The androgen receptor (AR) has been linked to bladder cancer (BCa) progression, but if this involves circular RNAs (circRNAs) remains unclear. Here, we find that AR alters the levels of circRNA‐FNTA ...(circFNTA) to increase BCa cell invasion and chemo‐resistance. Mechanistically, AR represses the RNA editing gene ADAR2 via direct binding to its 5′ promoter region to increase circFNTA levels, which then sponges the microRNA miR‐370‐3p to increase the expression of its host gene FNTA. This AR‐mediated ADAR2/circFNTA/miR‐370‐3p/FNTA pathway then activates KRAS signaling to alter BCa cell invasion and chemo‐sensitivity to cisplatin. A clinical BCa sample survey shows that circFNTA expression is elevated in BCa tissues, and results from a BCa mouse model indicate that depletion of circFNTA leads to the suppression of BCa metastases and increased cisplatin chemo‐sensitivity. Together, based on our results using multiple BCa cell lines and an in vivo mouse model we suggest that targeting this newly identified AR/ADAR2/circFNTA/miR‐370‐3p/FNTA/KRAS axis may lead to the development of therapies to suppress BCa metastasis and to increase its chemo‐sensitivity.
Synopsis
The androgen receptor‐regulated circFNTA alters bladder cancer invasion and chemo‐resistance via modulating the miR‐370‐3p/FNTA/KRAS axis. Targeting this signaling pathway might establish novel therapies to suppress bladder cancer progression.
The androgen receptor represses the RNA editing gene ADAR2 to increase circFNTA expression.
circFNTA sponges miR‐370‐3p to increase the expression of its host gene FNTA.
AR‐mediated ADAR2/circFNTA/miR‐370‐3p/FNTA signaling activates KRAS to alter cell invasion and chemo‐sensitivity.
The androgen receptor‐regulated circFNTA alters bladder cancer invasion and chemo‐resistance via modulating the miR‐370‐3p/FNTA/KRAS axis. Targeting this signaling pathway might establish novel therapies to suppress bladder cancer progression.
Cutaneous malignant melanoma is an aggressive cancer of melanocytes with a strong propensity to metastasize. We posit that melanoma cells acquire metastatic capability by adopting an embryonic-like ...phenotype, and that a lineage approach would uncover metastatic melanoma biology. Using a genetically engineered mouse model to generate a rich melanoblast transcriptome dataset, we identify melanoblast-specific genes whose expression contribute to metastatic competence and derive a 43-gene signature that predicts patient survival. We identify a melanoblast gene, KDELR3, whose loss impairs experimental metastasis. In contrast, KDELR1 deficiency enhances metastasis, providing the first example of different disease etiologies within the KDELR-family of retrograde transporters. We show that KDELR3 regulates the metastasis suppressor, KAI1, and report an interaction with the E3 ubiquitin-protein ligase gp78, a regulator of KAI1 degradation. Our work demonstrates that the melanoblast transcriptome can be mined to uncover targetable pathways for melanoma therapy.
During respiration, particulate matter with a diameter of 2.5 µm or less (PM
) suspended in the atmosphere enters the terminal alveoli and blood. PM
particles can attach to toxic substances, ...resulting in health problems. Limited information is available regarding the effects of prenatal exposure to water-soluble PM
(WS-PM
) and water-insoluble PM
(WI-PM
) on male reproduction. In addition, whether exposure to these particles has transgenerational effects remains unknown. We investigated whether prenatal exposure to WS-PM
and WI-PM
disrupts sperm function in generations F1, F2, and F3 of male mice. Pregnant BALB/c mice were treated using intratracheal instillation on gestation days 7, 11, and 15 with 10 mg of a water extract or insoluble PM
. On postnatal day 105, epididymal sperm count, motility, morphology, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) production, the sperm chromatin DNA fragmentation index (DFI), and testicular DNA methyltransferase (Dnmt) levels were evaluated in all generations. Whole-genome bisulfite sequencing was used to analyze the DNA methylation status of generation F3. According to the results, exposure to WS-PM
affected sperm morphology, ROS production, and mean DFI in generation F1; ROS production and mean DFI in generation F2; and sperm morphology and MMP in generation F3. Similarly, exposure to WI-PM
affected sperm morphology, ROS production, mean DFI, %DFI, and Dnmt1 expression in generation F1; sperm morphology, MMP, and ROS production in generation F2; and sperm morphology, ROS, and %DFI in generation F3. Two hypermethylated genes, PRR16 and TJP2, were observed in the WS-PM
and WI-PM
groups, two hypomethylated genes, NFATC1 and APOA5, were observed in the WS-PM
group, and two hypomethylated genes, ZFP945 and GSE1, were observed in the WI-PM
group. Hence, prenatal exposure to PM
resulted in transgenerational epigenetic effects, which may explain certain phenotypic changes in male reproduction.
Carbon nanotube reinforced copper alloy (CNT/Cu) composites with high strength and good wear resistance have been developed using acid treatment, sintering processes and consolidation techniques. The ...effects of CNT reinforcement and grain size refinement on the mechanical properties and surface deformations of CNT/Cu composite coatings are investigated by means of nanoindentation and block-on-ring wear tests, respectively. High-resolution transmission electron microscopy (HRTEM), scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS) analyses reveal that the CNTs are firmly implanted in the Cu alloy due to the formation of Cu-oxides at the CNT-Cu interface. The effect of CNT addition on the CNT/Cu coating strength is significantly greater than that of grain size reinforcement. Finally, the present results indicate that the addition of CNTs to the Cu matrix reduces the surface deformations of the CNT/Cu composite coatings due to the formation of a carbonaceous solid-lubricant film at the contact interface during sliding.
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•Grain size refinement and CNT reinforcement for CNT/Cu composite are studied.•Morphological and structural characterizations of Cu-coated CNT are investigated.•Mechanical properties and surface deformations of CNT/Cu composites are examined.
Herein, we aim to develop a facile method for the fabrication of mechanical metamaterials from templated polymerization of thermosets including phenolic and epoxy resins using self-assembled block ...copolymer, polystyrene–polydimethylsiloxane with tripod network (gyroid), and tetrapod network (diamond) structures, as templates. Nanoindentation studies on the nanonetwork thermosets fabricated reveal enhanced energy dissipation from intrinsic brittle thermosets due to the deliberate structuring; the calculated energy dissipation for gyroid phenolic resins is 0.23 nJ whereas the one with diamond structure gives a value of 0.33 nJ. Consistently, the gyroid-structured epoxy gives a high energy dissipation value of 0.57 nJ, and the one with diamond structure could reach 0.78 nJ. These enhanced properties are attributed to the isotropic periodicity of the nanonetwork texture with plastic deformation, and the higher number of struts in the tetrapod diamond network in contrast to tripod gyroid, as confirmed by the finite element analysis.
The urothelium of the bladder, renal pelvis, ureter and urethra is maintained through the regulated proliferation and differentiation of urothelial stem and progenitor cells. These cells provide a ...rich source of a novel urothelial cell therapy approach that could be used to protect, regenerate, repair and restore a damaged urothelium. Urothelial injury caused by physical, chemical and microbial stress is the pathological basis of cystitis (bladder inflammation). The loss of urothelial integrity triggers a series of inflammatory events, resulting in pain and hematuria such as hemorrhage cystitis and interstitial cystitis. Here we investigate a novel cell therapy strategy to treat cystitis by protecting the urothelium from detrimental stresses through intravesically instilling porcine urothelial cells (PUCs) into the bladder. Using a chemical-induced urothelial injury mouse model of cyclophosphamide (CPP)-induced hemorrhagic cystitis, we determined how the intravesical instillation of PUCs could protect the urothelium from toxic attack from CPP metabolites. We show that intravesical PUC instillation protected the bladder from toxic chemical attack in mice receiving CPP with reduced inflammation and edema. Compared with the vehicle control mice, the proliferative response to chemical injury and apoptotic cells within the bladder tissues were reduced by intravesical PUC treatment. Furthermore, the urothelium integrity was maintained in the intravesical PUC-treated group. After xenogeneic PUCs were introduced and adhered to the mouse urothelium, immunological rejection responses were observed with increased neutrophil infiltration in the lamina propria and higher immune-related gene expression. Our findings provide an innovative and promising intravesical PUC cell therapy for cystitis with urothelial injury by protecting the urothelium from noxious agents.
Phosphorylation and dephosphorylation of viral movement proteins plays a crucial role in regulating virus movement. Our study focused on investigating the movement protein TGBp1 of
(BaMV), which is a ...single-stranded positive-sense RNA virus. Specifically, we examined four potential phosphorylation sites (S15, S18, T58, and S247) within the TGBp1 protein. To study the impact of phosphorylation, we introduced amino acid substitutions at the selected sites. Alanine substitutions were used to prevent phosphorylation, while aspartate substitutions were employed to mimic phosphorylation. Our findings suggest that mimicking phosphorylation at S15, S18 and T58 of TGBp1 might be linked to silencing suppressor activities. The phosphorylated form at these sites exhibits a loss of silencing suppressor activity, leading to reduced viral accumulation in the inoculated leaves. Furthermore, mimicking phosphorylation at residues S15 and S18 could diminish viral accumulation at the single-cell level, while doing so at residue T58 could influence virus movement. However, mimicking phosphorylation at residue S247 does not appear to be relevant to both functions of TGBp1. Overall, our study provides insights into the functional significance of specific phosphorylation sites in BaMV TGBp1, illuminating the regulatory mechanisms involved in virus movement and silencing suppression.
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•Thermal characteristics of Cu nanoparticles (NPs) are studied by MD simulations.•Surface effects on the coalescence and melting behaviors of Cu NPs are revealed.•Epitaxial nucleation ...of Cu NP thin films on a graphene surface is examined.•Structure evolutions and formations of nanoparticle thin films are investigated.
A detailed understanding of surface decoration and interconnecting technologies is essential in realizing high-performance functional devices incorporating metal nanoparticle/graphene nanohybrids. This study employs classical molecular dynamics (MD) simulations to investigate the formation of amorphous copper (Cu) layers on a graphene surface via the collision, coalescence and nucleation of individual Cu nanoparticles (NPs) at temperatures in the range of 300–1300 K. The results indicate that the coalescence and melting temperatures are both sensitive to the particle size and the presence of the substrate. Moreover, an epitaxial interaction is found between the Cu NPs and the graphene substrate, in which mobile Cu atoms are captured and dragged to the graphene surface to produce self-assembled NP layers via a nucleation process. A series of structural evolutions and phase transitions are revealed during thethermalization process of the NPs. Finally, the results show that the presence of the substrate and associated contact epitaxy phenomenon play a key role in governing the structural morphology and thermal behavior of the Cu NP-based thin film.
Metastatic castration-resistant prostate cancer (mCRPC) is a progressive stage of prostate cancer that often spreads to the bone. Radium-223, a bone-targeting radiopharmaceutical, has been shown to ...improve the overall survival in mCRPC in patients without visceral metastasis. However, the impact of prior systemic therapy on the treatment outcome of mCRPC patients receiving radium-223 remains unclear. This study aimed to investigate the optimal choice of systemic therapy before radium-223 in mCRPC patients. The study included 41 mCRPC patients who received radium-223 therapy, with 22 receiving prior enzalutamide and 19 receiving prior abiraterone. The results showed that the median overall survival was significantly longer in the enzalutamide group than in the abiraterone group (25.1 months vs. 14.8 months,
= 0.049). Moreover, the number of patients requiring blood transfusion was higher in the abiraterone group than in the enzalutamide group (9.1% vs. 26.3%,
= 0.16). The study also found that the number of doses of Radium-223 received was significantly associated with overall survival (≥5 vs. <5, HR 0.028, 95%CI 0.003-0.231,
= 0.001). Our study provides insights into the optimal treatment choice for mCRPC prior to radium-223, indicating that enzalutamide prior to radium-223 administration may have better outcomes compared to abiraterone in mCRPC patients without visceral metastasis.
In this brief, we propose a reconfigurable hardware architecture of successive cancellation (SC) decoder with supporting multiple modes. We also develop three design techniques, including low-area ...quantization scheme (LA-QS), high-efficient frozen-bit control scheme (HE-FBCS), and grouping storage circuit (GSC). In the ASIC design implementation via TSMC 40-nm CMOS technology, it only has a core area occupation of 1.312 mm 2 and supports 4 operating modes, ranging from 1024 to 8192 bits. It operates at maximal operating frequency of 1.0 GHz, delivering a maximal throughput of 3.341 Gbps. As compared with state-of-the-art works, our innovative and reconfigurable multi-mode Polar decoder architecture owns superior chip performance, especially in terms of total chip area cost and system throughput.
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