed spacer (ITS), intergenic spacer (IGS) and beta-tubulin (tub2) sequences were performed using primer pairs ITS1/ITS4, IGS-12a/NS1R, and tub2, respectively (Carbone and Kohn 1999; Scholin et al. 1994; White et al.,1990). A 568-bp ITS, a 366-bp IGS, and a 354-bp tub2 sequences (GenBank accession nos. OR647592, OR978282 and OR978283) were obtained. The ITS sequence exhibited over 99.6% similarity to Golovinomyces ambrosiae (MT929773) and G. cichoracearum (MH590731). The IGS sequence displayed 100% similarity to G. ambrosiae (MK383490) and G. ambrosiae (OK349420). The tub2 sequence displayed 100% similarity to G. ambrosiae (MW981257) and G. ambrosiae (MW981256). Phylogenetic analysis of IGS, ITS and tub2 also grouped obtained sequences within the G. ambrosiae complex. Based on the analysis of morphological characteristics and sequence identity, the pathogen was identified as G. ambrosiae. In order to satisfy Koch's postulates, an infected leaf was carefully pressed onto leaves of six healthy young B. pilosa plants, each grown in a separate pot. Additionally, a control group consisted of six non-inoculated plants. All plants were placed in a greenhouse: 25°C, 14/10-h light/dark photoperiod, and relative humidity 50%. After 10 days, the inoculated leaves exhibited powdery mildew colonies similar to those observed in the original infected plants. At 16 days, the inoculated leaves exhibited discoloration and premature leaf drop. The pathogenicity test was conducted twice. Microscopic observation and sequencing confirmed that isolated fungus was identical to the original pathogen. G. ambrosiae has previously been documented on B. pilosa in Fuzhou, Fujian Province, China (Mukhtar et al., 2022). However, to the best of our knowledge, this study represents the first report of powdery mildew caused by G. ambrosiae on B. pilosa in Shenzhen, Guangdong Province, China.

Multi-omics integration analysis: Tools and applications in environmental toxicology.

Nowadays, traditional single-omics study is not enough to explain the causality between molecular alterations and toxicity endpoints for environmental pollutants. With the development of high-throughput sequencing technology and high-resolution mass spectrometry technology, the integrative analysis of multi-omics has become an efficient strategy to understand holistic biological mechanisms and to uncover the regulation network in specific biological processes. This review summarized sample preparation methods, integration analysis tools and the application of multi-omics integration analyses in environmental toxicology field. Currently, omics methods have been widely applied being as the sensitivity of early biological response, especially for low-dose and long-term exposure to environmental pollutants. Integrative omics can reveal the overall changes of genes, proteins, and/or metabolites in the cells, tissues or organisms, which provide new insights into revealing the overall toxicity effects, screening the toxic targets, and exploring the underlying molecular mechanism of pollutants.

Medium-Chain Chlorinated Paraffins Trigger Thyroid Hormone Synthesis and Interfere with Mitochondrial Function in the Thyroid Gland.

Medium-chain chlorinated paraffins (MCCPs, C14-C17) are frequently detected in diverse environmental media. It has been proposed to be listed in Annex A of the Convention on Persistent Organic Pollutants in 2023. Although MCCPs are a crucial health concern, their toxicity remains unclear. This study investigated the toxic effects of MCCPs (0.1-50 mg/kg body weight/day) on the thyroid gland of female Sprague-Dawley rats and characterized the potential toxic pathways via transcriptomics and metabolomics approaches. MCCPs exposure caused histopathological changes to the endoplasmic reticula and mitochondria in thyroid follicular cells at a dose of 50 mg/kg bw/d and increased serum thyrotropin-releasing hormone, thyroid-stimulating hormones, and thyroxine when exposed to a higher dose of MCCPs. Transcriptomic analysis indicated the excessive expression of key genes related to thyroid hormone synthesis induced by MCCPs. Integrating the dual-omics analysis revealed mitochondrial dysfunction of the thyroid by mediating fatty acid oxidation, Kreb's cycle, and oxidative phosphorylation. Significant metabolic toxicity on the thyroid might be linked to the characteristics of the chlorine content of MCCPs. This study revealed the toxicity of MCCPs to the thyroid gland via triggering thyroid hormone synthesis and interfering with mitochondrial function, which can provide new insights into the modes of action and mechanism-based risk assessment of MCCPs.

Cyy-272, an indazole derivative, effectively mitigates obese cardiomyopathy as a JNK inhibitor.

Obesity has shown a global epidemic trend. The high-lipid state caused by obesity can maintain the heart in a prolonged low-grade inflammatory state and cause ventricular remodeling, leading to a series of pathologies, such as hypertrophy, fibrosis, and apoptosis, which eventually develop into obese cardiomyopathy. Therefore, prolonged low-grade inflammation plays a crucial role in the progression of obese cardiomyopathy, making inflammation regulation an essential strategy for treating this disease. Cyy-272, an indazole derivative, is an anti-inflammatory compound independently synthesized by our laboratory. Our previous studies revealed that Cyy-272 can exert anti-inflammatory effects by inhibiting the phosphorylation and activation of C-Jun N-terminal kinase (JNK), thereby alleviating lipopolysaccharide (LPS)-induced acute lung injury (ALI). The current study aimed to evaluate the potential of Cyy-272 to mitigate the occurrence and progression of obese cardiomyopathy through the inhibition of the JNK signaling pathway. Our results indicate that the compound Cyy-272 has encouraging therapeutic effects on obesity-induced cardiac injury. It significantly inhibits inflammation in cardiomyocytes and heart tissues induced by high lipid concentrations, further alleviating the resulting hypertrophy, fibrosis, and apoptosis. Mechanistically, the protective effect of Cyy-272 on obese cardiomyopathy can be attributed to its direct inhibition of JNK protein phosphorylation. In conclusion, we identified a novel compound, Cyy-272, capable of alleviating obese cardiomyopathy and confirmed that its effect is achieved through direct inhibition of JNK.

[Clinical phenotypes and genotypes of congenital fibrinogen disorder: an analysis of 16 children]. / 16ä¾‹å„¿ç«¥å ˆå¤©æ€§çº¤ç»´è›‹ç™½åŽŸç— çš„ä¸´åºŠè¡¨åž‹å’ŒåŸºå› åž‹åˆ†æž.

OBJECTIVES: To investigate the clinical phenotypes and genotypes of children with congenital fibrinogen disorder (CFD). METHODS: A retrospective analysis was conducted on the clinical data of 16 children with CFD. Polymerase chain reaction was used to amplify all exons and flanking sequences of the FGA, FGB, and FGG genes, and sequencing was performed to analyze mutation characteristics. RESULTS: Among the 16 children, there were 9 boys (56%) and 7 girls (44%), with a median age of 4 years at the time of attending the hospital. Among these children, 9 (56%) attended the hospital due to bleeding events, and 7 (44%) were diagnosed based on preoperative examination. The children with bleeding events had a significantly lower fibrinogen activity than those without bleeding events (P<0.05). Genetic testing was conducted on 12 children and revealed a total of 12 mutations, among which there were 4 novel mutations, i.e., c.80T>C and c.1368delC in the FGA gene and c.1007T>A and C.1053C>A in the FGG gene. There were 2 cases of congenital afibrinogenemia caused by null mutations of the FGA gene, with relatively severe bleeding symptoms. There were 7 cases of congenital dysfibrinogenemia mainly caused by heterozygous missense mutations of the FGG and FGA genes, and their clinical phenotypes ranged from asymptomatic phenotype to varying degrees of bleeding. CONCLUSIONS: The clinical phenotypes of children with CFD are heterogeneous, and the severity of bleeding is associated with the level of fibrinogen activity, but there is a weak association between clinical phenotype and genotype.

Unraveling the causality between gastroesophageal reflux disease and increased cancer risk: evidence from the UK Biobank and GWAS consortia.

BACKGROUND: Gastroesophageal reflux disease (GERD) is a common condition characterized by the reflux of stomach contents into the esophagus. Despite its widespread prevalence worldwide, the causal link between GERD and various cancer risks has not been fully established, and past medical research has often underestimated or overlooked this relationship. METHODS: This study performed Mendelian randomization (MR) to investigate the causal relationship between GERD and 19 different cancers. We leveraged data from 129,080 GERD patients and 473,524 controls, along with cancer-related data, obtained from the UK Biobank and various Genome-Wide Association Studies (GWAS) consortia. Single nucleotide polymorphisms (SNPs) associated with GERD were used as instrumental variables, utilizing methods such as inverse variance weighting, weighted median, and MR-Egger to address potential pleiotropy and confounding factors. RESULTS: GERD was significantly associated with higher risks of nine types of cancer. Even after adjusting for all known risk factors-including smoking, alcohol consumption, major depression, and body mass index (BMI)-these associations remained significant, with higher risks for most cancers. For example, the adjusted risk for overall lung cancer was (OR, 1.23; 95% CI: 1.14-1.33), for lung adenocarcinoma was (OR, 1.18; 95% CI: 1.03-1.36), for lung squamous cell carcinoma was (OR, 1.35; 95% CI: 1.19-1.53), and for oral cavity and pharyngeal cancer was (OR, 1.73; 95% CI: 1.22-2.44). Especially noteworthy, the risk for esophageal cancer increased to (OR, 2.57; 95% CI: 1.23-5.37). Mediation analyses further highlighted GERD as a significant mediator in the relationships between BMI, smoking, major depression, and cancer risks. CONCLUSIONS: This study identifies a significant causal relationship between GERD and increased cancer risk, highlighting its role in cancer development and underscoring the necessity of incorporating GERD management into cancer prevention strategies.