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Depleted uranium (DU) retains the radiological toxicities, which accumulates preferentially in the kidneys. Hedgehog (Hh) pathway plays a critical role in tissue injury. However, the role of Hh in DU‐induced nephrotoxicity was still unclear. This study was carried out to investigate the effect of Gli2, which was an important transcription effector of Hh signaling, on DU induced nephrotoxicity. To clarify it, CK19 positive tubular epithelial cells specific Gli2 conditional knockout (KO) mice model was exposed to DU, and then histopathological damage and Hh signaling pathway activation was analyzed. Moreover, HEK‐293 T cells were exposed to DU with Gant61 or Gli2 overexpression, and cytotoxicity of DU as analyzed. Results showed that DU caused nephrotoxicity accompanied by activation of Hh signaling pathway. Meanwhile, genetic KO of Gli2 reduced DU‐induced nephrotoxicity by normalizing biochemical indicators and reducing Hh pathway activation. Pharmacologic inhibition of Gli1/2 by Gant61 reduced DU induced cytotoxicity by inhibiting apoptosis, ROS formation and Hh pathway activation. However, overexpression of Gli2 aggravated DU‐induced cytotoxicity by increasing the levels of apoptosis and ROS formation. Taken together, these results revealed that Hh signaling negatively regulated DU‐inducted nephrotoxicity, and that inhibition of Gli2 might serve as a promising nephroprotective target for DU‐induced kidney injury. [ABSTRACT FROM AUTHOR]

Pseudorabies virus (PRV) variants have caused substantial economic losses in the swine industry in China since 2011. To surveil the genetic variation in PRV field strains, here, two novel variant strains of PRV were isolated from Shanxi Province in central China and were designated SX1910 and SX1911. To identify the genetic characteristics of the two isolates, their complete genomes were sequenced, and phylogenetic analysis and sequence alignment revealed that field PRV variants have undergone genetic variations; notably, the protein-coding sequences UL5, UL36, US1 and IE180 exhibited extensive variation and contained one or more hypervariable regions. Furthermore, we also found that the glycoproteins gB and gD of the two isolates had some novel amino acid (aa) mutations. Importantly, most of these mutations were located on the surface of the protein molecule, according to protein structure model analysis. We constructed a mutant virus of SX1911 with deletion of the gE and gI genes via CRISPR/Cas9. When tested in mice, SX1911-ΔgE/gI-vaccinated mice were protected within a comparable range to Bartha-K61-vaccinated mice. Additionally, a higher dose of inactivated Bartha-K61 protected the mice from lethal SX1911 challenge, while a lower neutralization titer, higher viral load and more severe microscopic lesions were displayed in Bartha-K61-vaccinated mice. These findings highlight the need for continuous monitoring of PRV and novel vaccine development or vaccination program design for PRV control in China. [ABSTRACT FROM AUTHOR]

The availability of nanoparticles (NPs) to deliver small interfering RNA (siRNA) has significantly expanded the specificity and range of 'druggable' targets for precision medicine in cancer. This is especially important for cancers such as triple negative breast cancer (TNBC) for which there are no targeted treatments. Our purpose here was to understand the role of tumor vasculature and vascular endothelial growth factor (VEGF) overexpression in a TNBC xenograft in improving the delivery and function of siRNA NPs using in vivo as well as ex vivo imaging. We used triple negative MDA-MB-231 human breast cancer xenografts derived from cells engineered to overexpress VEGF to understand the role of VEGF and vascularization in NP delivery and function. We used polyethylene glycol (PEG) conjugated polyethylenimine (PEI) NPs to deliver siRNA that downregulates choline kinase alpha (Chkα), an enzyme that is associated with malignant transformation and tumor progression. Because Chkα converts choline to phosphocholine, effective delivery of Chkα siRNA NPs resulted in functional changes of a significant decrease in phosphocholine and total choline that was detected with 1H magnetic resonance spectroscopy (MRS). We observed a significant increase in NP delivery and a significant decrease in Chkα and phosphocholine in VEGF overexpressing xenografts. Our results demonstrated the importance of tumor vascularization in achieving effective siRNA delivery and downregulation of the target gene Chkα and its function. [ABSTRACT FROM AUTHOR]

Light is one of the most important environmental filters for forest understory grass communities. It is predicted that light can select species with the same light requirements, resulting in a decrease in species compositional dissimilarity among grass communities experiencing the same light intensity, and an increase in community dissimilarity under variable light intensities. However, these predictions have been questioned recently in light of modern coexistence theories, and evidence for them in natural communities is often indistinguishable from patterns created by dispersal limitation and biotic interactions. To help fill this gap, we sampled 48 understory grass communities that had regenerated from the same soil seed bank in Southern China. Plots were established under a light intensity gradient. Changes in species composition and neighborhood densities were monitored over a growing season. Our experimental setup controls for bias from dispersal limitation and is useful for detecting the effects of biotic interactions at different intensities of light. As expected, (1) compositional dissimilarity of grass communities increased between communities with different light intensities. The extent to which communities became more dissimilar was positively correlated with the difference in the light intensity. (2) No significant change in compositional dissimilarity was observed among communities experiencing the same light intensity. (3) Finally, relative neighborhood density significantly decreased in communities with moderate to high shading treatments. Our results clearly show that light can drive compositional divergence among communities under different light densities. However, the light may not lead to convergence among communities experiencing the same low light intensity, because intense competition induced by low light might enlarge species compositional differences, as shown with the neighborhood density analysis. Therefore, our study provides more convincing evidence for the importance of light on understory grass communities in subtropical forests and highlights the need to jointly consider biotic interactions when testing for evidence for environmental filtering. [ABSTRACT FROM AUTHOR]

Based on density functional theory, the spontaneous separation in the mass-imbalanced Fermi-Fermi mixture is studied. The ground-state energy density functional is constructed with the effective contact interaction, with which the ground-state density profiles of the mixture are calculated under different conditions of mass-imbalance and coupling strength. The influence of mass-imbalance on the separation and the cloud size is analyzed. In addition, the system with both mass- and population-imbalance is also calculated and studied. Despite our rough treatment in the Thomas-Fermi approximation, it is hoped that the results may provide new clues to understand the nature of phase separation of a trapped ultracold gas in both theoretical and experimental researches in the future. [ABSTRACT FROM AUTHOR]

CoFe 2 O 4 &V 2 CT x hybrid material was synthesized as a high volumetric performance anode in lithium-ion batteries by an in-situ hydrothermal method. Multilayered V 2 CT x in the hybrid acts as a superior host for homogenous loading CoFe 2 O 4 nanoparticles due to the opened two-dimensional structure of MXene, favorable electrical conductivity and low Li+ diffusion barrier. XRD results confirmed CoFe 2 O 4 &V 2 CT x hybrid had been formed, and SEM images showed the spherical CoFe 2 O 4 nanoparticles were randomly deposited on the surface of accordion-like morphology MXene. Being an anode material, it exhibited a good reversible capacity of 638.6 mAh g−1 with 97.8 % coulombic efficiency after 100 cycles at 1 C. In addition, ex-situ X-ray photoelectron spectra revealed that a redox reaction was involved in the Li+ ions extraction/insertion process. Our work provides further insight into the hybrid application of the binary metal & layered MXene hybrids as high-performance anode electrodes for lithium-ion batteries. [Display omitted] • CFO&V 2 CT x hybrid material were prepared the by in-situ hydrothermal method. • CFO&V 2 CT x hybrid exhibited a reversible capacity of 638.6 mAh g−1 after 100 cycles at 1 C. • Ex-situ XPS revealed a redox reaction was involved in the Li+ ions extraction/insertion process. [ABSTRACT FROM AUTHOR]

There are few reports on the reproductive biology of celery, which produces small flowers in a long flowering period. Anther development was analyzed by paraffin sectioning and related genes were examined by transcriptome sequencing and qPCR. The development process was divided into nine stages based on the significant changes in the cell and tissue morphologies. These stages included: archesporial stage, sporogenous cell stage, microspore mother cell stage, dyad and tetrad stage, mononuclear microspore stage, late uninucleate microspore stage, binuclear cell stage, mature pollen stage, and dehiscence stage. A total of 1074 differentially expressed genes were identified by transcriptome sequencing in the early flower bud, middle flower bud, and early flowering period. Functional annotation indicated that these genes were involved in physiological and biochemical processes such as ribosomes metabolism, sugar metabolism, and amino acid metabolism. Transcription factors such as C2H2, AP2/ERF, bZIP, WRKY, and MYB played key regulatory roles in anther development and had different regulatory capabilities at various stages. The expression patterns based on qPCR and transcriptome data of the selected transcription factor genes showed consistency, suggesting that these genes played an important role in different flower development stages. These results provide a theoretical basis for molecular breeding of new celery varieties with pollen abortion. Furthermore, they have enriched research on the reproductive biology of celery and the Apiaceae family. [ABSTRACT FROM AUTHOR]

Abstract: Cancer and other acute and chronic diseases are results of perturbations of common molecular determinants in key biological and signaling processes. Imaging is critical for characterizing dynamic changes in tumors and metastases, the tumor microenvironment, tumor-stroma interactions, and drug targets, at multiscale levels. Magnetic resonance imaging (MRI) has emerged to be a primary imaging modality for both clinical and preclinical applications due to its advantages over other modalities, including sensitivity to soft tissues, nondepth limitations, and the use of nonionizing radiation. However, extending the application of MRI to achieve both qualitative and quantitative precise molecular imaging with the capability to quantify molecular biomarkers for early detection, staging, and monitoring therapeutic treatment requires the capacity to overcome several major challenges including the trade-off between metal-binding affinity and relaxivity, which is an issue frequently associated with small chelator contrast agents. In this review, we will introduce the criteria of ideal contrast agents for precision molecular imaging and discuss the relaxivity of current contrast agents with defined first shell coordination water molecules. We will then report our advances in creating a new class of protein-targeted MRI contrast agents (ProCAs) with contributions to relaxivity largely derived from the secondary sphere and correlation time. We will summarize our rationale, design strategy, and approaches to the development and optimization of our pioneering ProCAs with desired high relaxivity, metal stability, and molecular biomarker-targeting capability, for precision MRI. From first generation (ProCA1) to third generation (ProCA32), we have achieved dual high r1 and r2 values that are 6- to 10-fold higher than clinically approved contrast agents at magnetic fields of 1.5 T, and their relaxivity values at high field are also significantly higher, which enables high resolution during small animal imaging. Further engineering of multiple targeting moieties enables ProCA32 agents that have strong biomarker-binding affinity and specificity for an array of key molecular biomarkers associated with various chronic diseases, while maintaining relaxation and exceptional metal-binding and selectivity, serum stability, and resistance to transmetallation, which are critical in mitigating risks associated with metal toxicity. Our leading product ProCA32.collagen has enabled the first early detection of liver metastasis from multiple cancers at early stages by mapping the tumor environment and early stage of fibrosis from liver and lung in vivo, with strong translational potential to extend to precision MRI for preclinical and clinical applications for precision diagnosis and treatment., Competing Interests: Conflicts of interest and sources of funding: J.J.Y. holds shares in the company InLighta Biosciences LLC, which licenses the rights to commercialize protein-targeted MRI contrast agents. J.J.Y. is a named inventor on issued or pending patents (US8173105 [EP1901659], US8367040 [EP3378496] contrast agents, US9339559 [EP1928507, CA 2621763], US 10525150 targeted contrast agents, US9956304 [EP2257316], US15/910893, US17/068215 contrast agents and imaging, US15/572,863 [WO16793465.2] targeted contrast agents)., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Chronic lung diseases, such as idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD), are major leading causes of death worldwide and are generally associated with poor prognoses. The heterogeneous distribution of collagen, mainly type I collagen associated with excessive collagen deposition, plays a pivotal role in the progressive remodeling of the lung parenchyma to chronic exertional dyspnea for both IPF and COPD. To address the pressing need for noninvasive early diagnosis and drug treatment monitoring of pulmonary fibrosis, we report the development of human collagen-targeted protein MRI contrast agent (hProCA32.collagen) to specifically bind to collagen I overexpressed in multiple lung diseases. When compared to clinically approved Gd 3+ contrast agents, hProCA32.collagen exhibits significantly better r 1 and r 2 relaxivity values, strong metal binding affinity and selectivity, and transmetalation resistance. Here, we report the robust detection of early and late-stage lung fibrosis with stage-dependent MRI signal-to-noise ratio (SNR) increase, with good sensitivity and specificity, using a progressive bleomycin-induced IPF mouse model. Spatial heterogeneous mapping of usual interstitial pneumonia (UIP) patterns with key features closely mimicking human IPF, including cystic clustering, honeycombing, and traction bronchiectasis, were noninvasively detected by multiple MR imaging techniques and verified by histological correlation. We further report the detection of fibrosis in the lung airway of an electronic cigarette-induced COPD mouse model, using hProCA32.collagen-enabled precision MRI (pMRI), and validated by histological analysis. The developed hProCA32.collagen is expected to have strong translational potential for the noninvasive detection and staging of lung diseases, and facilitating effective treatment to halt further chronic lung disease progression., Competing Interests: The authors declare the following competing financial interest(s): J.J.Y. holds shares in the company InLighta Biosciences LLC, which licenses the rights to commercialize ProCAs. J.J.Y. is a named inventor on issued or pending patents (US8173105 (EP1901659), US8367040 (EP3378496) contrast agents, US9339559 (EP1928507, CA 2621763), US 10525150 targeted contrast agents, US9956304 (EP2257316), US15/910893, US17/068215 contrast agents and imaging, US15/572,863 (WO16793465.2) targeted contrast agents)., (© 2023 The Authors. Co-published by Nanjing University and American Chemical Society.)

Liver metastases often progress from primary cancers including uveal melanoma (UM), breast, and colon cancer. Molecular biomarker imaging is a new non-invasive approach for detecting early stage tumors. Here, we report the elevated expression of chemokine receptor 4 (CXCR4) in liver metastases in UM patients and metastatic UM mouse models, and development of a CXCR4-targeted MRI contrast agent, ProCA32.CXCR4, for sensitive MRI detection of UM liver metastases. ProCA32.CXCR4 exhibits high relaxivities ( r 1 = 30.9 mM -1 s -1 , r 2 = 43.2 mM -1 s -1 , 1.5 T; r 1 = 23.5 mM -1 s -1 , r 2 = 98.6 mM -1 s -1 , 7.0 T), strong CXCR4 binding ( K d = 1.10 ± 0.18 μM), CXCR4 molecular imaging capability in metastatic and intrahepatic xenotransplantation UM mouse models. ProCA32.CXCR4 enables detecting UM liver metastases as small as 0.1 mm 3 . Further development of the CXCR4-targeted imaging agent should have strong translation potential for early detection, surveillance, and treatment stratification of liver metastases patients., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

BACKGROUND This study aimed to investigate the molecular mechanisms associated with the effects of propofol in a rat model of pain due to inflammation following subcutaneous injection with complete Freund's adjuvant (CFA). MATERIAL AND METHODS Sprague-Dawley rats were injected subcutaneously in the paw with CFA. Propofol or saline was administered by tail vein injection. After CFA treatment for 0 hours, 4 hours, 1 day, 4 days, 7 days, and 14 days, the behavior of the rats was assessed. An enzyme-linked immunosorbent assay (ELISA) measured serum levels of proinflammatory cytokines, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1ß, and IL-6. Western blot and the quantitative reverse-transcription polymerase chain reaction (qRT-PCR) were used to detect levels of p38MAPK and NF-kappaB related mRNA and proteins, including p-p38, p38, p65, p-p65, NOD-like receptor family protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC) and caspase-1 in rat spinal cord tissues. RESULTS Injection of CFA significantly reduced the mechanical withdrawal threshold (MWT), thermal withdrawal latency (TWL), and frequency responses to cold stimulation. Propofol treatment significantly reduced serum levels of TNF-alpha, IL-1ß, and IL-6. Protein expression levels of p-p38 and p-p65 were upregulated in the rat model, which were inhibited by propofol treatment. CFA injection increased the expression levels of NLRP3, ASC, and caspase-1 in the spinal cord tissues of rats, which were reduced by propofol treatment. CONCLUSIONS In a rat model of pain following subcutanous injection with CFA, propofol reduced CFA-induced pain and inhibited the inflammatory response through the p38MAPK-nuclear factor-kappaB (NF-kappaB) pathway and the NLRP3 inflammasome.