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N-linked glycoproteins are rich in seminal plasma, playing essential roles in supporting sperm function and fertilization process. The alteration of seminal plasma glycans and its correspond glycoproteins may lead to sperm dysfunction and even infertility. In present study, an integrative analysis of glycoproteomic and proteomic was performed to investigate the changes of site-specific glycans and glycoptoteins in seminal plasma of asthenozoospermia. By large scale profiling and quantifying 5,018 intact N-glycopeptides in seminal plasma, we identified 92 intact N-glycopeptides from 34 glycoproteins changed in asthenozoospermia. Especially, fucosylated glycans containing lewis x, lewis y and core fucosylation were significantly up-regulated in asthenozoospermia compared to healthy donors. The up-regulation of fucosylated glycans in seminal plasma may interfere sperm surface compositions and regulation of immune response, which subsequently disrupts sperm function. Three differentiated expression of seminal vesicle-specific glycoproteins (fibronectin, seminogelin-2, and glycodelin) were also detected with fucosylation alteration in seminal plasma of asthenozoospermia. The interpretation of the altered site-specific glycan structures provides data for the diagnosis and etiology analysis of male infertility, as well as providing new insights into the potential therapeutic targets for male infertility.
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Astenozoospermia , Fucosa , Semen , Humanos , Masculino , Astenozoospermia/metabolismo , Semen/metabolismo , Semen/química , Fucosa/metabolismo , Glicoproteínas/metabolismo , Proteómica , Adulto , Regulación hacia Arriba , Polisacáridos/metabolismo , Polisacáridos/química , Glicosilación , Glicopéptidos/metabolismo , Glicopéptidos/análisisRESUMEN
Background: Innovative treatment strategies for early-stage breast cancer (BC) are urgently needed. Tumors originating from mammary ductal cells present an opportunity for targeted intervention. Methods: We explored intraductal therapy via natural nipple openings as a promising non-invasive approach for early BC. Using functional Near-infrared II (NIR-II) nanomaterials, specifically NIR-IIb quantum dots conjugated with Epep polypeptide for ductal cell targeting, we conducted in situ imaging and photothermal ablation of mammary ducts. Intraductal administration was followed by stimulation with an 808 nm laser. Results: This method achieved precise ductal destruction and heightened immunological responses in the microenvironment. The technique was validated in mouse models of triple-negative BC and a rat model of ductal carcinoma in situ, demonstrating promising therapeutic potential for localized BC treatment and prevention. Conclusion: Our study demonstrated the effectiveness of NIR-II nanoprobes in guiding non-invasive photothermal ablation of mammary ducts, offering a compelling avenue for early-stage BC therapy.
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Neoplasias de la Mama , Terapia Fototérmica , Puntos Cuánticos , Animales , Femenino , Ratones , Ratas , Neoplasias de la Mama/terapia , Terapia Fototérmica/métodos , Humanos , Línea Celular Tumoral , Modelos Animales de Enfermedad , Carcinoma Intraductal no Infiltrante/terapiaRESUMEN
Two-dimensional-material-based memristors are emerging as promising enablers of new computing systems beyond von Neumann computers. However, the most studied anion-vacancy-enabled transition metal dichalcogenide memristors show many undesirable performances, e.g., high leakage currents, limited memory windows, high programming currents, and limited endurance. Here, we demonstrate that the emergent van der Waals metal phosphorus trisulfides with unconventional nondefective vacancy provide a promising paradigm for high-performance memristors. The different vacancy types (i.e., defective and nondefective vacancies) induced memristive discrepancies are uncovered. The nondefective vacancies can provide an ultralow diffusion barrier and good memristive structure stability giving rise to many desirable memristive performances, including high off-state resistance of 1012 Ω, pA-level programming currents, large memory window up to 109, more than 7-bit conductance states, and good endurance. Furthermore, a high-yield (94%) memristor crossbar array is fabricated and implements multiple image processing successfully, manifesting the potential for in-memory computing hardware.
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Microplastics, with intricate physical and chemical characteristics, infiltrate the food chain and extensively impact ecosystems. Despite acknowledging the link between environmental pollution and declining fertility, the specific mechanisms affecting reproductive health remain to be elucidated. This review emphasizes the global correlation between microplastics and subfertility, focusing on entry pathways and impacts on ecosystems. Research suggests that microplastics disrupt the neuroendocrine system, influencing sex hormone synthesis through the hypothalamic-pituitary-gonadal (HPG) axis. In the reproductive system, microplastics interfere with the blood-testis barrier, impairing spermatogenesis in males, and causing placental dysfunction, ovarian atrophy, endometrial hyperplasia, and fibrosis in females. Moreover, microplastics potentially affect offspring's lipid metabolism and reproductive functions. However, complex microplastic compositions and detection method limitations impede research progress. Mitigation strategies for reproductive effects, combined with addressing microplastic pollution through sustainable practices, are imperative. This review underscores the urgency of global initiatives and collaborative research to safeguard reproductive health amid escalating microplastic contamination.
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Microplásticos , Salud Reproductiva , Contaminantes Químicos del Agua , Contaminantes Químicos del Agua/análisis , Humanos , Femenino , Masculino , Animales , Reproducción/efectos de los fármacosRESUMEN
Poliovirus receptor-related immunoglobulin domain-containing protein, or PVRIG, is a newly discovered immune checkpoint that has emerged as a promising target for cancer immunotherapy. It is primarily expressed on activated T and natural killer (NK) cells, and once engaged with its ligand, PVRL2, it induces inhibitory signaling in T cells, thereby promoting the functional exhaustion of tumor-infiltrating lymphocytes (TILs). Here, we characterized IBI352g4a, a novel humanized anti-PVRIG antibody with Fc-competent function, explored the mechanism of its antitumor activity in preclinical models, and systemically evaluated the contribution of FcrR engagement to PVRIG blockade-induced antitumor activity. IBI352g4a binds to the extracellular domain of human PVRIG with high affinity (Kd = 0.53 nM) and specificity, and fully blocks the interaction between PVRIG and its ligand PVRL2. Unlike other immune checkpoints, IBI352g4a significantly induced NK cell activation and degranulation, but had a minimal effect on T-cell activation in in vitro functional assays. IBI352g4a induced strong antitumor effect in several preclinic models, through in vivo mechanism analysis we found that both NK and T cells contribute to the antitumor effect, but NK cells play predominant roles. Specifically, a single dose of IBI352g4a induced significant NK cell activation in TILs, but T-cell activation was observed only after the second dose. Moreover, the Fc effector function is critical for both NK cell activation and treatment efficacy in vitro and in vivo. Our study, for the first time, demonstrates that both NK activation and FcrR engagement are required for antitumor efficacy induced by PVRIG blockade.
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Células Asesinas Naturales , Neoplasias , Humanos , Ligandos , Inmunoterapia , Linfocitos Infiltrantes de Tumor , Neoplasias/metabolismoRESUMEN
Memristors are considered promising energy-efficient artificial intelligence hardware, which can eliminate the von Neumann bottleneck by parallel in-memory computing. The common imperfection-enabled memristors are plagued with critical variability issues impeding their commercialization. Reported approaches to reduce the variability usually sacrifice other performances, e.g., small on/off ratios and high operation currents. Here, we demonstrate an unconventional Ag-doped nonimperfection diffusion channel-enabled memristor in van der Waals indium phosphorus sulfide, which can combine ultralow variabilities with desirable metrics. We achieve operation voltage, resistance, and on/off ratio variations down to 3.8, 2.3, and 6.9% at their extreme values of 0.2 V, 1011 ohms, and 108, respectively. Meanwhile, the operation current can be pushed from 1 nA to 1 pA at the scalability limit of 6 nm after Ag doping. Fourteen Boolean logic functions and convolutional image processing are successfully implemented by the memristors, manifesting the potential for logic-in-memory devices and efficient non-von Neumann accelerators.
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The impaired endometrial receptivity is a major factor contributing to infertility in patients with endometriosis (EM), but the underlying mechanism remains unclear. Our study aimed to investigate the role of Kruppel-like factor 15 (KLF15) in endometrial receptivity and its regulation in EM. We observed a significant decrease in KLF15 expression in the mid-secretory epithelial endometrial cells of EM patients compared to normal females without EM. To confirm the role of KLF15 in endometrial receptivity, we found a significantly reduced KLF15 expression and a significant decrease in embryo implantation number in the rat model via uterine horn infection with siRNA. This highlights the importance of KLF15 as a regulator receptivity. Furthermore, through ChIP-qPCR, we discovered that the progesterone receptor (PR) directly binds to KLF15 promoter regions, indicating that progesterone resistance may mediate the decrease in KLF15 expression in EM patients. Additionally, we found that the mid-secretory endometrium of EM patients exhibited impaired epithelial-mesenchymal transition (EMT). Knockdown of KLF15 upregulated E-cadherin and downregulated vimentin expression, leading to inhibited invasiveness and migration of Ishikawa cells. Overexpression KLF15 promotes EMT, invasiveness, and migration ability, and increases the attachment rate of JAR cells to Ishikawa cells. Through RNA-seq analysis, we identified TWIST2 as a downstream gene of KLF15. We confirmed that KLF15 directly binds to the promoter region of TWIST2 via ChIP-qPCR, promoting epithelial cell EMT during the establishment of endometrial receptivity. Our study reveals the involvement of KLF15 in the regulation of endometrial receptivity and its downstream effects on EMT. These findings provide valuable insights into potential therapeutic approaches for treating non-receptive endometrium in patients with EM.
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Endometriosis , Transición Epitelial-Mesenquimal , Factores de Transcripción de Tipo Kruppel , Animales , Femenino , Humanos , Ratas , Cadherinas/genética , Cadherinas/metabolismo , Cadherinas/farmacología , Implantación del Embrión/fisiología , Endometriosis/genética , Endometriosis/metabolismo , Endometriosis/patología , Endometrio/metabolismo , Células Epiteliales , Transición Epitelial-Mesenquimal/genética , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismoRESUMEN
BACKGROUND: Most disease resistance (R) genes in plants encode proteins that contain leucine-rich-repeat (LRR) and nucleotide-binding site (NBS) domains, which belong to the NBS-LRR family. The sequenced genomes of Fusarium wilt-susceptible Vernicia fordii and its resistant counterpart, Vernicia montana, offer significant resources for the functional characterization and discovery of novel NBS-LRR genes in tung tree. RESULTS: Here, we identified 239 NBS-LRR genes across two tung tree genomes: 90 in V. fordii and 149 in V. montana. Five VmNBS-LRR paralogous were predicted in V. montana, and 43 orthologous were detected between V. fordii and V. montana. The orthologous gene pair Vf11G0978-Vm019719 exhibited distinct expression patterns in V. fordii and V. montana: Vf11G0978 showed downregulated expression in V. fordii, while its orthologous gene Vm019719 demonstrated upregulated expression in V. montana, indicating that this pair may be responsible for the resistance to Fusarium wilt in V. montana. Vm019719 from V. montana, activated by VmWRKY64, was shown to confer resistance to Fusarium wilt in V. montana by a virus-induced gene silencing (VIGS) experiment. However, in the susceptible V. fordii, its allelic counterpart, Vf11G0978, exhibited an ineffective defense response, attributed to a deletion in the promoter's W-box element. CONCLUSIONS: This study provides the first systematic analysis of NBS-LRR genes in the tung tree and identifies a candidate gene that can be utilized for marker-assisted breeding to control Fusarium wilt in V. fordii.
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Fusarium , Nucleótidos , Fusarium/genética , Fitomejoramiento , Secuencia de Bases , Proteínas/genética , Resistencia a la Enfermedad/genética , Proteínas de Plantas/genéticaRESUMEN
Dwarfing rootstocks have transformed the production of cultivated apples; however, the genetic basis of rootstock-induced dwarfing remains largely unclear. We have assembled chromosome-level, near-gapless and haplotype-resolved genomes for the popular dwarfing rootstock 'M9', the semi-vigorous rootstock 'MM106' and 'Fuji', one of the most commonly grown apple cultivars. The apple orthologue of auxin response factor 3 (MdARF3) is in the Dw1 region of 'M9', the major locus for rootstock-induced dwarfing. Comparing 'M9' and 'MM106' genomes revealed a 9,723-bp allele-specific long terminal repeat retrotransposon/gypsy insertion, DwTE, located upstream of MdARF3. DwTE is cosegregated with the dwarfing trait in two segregating populations, suggesting its prospective utility in future dwarfing rootstock breeding. In addition, our pipeline discovered mobile mRNAs that may contribute to the development of dwarfed scion architecture. Our research provides valuable genomic resources and applicable methodology, which have the potential to accelerate breeding dwarfing rootstocks for apple and other perennial woody fruit trees.
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Malus , Malus/genética , Haplotipos/genética , Raíces de Plantas/genética , Fitomejoramiento , FenotipoRESUMEN
PURPOSE: Can small RNA derived from embryos in conditioned embryo culture medium (ECM) influence embryo implantation? METHODS: We employed small RNA sequencing to investigate the expression profiles of transfer RNA-derived small RNA (tsRNA) and microRNA (miRNA) in ECM from high-quality and low-quality embryos. Quantitative real-time PCR was employed to validate the findings of small RNA sequencing. Additionally, we conducted bioinformatics analysis to predict the potential functions of these small RNAs in embryo implantation. To establish the role of tiRNA-1:35-Leu-TAG-2 in embryonic trophoblast cell adhesion, we utilized co-culture systems involving JAR and Ishikawa cells. RESULTS: Our analysis revealed upregulation of nine tsRNAs and four miRNAs in ECM derived from high-quality embryos, whereas 37 tsRNAs and 12 miRNAs exhibited upregulation in ECM from low-quality embryos. The bioinformatics analysis of tsRNA, miRNA, and mRNA pathways indicated that their respective target genes may play pivotal roles in both embryo development and endometrial receptivity. Utilizing tiRNA mimics, we demonstrated that the prominently expressed tiRNA-1:35-Leu-TAG-2 in the low-quality ECM group can be internalized by Ishikawa cells. Notably, transfection of tiRNA-1:35-Leu-TAG-2 into Ishikawa cells reduced the attachment rate of JAR spheroids. CONCLUSION: Our investigation uncovers significant variation in the expression profiles of tsRNAs and miRNAs between ECM derived from high- and low-quality embryos. Intriguingly, the release of tiRNA-1:35-Leu-TAG-2 by low-quality embryos detrimentally affects embryo implantation and endometrial receptivity. These findings provide fresh insights into understanding the molecular foundations of embryo-endometrial communication.
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MicroARNs , Humanos , Femenino , MicroARNs/genética , MicroARNs/metabolismo , Implantación del Embrión/genética , Embrión de Mamíferos/metabolismo , Técnicas de Cocultivo , Desarrollo Embrionario/genética , Endometrio/metabolismoRESUMEN
Purpose: Timely medical attention is crucial for patients with Acute Ischemic Stroke (AIS), as delays can significantly impact therapeutic outcomes. These delays are influenced by a combination of socio-cultural, educational, and clinical factors. Patients and Methods: An in-depth analysis was conducted to assess the prevalence and median duration of healthcare-seeking delays in AIS patients. The study specifically investigated the independent impacts of sociocultural and clinical determinants on these delays, with a focus on immigrant status, gender disparities, and educational levels. Multivariate regression analysis was employed to identify these independent effects while controlling for potential confounding factors. Results: Among 1419 AIS patients, 82.52% (n = 1171) experienced delays exceeding 2 hours from symptom onset of symptoms to hospital arrival. The median delay was 12.3 hours. Immigrant populations encountering longer delays compared to native groups. Younger males (<45 years) and elderly females were more prone to delay in healthcare-seeking. Identified independent risk factors for delay included male gender (OR = 1.65 [95% CI:1.14-2.48]), self-acknowledged diabetes (OR = 2.50 [95% CI:1.21-5.17]), small vessel (OR = 2.07 [95% CI:1.27-3.36]), and wake stroke (OR = 7.04 [95% CI:3.69-13.44]). Educational background (high school and above), GCS score with 3-8 points (OR = 0.52 [95% CI:0.09-0.69]), understanding stroke-related knowledge (OR = 0.26 [95% CI:0.09-0.44]), conscious disturbance (OR = 0.25 [95% CI:0.10-0.62]) and limb weakness (OR=0.21[95% CI:0.21-0.49]) are protective factors for timely treatment. Conclusion: Immigrant populations experienced longer delays from symptom onset to hospital arrival. The crucial roles of education and knowledge about stroke underscore the need for enhanced health literacy campaigns and public awareness, with a targeted focus on younger males and elderly females.
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Shewanella is a prevalent bacterial genus in deep-sea environments including marine sediments, exhibiting diverse metabolic capabilities that indicate its significant contributions to the marine biogeochemical cycles. However, only a few Shewanella phages were isolated and deposited in the NCBI database. In this study, we report the isolation and characterization of a novel Shewanella phage, vB_SbaS_Y11, that infects Shewanella KR11 and was isolated from the sewage in Qingdao, China. Transmission electron microscopy revealed that vB_SbaS_Y11 has an icosahedral head and a long tail. The genome of vB_SbaS_Y11 is a linear, double-stranded DNA with a length of 62,799 bp and a G+C content of 46.9%, encoding 71 putative open reading frames. No tRNA genes or integrase-related feature genes were identified. An uncharacterized anti-CRISPR AcrVA2 gene was detected in its genome. Phylogenetic analysis based on the amino acid sequences of whole genomes and comparative genomic analyses indicate that vB_SbaS_Y11 has a novel genomic architecture and shares low similarity to Pseudomonas virus H66 and Pseudomonas phage F116. vB_SbaS_Y11 represents a potential new family-level virus cluster with eight metagenomic assembled viral genomes named Ranviridae.IMPORTANCEThe Gram-negative Shewanella bacterial genus currently includes about 80 species of mostly aquatic Gammaproteobacteria, which were isolated around the globe in a multitude of environments, such as freshwater, seawater, coastal sediments, and the deepest trenches. Here, we present a Shewanella phage vB_SbaS_Y11 that contains an uncharacterized anti-CRISPR AcrVA2 gene and belongs to a potential virus family, Ranviridae. This study will enhance the knowledge about the genome, diversity, taxonomic classification, and global distribution of Shewanella phage populations.
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Bacteriófagos , Shewanella , Bacteriófagos/genética , Shewanella/genética , Filogenia , Análisis de Secuencia de ADN , Genoma Viral , Sistemas de Lectura Abierta , ADN Viral/genéticaRESUMEN
Adhesion to gastrointestinal tract is crucial for bifidobacteria to exert their probiotic effects. Our previous work found that bile salts significantly enhance the adhesion ability of Bifidobacterium longum BBMN68 to HT-29 cells. In this study, trypsin-shaving and LC-MS/MS-based surface proteomics were employed to identify surface proteins involved in bile stress response. Among the 829 differentially expressed proteins, 56 up-regulated proteins with a fold change >1.5 were subjected to further analysis. Notably, the minor pilin subunit FimB was 4.98-fold up-regulated in response to bile stress. In silico analysis and RT-PCR confirmed that gene fimB, fimA and srtC were co-transcribed and contributed to the biosynthesis of sortase-dependent pili Pil1. Moreover, scanning electron microscopy and immunogold electron microscopy assays showed increased abundance and length of Pil1 on BBMN68 under bile stress. As the major pilin subunit FimA serves as adhesion component of Pil1, an inhibition assay using anti-FimA antibodies further confirmed the critical role of Pil1 in mediating the adhesion of BBMN68 to HT-29 cells under bile stress. Our findings suggest that the up-regulation of Pil1 in response to bile stress enhances the adhesion of BBMN68 to intestinal epithelial cells, highlighting a novel mechanism of gut persistence in B. longum strains.
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Bifidobacterium longum , Humanos , Bifidobacterium longum/genética , Proteínas Fimbrias/genética , Proteínas Fimbrias/farmacología , Bilis , Regulación hacia Arriba , Células HT29 , Cromatografía Liquida , Espectrometría de Masas en TándemRESUMEN
Stroke is the leading cause of death and disability among people in China, and it leads to heavy burdens for patients, their families and society. An accurate prediction of the risk of stroke has important implications for early intervention and treatment. In light of recent advances in machine learning, the application of this technique in stroke prediction has achieved plentiful promising results. To detect the relationship between potential factors and the risk of stroke and examine which machine learning method significantly can enhance the prediction accuracy of stroke. We employed six machine learning methods including logistic regression, naive Bayes, decision tree, random forest, K-nearest neighbor and support vector machine, to model and predict the risk of stroke. Participants were 233 patients from Sichuan and Chongqing. Four indicators (accuracy, precision, recall and F1 metric) were examined to evaluate the predictive performance of the different models. The empirical results indicate that random forest yields the best accuracy, recall and F1 in predicting the risk of stroke, with an accuracy of .7548, precision of .7805, recall of .7619 and F1 of .7711. Additionally, the findings show that age, cerebral infarction, PM 8 (an anti-atrial fibrillation drug), and drinking are independent risk factors for stroke. Further studies should adopt a broader assortment of machine learning methods to analyze the risk of stroke, by which better accuracy can be expected. In particular, RF can successfully enhance the forecasting accuracy for stroke.
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Fibrilación Atrial , Accidente Cerebrovascular , Humanos , Teorema de Bayes , Infarto Cerebral , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/etiología , Aprendizaje AutomáticoRESUMEN
Vibrio is a prevalent bacterial genus in aquatic environments and exhibits diverse metabolic capabilities, playing a vital role in marine biogeochemical cycles. This study isolated a novel virus infecting Vibrio cyclitrophicus, vB_VviC_ZQ26, from coastal waters near Qingdao, China. The vB_VviC_ZQ26 comprises a linear double-stranded DNA genome with a length of 42,982 bp and a G + C content of 43.21 %, encoding 72 putative open reading frames (ORFs). Transmission electron microscope characterization indicates a siphoviral-morphology of vB_VviC_ZQ26. Nucleic-acids-wide analysis indicates a tetranucleotide frequency deviation for genomic segments encoding putative gene transfer agent protein (GTA) and coil-containing protein, implying divergent origins occurred in different parts of viral genomes. Phylogenetic and genome-content-based analysis suggest that vB_VviC_ZQ26 represents a novel vibriophage-specific family designated as Coheviridae. From the result of biogeographic analysis, Coheviridae is mainly colonized in the temperate and tropical epipelagic zones. This study describes a novel vibriophage infecting V. cyclitrophicus, shedding light on the evolutionary divergence of different parts of the viral genome and its ecological footprint in marine environments.
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Bacteriófagos , Vibrio , Filogenia , Vibrio/genética , ADN , Genoma Viral , Sistemas de Lectura Abierta , ADN Viral/genéticaRESUMEN
The effective components of flavonoids in the "Pueraria lobata-Hovenia dulcis" drug pair have low bioavailability in vivo due to their unstable characteristics. This study used microemulsions with amphoteric carrier properties to solve this problem. The study drew pseudo-ternary phase diagrams through titration compatibility experiments of the oil phase with emulsifiers and co-emulsifiers and screened the prescription composition of blank microemulsions. The study used average particle size and PDI as evaluation indicators, and the central composite design-response surface method(CCD-RSM) was used to optimize the prescription; high-dosage drug-loaded microemulsions were obtained, and their physicochemical properties, appearance, and stability were evaluated. The results showed that when ethyl butyrate was used as the oil phase, polysorbate 80(tween 80) as the surfactant, and anhydrous ethanol as the cosurfactant, the maximum microemulsion area was obtained. When the difference in results was small, K_(m )of 1â¶4 was chosen to ensure the safety of the prescription. The prescription composition optimized by the CCD-RSM was ethyl butyrate(16.28%), tween 80(9.59%), and anhydrous ethanol(38.34%). When the dosage reached 3% of the system mass, the total flavonoid microemulsion prepared had a clear and transparent appearance, with average particle size, PDI, and potential of(74.25±1.58)nm, 0.277±0.043, and(-0.08±0.07) mV, respectively. The microemulsion was spherical and evenly distributed under transmission electron microscopy. The centrifugal stability and temperature stability were good, and there was no layering or demulsification phenomenon, which significantly improved the in vitro dissolution of total flavonoids.
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Polisorbatos , Pueraria , Polisorbatos/química , Flavonoides , Tensoactivos/química , Etanol , Emulsiones , Tamaño de la Partícula , SolubilidadRESUMEN
Recently, endoradiotherapy based on actinium-225 (225Ac) has attracted increasing attention, which is due to its α particles can generate maximal damage to cancer cells while minimizing unnecessary radiation effects on healthy tissues. Herein, 111In/225Ac-radiolabeled conjugated polymer nanoparticles (CPNs) coated with amphiphilic polymer DSPE-PEG-DOTA have been developed as a new injectable nano-radiopharmaceuticals for cancer endoradiotherapy under the guidance of nuclear imaging. Single photon emission computed tomography/computed tomography (SPECT/CT) using 111In-DOTA-PEG-CPNs as nano probe indicates a prolonged retention of radiolabeled nanocarriers, which was consistent with the in vivo biodistribution examined by direct radiometry analysis. Significant inhibition of tumor growth has been observed in murine 4T1 models treated with 225Ac-DOTA-PEG-CPNs when compared to mice treated with PBS or DOTA-PEG-CPNs. The 225Ac-DOTA-PEG-CPNs group experienced no single death within 24 days with the median survival considerably extended to 35 days, while all the mice treated with PBS or DOTA-PEG-CPNs died at 20 days post injection. Additionally, the histopathology studies demonstrated no obvious side effects on healthy tissues after treatment with 225Ac-DOTA-PEG-CPNs. All these results reveal that the new 225Ac-labeled DOTA-PEG-CPNs is promising as paradigm for endoradiotherapy.
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Nanopartículas , Neoplasias , Animales , Ratones , Polímeros , Distribución Tisular , Radiofármacos/farmacología , Radiofármacos/uso terapéutico , Línea Celular TumoralRESUMEN
Histone deacetylase 6 (HDAC6) is a unique member of the HDAC family mainly targeting cytosolic nonhistone substrates, such as α-tubulin, cortactin, and heat shock protein 90 to regulate cell proliferation, metastasis, invasion, and mitosis in tumors. We describe the identification and characterization of a series of 2-(difluoromethyl)-1,3,4-oxadiazoles (DFMOs) as selective nonhydroxamic acid HDAC6 inhibitors. By comparing structure-activity relationships and performing quantum mechanical calculations of the HDAC6 catalytic mechanism, we show that potent oxadiazoles are electrophilic substrates of HDAC6 and propose a mechanism for the bioactivation. We also observe that the inherent electrophilicity of the oxadiazoles makes them prone to degradation in water solution and the generation of potentially toxic products cannot be ruled out, limiting the developability for chronic diseases. However, the oxadiazoles demonstrate high oral bioavailability and low in vivo clearance and are excellent tools for studying the role of HDAC6 in vitro and in vivo in rats and mice.
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Neoplasias , Oxadiazoles , Ratas , Ratones , Animales , Histona Desacetilasa 6 , Oxadiazoles/farmacología , Tubulina (Proteína)/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/químicaRESUMEN
Soft swimming microrobots have attracted considerable attention due to their potential applications in diverse fields ranging from biomedicines to environmental remediation. The locomotion control is of importance to the research of micromachines and microrobots. Inspired by the motility strategies of living microorganisms, such as flagella, cilia, and euglenoids, we focus on propulsion mechanisms with a design of Janus magnetoelastic crystalline membrane microswimmers actuated by time-varying magnetic fields. Such a Janus swimmer consists of a ferromagnetic cap completed by a magnetoelastic membrane body, where superparamagnetic particles are uniformly distributed on the surface. Under the influence of external magnetic fields, the swimmer undergoes complex shape transitions due to the interplay between the magnetic dipole-dipole interactions, the elasticity of the magnetoelastic membranes, and also the hydrodynamics of surrounding fluids. We show that those shape changes are nonreciprocal, which can generate locomotion such that the propulsion speed can be optimized by tailoring the membrane elastic properties. Besides, we also demonstrate that the Janus swimmer can be magnetically guided in a spiral trajectory. With such adequate control of locomotion in both speed and direction via non-invasive magnetic fields, this study provides another promising candidate design for the future development of microswimmers.
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Cyanophages play a crucial role in the biogeochemical cycles of aquatic ecosystems by affecting the population dynamics and community structure of cyanobacteria. In this study, a novel cyanophage, Nanhaivirus ms29, that infects Synechococcus sp. MW02 was isolated from the ocean basin in the South China Sea. It was identified as a T4-like phage using transmission electron microscopy. Phylogenetic analysis demonstrated that this cyanophage is distinct from other known T4-like cyanophage, belonging to a novel genus named Nanhaivirus within the family Kyanoviridae, according to the most recent classification proposed by the International Committee on Taxonomy of Viruses (ICTV). The genome of this novel cyanophage is composed of 178,866 bp of double-stranded DNA with a G + C content of 42.5%. It contains 217 potential open reading frames (ORFs) and 6 tRNAs. As many as 30 auxiliary metabolic genes (AMGs) were identified in the genome, which related to photosynthesis, carbon metabolism, nutrient uptake and stress tolerance, possibly reflecting a genomic adaption to the oligotrophic environment. Read-mapping analysis showed that Nanhaivirus ms29 mainly distributed in temperate and tropical epipelagic waters. This study enriches of the virus gene database of cyanophages and provides valuable insights into the phylogeny of cyanophages and their interactions with their hosts.