Emerging concern on air pollution and health: Trade-off between air pollution exposure and physical activity.

Air pollution is a major contributor to the global disease burden, especially affecting respiratory and cardiovascular health. However, physical activity is associated with improved lung function, a slower decline in lung function, and lower mortality. The public is more likely to be exposed to air pollution during outdoor physical activity. However, studies on how long-term and short-term exposure to air pollution interacts with physical activity yield inconsistent results, and the thresholds for air pollution and physical activity remain unclear. Thus, more studies are needed to provide sufficient evidence to guide the public to safely engage in outdoor physical activity when exposed to air pollution.

Small Mitochondria-Targeting Fluorophore with Multifunctional Therapeutic Activities against Prostate Cancer via the HIF1α/OATPs Pathway.

Prostate cancer (PCa) is considered to be the most prevalent malignancy in males worldwide. Abiraterone is a 17α-hydroxylase/C17, 20-lyase (CYP17) inhibitor that has been approved for use in patients with prostate cancer. However, several negative aspects, such as drug resistance, toxicity, and lack of real-time monitoring of treatment responses, could appear with long-term use. Therefore, the development of anticancer agents with specific targeting to avoid side effects is imperative. Here, we used MHI-148, a type of heptamethine cyanine (HC) near-infrared fluorescence dye (NIRF), as a prototype structure to synthesize two theranostic agents, Abi-DZ-1 and Abi-783. The new compound Abi-DZ-1 retained the excellent photophysical characteristics and NIRF imaging property of MHI-148, and it could preferentially accumulate in prostate cancer cells but not in normal prostate epithelial cells via the HIF1α/organic anion-transporting polypeptides axis. NIRF imaging using Abi-DZ-1 selectively identified tumors in mice bearing PCa xenografts. Moreover, Abi-DZ-1 treatment significantly retarded the tumor growth in both a cell-derived xenograft model and a patient-derived tumor xenograft model. This finding demonstrated that Abi-DZ-1 may hold promise as a potential multifunctional theranostic agent for future tumor-targeted imaging and precision therapy. Constructing theranostic agents using the NIRF dye platform holds great promise in accurate therapy and intraoperative navigation.

Development of SV2A Ligands for Epilepsy Treatment: A Review of Levetiracetam, Brivaracetam, and Padsevonil.

Epilepsy is a common neurological disorder that is primarily treated with antiseizure medications (ASMs). Although dozens of ASMs are available in the clinic, approximately 30% of epileptic patients have medically refractory seizures; other limitations in most traditional ASMs include poor tolerability and drug-drug interactions. Therefore, there is an urgent need to develop alternative ASMs. Levetiracetam (LEV) is a first-line ASM that is well tolerated, has promising efficacy, and has little drug-drug interaction. Although it is widely accepted that LEV acts through a unique therapeutic target synaptic vesicle protein (SV) 2A, the molecular basis of its action remains unknown. Even so, the next-generation SV2A ligands against epilepsy based on the structure of LEV have achieved clinical success. This review highlights the research and development (R&D) process of LEV and its analogs, brivaracetam and padsevonil, to provide ideas and experience for the R&D of novel ASMs.

Pulmonary artery aneurysm caused by infective endarteritis attributed to patent ductus arteriosus in children: a case report and literature review.

We report a case of a 10-year-old male patient with pulmonary artery aneurysm (PAA) caused by infective endarteritis of the pulmonary artery attributed to patent ductus arteriosus. He was found to have patent ductus arteriosus at the age of 2, but he was not treated because of the absence of symptoms and normal physical development. He sought medical attention for fever and cough in August 2022. Echocardiography showed pulmonary artery aneurysm, intrapulmonary artery bulge, patent ductus arteriosus, and pericardial effusion. Contrast-enhanced CT showed pulmonary artery aneurysm, patent ductus arteriosus, and a slight compression of the left main bronchus. Surgery was performed to reconstruct the main pulmonary trunk and repair the ductus arteriosus in November 2022. The surgical outcomes were satisfactory.

CircPCBL: Identification of Plant CircRNAs with a CNN-BiGRU-GLT Model.

Circular RNAs (circRNAs), which are produced post-splicing of pre-mRNAs, are strongly linked to the emergence of several tumor types. The initial stage in conducting follow-up studies involves identifying circRNAs. Currently, animals are the primary target of most established circRNA recognition technologies. However, the sequence features of plant circRNAs differ from those of animal circRNAs, making it impossible to detect plant circRNAs. For example, there are non-GT/AG splicing signals at circRNA junction sites and few reverse complementary sequences and repetitive elements in the flanking intron sequences of plant circRNAs. In addition, there have been few studies on circRNAs in plants, and thus it is urgent to create a plant-specific method for identifying circRNAs. In this study, we propose CircPCBL, a deep-learning approach that only uses raw sequences to distinguish between circRNAs found in plants and other lncRNAs. CircPCBL comprises two separate detectors: a CNN-BiGRU detector and a GLT detector. The CNN-BiGRU detector takes in the one-hot encoding of the RNA sequence as the input, while the GLT detector uses k-mer (k = 1 - 4) features. The output matrices of the two submodels are then concatenated and ultimately pass through a fully connected layer to produce the final output. To verify the generalization performance of the model, we evaluated CircPCBL using several datasets, and the results revealed that it had an F1 of 85.40% on the validation dataset composed of six different plants species and 85.88%, 75.87%, and 86.83% on the three cross-species independent test sets composed of Cucumis sativus, Populus trichocarpa, and Gossypium raimondii, respectively. With an accuracy of 90.9% and 90%, respectively, CircPCBL successfully predicted ten of the eleven circRNAs of experimentally reported Poncirus trifoliata and nine of the ten lncRNAs of rice on the real set. CircPCBL could potentially contribute to the identification of circRNAs in plants. In addition, it is remarkable that CircPCBL also achieved an average accuracy of 94.08% on the human datasets, which is also an excellent result, implying its potential application in animal datasets. Ultimately, CircPCBL is available as a web server, from which the data and source code can also be downloaded free of charge.

Relationship between serum homocysteine, fibrinogen, lipoprotein-a level, and peripheral arterial disease: a dose-response meta-analysis.

AIM: At present, the relationship between serum homocysteine (Hcy), fibrinogen (FIB), lipoprotein-a (LPa), and PAD is uncertain, and there has been no meta-analysis to establish the dose-response relationship between their exposure levels and PAD. METHODS AND RESULTS: Relevant literature published in PubMed, Embase, and Web of Science was retrieved. The robust error meta-regression method was used to assess the linear and non-linear dose-response relationship between exposure level and PAD risk. A total of 68 articles, involving 565,209 participants, were included. Combined with continuous variables, the serum Hcy, FIB, and LPa levels of PAD patients were significantly higher than those of healthy individuals. The odds ratios (ORs) of PAD for individuals with high Hcy, FIB, and LPa levels compared with those with low levels were 1.47, 1.14, and 1.76, respectively. The study also showed that circulating Hcy, FIB, and LPa were significantly elevated in patients with PAD compared with controls. The level of Hcy and the risk of PAD presented a U-shaped distribution. The nonlinear dose-response model showed that each 1 µmol/L increase in serum Hcy increased the risk of PAD by 7%. Similarly, for each 10 mg/dL FIB and 10 mg/dL LPa increases, the risk of PAD increased by 3% and 6%, respectively. CONCLUSIONS: This meta-analysis provided evidence that elevated Hcy, PIB, and LPa levels may increase the risk of PAD, and the risk of PAD increases with the increase in serum exposure within a certain range. By controlling Hcy level, the incidence of PAD may be reduced to control the PAD growing epidemic. TRIAL REGISTRATION NUMBER: PROSPERO (CRD42021250501), https://www.crd.york.ac.uk/prospero/.

The Application of [68Ga]-Labeled FAPI-04 PET/CT for Targeting and Early Detection of Pancreatic Carcinoma in Patient-Derived Orthotopic Xenograft Models.

[18F]FDG as a probe of PET/CT is a radiolabeled glucose analogue taken up by most cells, but its batch activity is limited. [68Ga]FAPI-04 is a promising alternative based on a fibroblast activation protein-specific inhibitor (FAPI) labeled with radiotracer FAP. Here, a series of databases suggested that FAP expression was significantly different in pancreatic cancer compared to normal tissue. The FAP-positive fibroblasts were evaluated around the tumor cells and the stroma. A patient-derived orthotopic xenograft (PDOX) model of pancreatic adenocarcinoma (PDAC) exhibits significantly higher quantitative uptake of [68Ga]FAPI-04 (P < 0.05) than [18F]FDG PET/CT in various organs. Because of relatively high (T/M) ratios, the [68Ga]FAPI-04 is excellent for B-mode ultrasound, NIRF, and PET/CT. Thus, [68Ga]FAPI-04 PET displayed a better tumor specificity and can be a potential application for the early detection of pancreatic cancer.

Lipocalin 2 may be a key factor regulating the chemosensitivity of pancreatic cancer to gemcitabine.

Owing to the high heterogeneity of pancreatic cancer, patient-derived xenografts (PDX) can compensate for the defects of cell line-derived xenografts (CDX) and also better preserve the heterogeneity and tumor microenvironment of primary tumors. Further, gemcitabine, which is used for the treatment of various cancers, is prone to tumor drug resistance, and this limits its sustained efficacy. Therefore, in this study, our objective was to screen appropriate individual therapeutic drugs for pancreatic cancer. To this end, we established pancreatic cancer PDX models from different patients and screened gemcitabine sensitivity regulatory molecules via high-throughput transcriptome sequencing and bioinformatics analysis. Based on the results obtained, gemcitabine was identified as the most suitable chemotherapeutic drug in a variety of PDX models. Additionally, our results indicated that Lipocalin 2 (LCN 2) may play an important role in the sensitivity of pancreatic cancer to gemcitabine treatment. Thus, the study provides a new potential intervention target for the treatment of pancreatic cancer in clinical practice.

Transcriptomics and metabolomics reveal the induction of flavonoid biosynthesis pathway in the interaction of Stylosanthes-Colletotrichum gloeosporioides.

Colletotrichum, a hemibiotrophic fungal pathogen with a broad host range, causes a yield-limiting disease called anthracnose. Stylo (Stylosanthes) is a dominant pasture legume in tropics and subtropics, and anthracnose is one of its most destructive disease. Resistance mechanisms against anthracnose in stylo are poorly understood, thus hindering the development of resistant varieties. We performed time-resolved leaf transcriptomics, metabolomics and in vitro inhibition assay to investigate the defense responses against Colletotrichum gloeosporioides in stylo. Transcriptomics demonstrated that flavonoid biosynthetic genes were significantly induced during the infection. Consistently, metabolomics also showed the increased accumulation of flavonoid compounds. In vitro assays showed that phloretin and naringenin inhibited the mycelial growth, and apigenin, daidzein, quercetin and kaempferol suppressed conidial germination of Colletotrichum strains. Together, our results suggest that stylo plants cope with C. gloeosporioides by up-regulation of genes and compounds in flavonoid biosynthesis pathway, providing potential targets for resistance breeding.

Hormetic dose-responses for silver antibacterial compounds, quorum sensing inhibitors, and their binary mixtures on bacterial resistance of Escherichia coli.

Silver antibacterial compounds (SACs) and quorum sensing inhibitors (QSIs), as the potential antibiotic substitutes, have been recommended to prevent and treat microbial infections for the purpose of controlling the increasingly serious bacterial resistance induced by the abuse of antibiotics. However, there is little information regarding the resistance risk of these compounds, especially their mixtures. In this study, bacterial mutation and RP4 plasmid conjugative transfer among bacteria were used to characterize the bacterial endogenous and exogenous resistance, respectively. The effects of SACs (including silver nitrate (AgNO3) and silver nanoparticle (AgNP)), QSIs, and their binary mixtures on the bacterial resistance were investigated via setting the frequency of mutation and conjugative transfer in Escherichia coli (E. coli) as the test endpoints. The results indicated that these two endpoints exhibited hormetic dose-responses to each treatment. Furthermore, the joint resistance actions between SACs and QSIs were all judged to be antagonism. Correlation analysis suggested that the promotion of the bacterial resistance in each treatment was closely related to its toxicity. It was speculated that AgNO3 and AgNP might both release Ag+ ions to facilitate the E. coli resistance, while QSIs probably acted on LsrR and SdiA proteins to stimulate the bacterial mutation and accelerate the RP4 plasmid conjugative transfer, respectively. These findings imply that the bacteria may generate targeted stress response to the survival pressure from environmental compounds, displaying hormetic phenomenon in resistance-related test endpoints. This study provides a new insight into the resistance risk induced by SACs and QSIs, benefiting the environmental risk assessment of these compounds from the perspective of bacterial resistance.

Establishment and characterization of patient-derived xenografts for hormone-naïve and castrate-resistant prostate cancers to improve treatment modality evaluation.

Prostate cancer (PC) is a heterogeneous disease characterized by variable morphological patterns. Thus, establishing a patient-derived xenograft (PDX) model that retains the key features of the primary tumor for each type of PC is important for appropriate evaluation. In this study, we established PDX models of hormone-naïve (D17225) and castration-resistant (B45354) PC by implanting fresh tumor samples, obtained from patients with advanced PC under the renal capsule of immune-compromised mice. Supplementation with exogenous androgens shortened the latent period of tumorigenesis and increased the tumor formation rate. The PDX models exhibited the same major genomic and phenotypic features of the disease in humans and maintained the main pathological features of the primary tumors. Moreover, both PDX models showed different outcomes after castration or docetaxel treatment. The hormone-naïve D17225 PDX model displayed a range of responses from complete tumor regression to overt tumor progression, and the development of castrate-resistant PC was induced after castration. The responses of the two PDX models to androgen deprivation and docetaxel were similar to those observed in patients with advanced PC. These new preclinical PC models will facilitate research on the mechanisms underlying treatment response and resistance.

Mediated Imaging and Improved Targeting of Farnesylthiosalicylic Acid Delivery for Pancreatic Cancer via Conjugation with Near-Infrared Fluorescence Heptamethine Carbocyanine Dye.

S-trans-trans-Farnesylthiosalicylic acid (FTS) is a Ras inhibitor that exhibits desirable anticancer property and currently undergoing clinical trials for pancreatic cancer (PC). However, its poor water solubility and low bioavailability have severely hampered clinical applications. A strategy to improve FTS bioavailability is to develop a suitable drug delivery method. Here, we use a near-infrared fluorescence (NIRF) heptamethine carbocyanine (HC) dye conjugated with FTS (to produce FTS-148) as a drug delivery system to enhance FTS bioavailability. We further investigate its tumor-targeting functions. FTS-148 displayed better bioavailability and photophysical property and selective recognition of cancer cells. FTS-148 significantly reduced PC cell proliferation, and more effective than FTS in restricting tumor growth both in a cell-derived xenograft (CDX) model and a patient-derived tumor xenograft (PDX) model. FTS-148 can specifically recognize PC cells in mice subcutaneous models or rabbit orthotopic models and allows real-time monitoring of the therapeutic effects by NIRF optical imaging. FTS-148 treatment significantly reduced Ras expression in PC cells and increased tumor tissue apoptosis. In short, FTS conjugated with HC dye had enhanced bioavailability and tumor-targeting property. It provides a potential agent for imaging and therapy of PC.

Patient-derived bladder cancer xenograft models reveal VEGF and CDK4 enhancing tumor metastasis behavior.

New strategies to treat advanced bladder cancer are urgently required. A patient-derived xenograft (PDX) model has become a useful tool to evaluate chemotherapeutics and investigate personalized cancer treatment options. In this study, fresh human bladder cancer specimens (C09303 and C21391) were transplanted subcutaneously into nude mice to establish PDX models. These models well retained pathological characteristics and molecular markers of the original tumor. Primary cells derived from C09303 were cultured and perfused into the bladders of nude mice to establish orthotopic xenograft models. Evident signals of lung and kidney metastases were detected by whole-body optical imaging. Gemcitabine displayed a significant therapeutic effect on the subcutaneous or orthotopic xenograft tumors of C09303. In vitro, matrigel invasion assays showed that C09303 primary culture cells are remarkably invasive. To study the metastatic properties of C09303, we sequenced the genomes of C09303 and C21391, and found that the expression of VEGF and CDK4 was significantly upregulated, and VEGF-knockdown or CDK4-knockdown C09303 cells showed attenuated invasiveness and migration. This PDX model revealed that VEGF and CDK4 enhanced tumor metastasis behavior, suggesting them as novel molecular therapeutic targets. This framework provides a tool for research on metastasis mechanism and individualized treatment for bladder cancer.

Effects of Mycobacterium tuberculosis Mutant Strain Hsp16.3 Gene on Murine RAW 264.7 Macrophage Autophagy.

Heat shock protein Hsp16.3 is closely related to latent Mycobacterium tuberculosis (MTB) infection and plays an important role in sustained survival when MTB is dormant. In this study, the Hsp16.3 gene mutant MTB H37Rv strain (Hsp16.3ΔMTB) was obtained through gene recombination and infected into murine RAW 264.7 macrophages. Western blotting and immunofluorescence showed increased expression of the autophagy-related protein LC3, and transmission electron microscopy showed significantly increased macrophage autophagosomes, suggesting that Hsp16.3ΔMTB facilitates murine macrophage autophagy. These findings have implications for preventing and controlling tuberculosis.

Re-evaluation the immune efficacy of Newcastle disease virus vaccine in commercial laying chickens.

Newcastle disease virus (NDV) infection causes serious problems in laying chickens, like reducing egg production, increasing rate of abnormal eggs in spite of strict vaccination in layer farms program. A new evaluation system is needed to show complete protection of the immunization in laying chickens based on the egg-laying performance, rather than clinical signs of the disease. In this study, laying chickens with different anti-NDV HI (hemagglutination-inhibition) antibody titer after vaccination were divided into different groups. These chickens were then challenged with field isolated highly virulent NDV strains. Results showed that the chickens in low HI titers group (5log2 to 8log2) and medium HI titers group (9log2 to 11log2) had atypical symptoms, produced abnormal eggs, and shed virus. Whereas, with HI titers≥12log2, the chickens were completely protected, and did not show symptoms, or produce abnormal eggs or shed virus. Morbidity, positive viral shedding rate and abnormal egg-rate decreased with increase in pre-challenge HI antibody titer. Our result suggested that 12log2 is the threshold of the HI antibody in providing complete protection to laying chickens under field condition, and protective efficacy is correlated with HI antibody titer. This study provides a valuable reference for the vaccination and control of ND in poultry.

S-thanatin functionalized liposome potentially targeting on Klebsiella pneumoniae and its application in sepsis mouse model.

S-thanatin (Ts) was a short antimicrobial peptide with selective antibacterial activity. In this study, we aimed to design a drug carrier with specific bacterial targeting potential. The positively charged Ts was modified onto the liposome surface by linking Ts to the constituent lipids via a PEG linker. The benefits of this design were evaluated by preparing a series of liposomes and comparing their biological effects in vitro and in vivo. The particle size and Zeta potential of the constructed liposomes were measured with a Zetasizer Nano ZS system and a confocal laser scanning microscope. The in vitro drug delivery potential was evaluated by measuring the cellular uptake of encapsulated levofloxacin using HPLC. Ts-linked liposome or its conjugates with quantum dots favored bacterial cells, and increased the bacterial uptake of levofloxacin. In antimicrobial assays, the Ts and levofloxacin combination showed a synergistic effect, and Ts-LPs-LEV exhibited excellent activity against the quality control stain Klebsiella pneumoniae ATCC 700603 and restored the susceptibility of multidrug-resistant K. pneumoniae clinical isolates to levofloxacin in vitro. Furthermore, Ts-LPs-LEV markedly reduced the lethality rate of the septic shock and resulted in rapid bacterial clearance in mouse models receiving clinical multidrug resistant (MDR) isolates. These results suggest that the Ts-functionalized liposome may be a promising antibiotic delivery system for clinical infectious disorders caused by MDR bacteria, in particular the sepsis related diseases.

Genomic characterisation of two virulent Newcastle disease viruses isolated from crested ibis (Nipponia nippon) in China.

This paper describes the complete genomic sequences of two virulent Newcastle disease virus (NDV) isolates, Shaanxi06 (prevalent genotype VIId) and Shaanxi10 (novel sub-genotype VIi), from sick crested ibises. The genomes of both isolates were 15,192 nt long and consisted of six genes in the order of 3'-NP-P-M-F-HN-L-5'. The genomes of the two isolates were highly similar to other reference NDV strains. However, some unique features were found in the HN protein of Shaanxi06 and the F gene end of Shaanxi10. Shaanxi06 and Shaanxi10 shared the same virulent motif (112-)R-R-Q-K-R-F(-117) at the F protein cleavage site, which coincided with previous pathogenicity test results. Phylogenetic analysis revealed that both isolates were clustered within class II NDV, with Shaanxi06 in genotype VII and Shaanxi10 in genotype VI. Both isolates shared high homology with the prevalent genotype NDV strains that circulate in fowls and waterfowls. This study is the first to provide genomic information about a novel sub-genotype VIi NDV strain and another genotype VIId virus, which will be useful for subsequent investigations.

Characterization of genotype IX Newcastle disease virus strains isolated from wild birds in the northern Qinling Mountains, China.

This study was conducted to evaluate the virulence and evolution of genotype IX Newcastle disease virus (NDV) isolates obtained from wild birds in the northern Qinling Mountains of China. Five isolates were obtained from 374 larynx and cloacae swabs, which were collected from multiple asymptomatic wild bird species from August 2008 to July 2011, and were subsequently characterized by pathotype and genotype. Deduced amino acid sequences revealed that all five NDV isolates exhibited velogenic fusion protein cleavage sites motif (112)R-R-Q-R-R-F(117), shared as high as 99.8-99.9 % homology with each other, and varied in pathotype by intracerebral pathogenicity indices (ICPI) of 0.425-1.638. Phylogenetic analysis showed that all five isolates were clustered to genotype IX NDV. This is the first study to confirm multiple asymptomatic wild bird species as natural carriers of virulent genotype IX NDV. A novel NDV isolate from the Spotted-necked Dove (family Columbidae) exhibited discordance between its lentogenic ICPI and its virulent proteolytic cleavage site motif (112)R-R-Q-R-R-F(117). Although the five isolates underwent several amino acid mutations in the fusion protein, evidence of continuous evolutionary divergence did exist in the genotype IX NDV, which was always regarded as a conservative genotype.

Phylogenetic characterization and virulence of two Newcastle disease viruses isolated from wild birds in China.

Wild birds are considered as a natural reservoir of Newcastle disease virus (NDV). However, there is no information about genotype IX NDV from wild birds, especially from Columbiformes. In this study, two genotype IX NDV viruses were isolated from wild birds. One was from Eurasian Blackbird, while the other was from Spotted-necked dove. After purification by plaque technique, complete genomes of both viruses were sequenced. Phylogenetic analysis of partial fusion (F) gene and complete genome indicated both strains belonged to genotype IX. Based on intracerebral pathogenicity index (ICPI), the virus from Eurasian Blackbird was velogenic virus, while the strain from Spotted-necked dove was lentogenic virus. However, both strains showed one of velogenic cleavage sites. In addition, the strain from Eurasian Blackbird showed greater replication ability and generated larger fusion foci in vitro than that of strain from Spotted-necked dove. Comparing all the corresponding protein sequences of both strains, there were only 9 different amino acid residues between them. Furthermore, after analysis of these differences, the information about lentogenic NDV with multi-basic cleavage site was presented.