Search

Abstract The PEGylated ultrasmall iron oxide nanoparticles (PUSIONPs) exhibit longer blood residence time and better biodegradability than conventional gadolinium‐based contrast agents (GBCAs), enabling prolonged acquisitions in contrast‐enhanced magnetic resonance angiography (CE‐MRA) applications. The image quality of CE‐MRA is dependent on the contrast agent concentration and the parameters of the pulse sequences. Here, a closed‐form mathematical model is demonstrated and validated to automatically optimize the concentration, echo time (TE), repetition time (TR) and flip angle (FA). The pharmacokinetic studies are performed to estimate the dynamic intravascular concentrations within 12 h postinjection, and the adaptive concentration‐dependent sequence parameters are determined to achieve optimal signal enhancement during a prolonged measurement window. The presented model is tested on phantom and in vivo rat images acquired from a 3T scanner. Imaging results demonstrate excellent agreement between experimental measurements and theoretical predictions, and the adaptive sequence parameters obtain better signal enhancement than the fixed ones. The low‐dose PUSIONPs (0.03 mmol kg−1 and 0.05 mmol kg−1) give a comparable signal intensity to the high‐dose one (0.10 mmol kg−1) within 2 h postinjection. The presented mathematical model provides guidance for the optimization of the concentration and sequence parameters in PUSIONPs‐enhanced MRA, and has great potential for further clinical translation.

Abstract The early diagnosis of hepatocellular carcinomas (HCCs) remains challenging in the clinic. Primovist‐enhanced magnetic resonance imaging (MRI) aids HCC diagnosis but loses sensitivity for tumors

Abstract Recent development of new immune checkpoint inhibitors has been particularly successfully in cancer treatment, but still the majority patients fail to benefit. Converting resistant tumors to immunotherapy sensitive will provide a significant improvement in patient outcome. Here we identify Mi-2β as a key melanoma-intrinsic effector regulating the adaptive anti-tumor immune response. Studies in genetically engineered mouse melanoma models indicate that loss of Mi-2β rescues the immune response to immunotherapy in vivo. Mechanistically, ATAC-seq analysis shows that Mi-2β controls the accessibility of IFN-γ-stimulated genes (ISGs). Mi-2β binds to EZH2 and promotes K510 methylation of EZH2, subsequently activating the trimethylation of H3K27 to inhibit the transcription of ISGs. Finally, we develop an Mi-2β-targeted inhibitor, Z36-MP5, which reduces Mi-2β ATPase activity and reactivates ISG transcription. Consequently, Z36-MP5 induces a response to immune checkpoint inhibitors in otherwise resistant melanoma models. Our work provides a potential therapeutic strategy to convert immunotherapy resistant melanomas to sensitive ones.

Abstract Background Neuromyelitis optica spectrum disorder (NMOSD) is a recurring inflammatory demyelinating disease that is commonly observed in Asian countries like China. Prior investigations have shown that mycophenolate mofetil (MMF) with better biocompatibility compared to azathioprine (AZA), and can prevent relapses of NMOSD, but the efficacy was controversially reported in different NMOSD cases. We aimed to explore the factors that weaken efficacy of MMF in NMOSD. Methods A total of 34 NMOSD patients treated with MMF were prospectively enrolled and grouped according to the therapeutic efficacy as effective group (EG, n = 23) versus less-effective group (LEG, n = 11). The purine metabolites were profiled in serum samples and gut microbiota was analyzed using 16S rRNA sequencing with stool samples from the same patients. Results Purine salvage pathway (PSP) metabolites (inosine, hypoxanthine, xanthine, guanine and uric acid) in the serum of NMOSD patients were elevated in the LEG compared to EG (p

The wound mechanism, injury characteristics and treatment principles of anti-armored vehicle ammunition against armored crew in the past 20 years are summarized in this paper. Shock vibration, metal jet, depleted uranium aerosol and post armor breaking effect are the main factors for wounding armored crew. Their prominent characteristics are severe injury, high incidence of bone fracture, high rate of depleted uranium injury, and high incidence of multiple/combined injuries. During the treatment, attention must be paid on that the space of armored vehicle is limited, and the casualties should be moved outside of the cabin for comprehensive treatment. Especially, the management of depleted uranium injury and burn/inhalation injury are more important than other injuries for the armored wounds.

Abstract Viruses have evolved various strategies to achieve early infection by initiating transcription of their own early genes via host transcription factors, such as NF-κb, STAT, and AP1. How the host copes with this immune escape has been a topic of interest. Tripartite motif (TRIM) family proteins with RING-type domains have E3 ubiquitin ligase activity and are known as host restriction factors. Trim has been reported to be associated with phagocytosis and is also believed to be involved in the activation of autophagy. Preventing the virus from entering the host cell may be the most economical way for the host to resist virus infection. The role of TRIM in the early stage of virus infection in host cells remains to be further interpreted. In the current study, a crayfish TRIM with a RING-type domain, designated as PcTrim, was significantly upregulated under white spot syndrome virus (WSSV) infection in the red swamp crayfish (Procambarus clarkii). Recombinant PcTrim significantly inhibited WSSV replication in crayfish. RNAi targeting PcTrim or blocking PcTrim with an antibody promoted WSSV replication in crayfish. Pulldown and co-IP assays showed that PcTrim can interact with the virus protein VP26. PcTrim restricts the expression level of dynamin, which is involved in the regulation of phagocytosis, by inhibiting AP1 entry into the nucleus. AP1-RNAi effectively reduced the expression levels of dynamin and inhibited host cell endocytosis of WSSV in vivo. Our study demonstrated that PcTrim might reduce early WSSV infection by binding to VP26 and then inhibiting AP1 activation, resulting in reduced endocytosis of WSSV in crayfish hemocytes. Video Abstract

The widespread of tetracycline (TC) residues in anthropogenic and natural environments pose an immediate threat to public health. Herein, we established the TET-Yeasate, an approach based on whole-cell lysate of engineered yeast, to mitigate the TC contamination in environment. The TET-Yeasate is defined as the biological matrix of whole cell lysate from engineered yeast that containing TC-degradative components (Tet(X), NADPH, Mg2+) and protective macromolecules. The TET-Yeasate was able to efficiently eliminate TC residues in tap water (98.8%), lake water (77.6%), livestock sewage (87.3%) and pharmaceutical wastewater (35.3%) without necessity for exogenous addition of expensive cofactors. The TET-Yeasate was further developed into lyophilized form for ease of storage and delivery. The TET-Yeasate in lyophilized form efficiently removed up to 74.6% TC residue within 0.25 h. In addition, the lyophilization confers promising resilience to TET-Yeasate against adverse temperatures and pH by maintaining degradation efficacy of 85.69%−97.83%. The stability test demonstrated that the biomacromolecules in lysate served as natural protectants that exerted extensive protection on TET-Yeasate during the 14-day storage at various conditions. In addition, 5 potential degradation pathways were elaborated based on the intermediate products. Finally, the analysis indicated that TET-Yeasate enjoyed desirable bio- and eco-safety without introduction of hazardous intermediates and spread of resistance genes. To summary, the TET-Yeasate based on whole cell lysate of engineered yeast provides a cost-effective and safe alternative to efficiently remove TC residues in environment, highlighting the great potential of such whole-cell based methods in environmental decontamination.

China, like many countries, is under great pressure to reduce climate change and adapt to current situations while simultaneously undertaking economic development and transformation. This study takes advantage of climate opportunities and provides a new concept and mode of urban climate services in order to address climate change. Eighteen indicators based on climate and climate-related variables were used to provide an assessment, in the form of an index, of how livable a city is depending on prevailing climatic conditions. The resulting index can also be used to investigate how recent and future changes in the climatic conditions could affect livability. All Chinese cities and regions share the common goals of promoting low-carbon development, improving resilience against climate change, and integrating economic growth with climate actions. Climate services have been developed in China to provide decision-makers this measure of livability. Such a move facilitates sustainable development alongside economic growth by aiding government efforts in climate adaptation and low-carbon development. Our approach represents multidisciplinary and demand-driven research on adaptation to and the impacts of regional climate change, thereby transforming climate science into a climate service and ensuring that climate information can be provided in a scientific, practical, and customized way for policy-makers. The outputs can be used locally to take concrete climate actions and integrate climate services into decision-making processes.

Toll and Toll-like receptors (TLRs) play essential roles in the innate immunity of Drosophila and mammals. Recent studies have revealed the presence of Toll-mediated immune signaling pathways in shrimp. However, the recognition and activation mechanism of Toll signaling pathways in crustaceans remain poorly understood due to the absence of key recognition molecules, such as peptidoglycan recognition proteins. Here, a novel MD2-related lipid-recognition (ML) member named PvML1 was characterized in Penaeus vannamei. We found that PvML1 shared a similar 3D structure with human MD2 that could specifically recognize lipopolysaccharides (LPS) participating in LPS-mediated TLR4 signaling. PvML1 was highly expressed in hemocytes and remarkably upregulated after Vibrio parahemolyticus challenge. Furthermore, the binding and agglutinating assays showed that PvML1 possessed strong binding activities to LPS and its key portion lipid A as well as Vibrio cells, and the binding of PvML1 with bacterial cells led to the agglutination of bacteria, suggesting PvML1 may act as a potential pathogen recognition protein upon interaction with LPS. Besides, coating V. parahemolyticus with recombinant PvML1 promoted bacterial clearance in vivo and increased the survival rate of bacterium-challenged shrimp. This result was further confirmed by RNAi experiments. The knockdown of PvML1 remarkably suppressed the clearance of bacteria in hemolymph and decreased the survival rate of infected shrimp. Meanwhile, the silencing of PvML1 severely impaired the expression of a few antimicrobial peptides (AMPs). These results demonstrated the significant correlation of bacterial clearance mediated by PvML1 with the AMP expression. Interestingly, we found that PvML1 interacted with the extracellular region of PvToll2, which had been previously shown to participate in bacterial clearance by regulating AMP expression. Taken together, the proposed antibacterial model mediated by PvML1 might be described as follows. PvML1 acted as a potential recognition receptor for Gram-negative bacteria by binding to LPS, and then it activated PvToll2-mediated signaling pathway by interacting with PvToll2 to eliminate invading bacteria through producing specific AMPs. This study provided new insights into the recognition and activation mechanism of Toll signaling pathways of invertebrates and the defense functions of ML members.

Although human gC1qR is a multi-ligand binding protein with diverse biological functions, the functions of invertebrate gC1qR homologues remain largely unknown. In the present study, we characterized a novel gC1qR homologue, namely SpgC1qR, from mud crab Scylla paramamosain. SpgC1qR shared high identity and similar three-dimensional structure with human gC1qR. After challenge with White spot syndrome virus (WSSV), the transcripts of SpgC1qR were significantly increased, suggesting that SpgC1qR may be involved in antiviral immune response. To reveal the likely antiviral activity of SpgC1qR, the proliferation profile of WSSV in SpgC1qR-silenced crabs was examined. The result showed that knockdown of SpgC1qR by RNAi facilitated viral proliferation in vivo. This result was further confirmed by a SpgC1qR pre-incubation assay, in which pre-incubating WSSV particles with rSpgC1qR dramatically suppressed viral replication. Moreover, a GST pull-down assay revealed that SpgC1qR specifically bound to the viral envelope protein VP28. These findings clearly demonstrated that SpgC1qR specifically interacted with viral envelope protein VP28 and restricted WSSV replication, suggesting that it played a crucial role in anti-WSSV immune response of mud crab. This study provided new insights into the antiviral mechanism mediated by SpgC1qR and the biological functions of invertebrate gC1qR homologues.

Previous studies have shown that the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway has antiviral functions or is beneficial for viral replication, however, the detail mechanisms by which mTORC1 enhances viral infection remain unclear. Here, we found that proliferation of white spot syndrome virus (WSSV) was decreased after knockdown of mTor (mechanistic target of rapamycin) or injection inhibitor of mTORC1, rapamycin, in Marsupenaeus japonicus, which suggests that mTORC1 is utilized by WSSV for its replication in shrimp. Mechanistically, WSSV infects shrimp by binding to its receptor, polymeric immunoglobulin receptor (pIgR), and induces the interaction of its intracellular domain with Calmodulin. Calmodulin then promotes the activation of protein kinase B (AKT) by interaction with the pleckstrin homology (PH) domain of AKT. Activated AKT phosphorylates mTOR and results in the activation of the mTORC1 signaling pathway to promote its downstream effectors, ribosomal protein S6 kinase (S6Ks), for viral protein translation. Moreover, mTORC1 also phosphorylates eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1), which will result in the separation of 4EBP1 from eukaryotic translation initiation factor 4E (eIF4E) for the translation of viral proteins in shrimp. Our data revealed a novel pathway for WSSV proliferation in shrimp and indicated that mTORC1 may represent a potential clinical target for WSSV control in shrimp aquaculture.

Trained immunity is driven by metabolism and epigenetics in innate immune cells in mammals. The phenomenon of trained immunity has been identified in invertebrates, including shrimp, but the underlying mechanisms remain unclear. To elucidate mechanisms of trained immunity in shrimp, the metabolomic changes in hemolymph of Marsupenaeus japonicus trained by the UV-inactivated white spot syndrome virus (UV-WSSV) were analyzed using tandem gas chromatography–mass/mass spectrometry. The metabolomic profiles of shrimp trained with UV-WSSV followed WSSV infection showed significant differences comparison with the control groups, PBS injection followed WSSV infection. 16 differential metabolites in total of 154 metabolites were identified, including D-fructose-6-phosphate, D-glucose-6-phosphate, and D-fructose-6-phosphate, and metabolic pathways, glycolysis, pentose phosphate pathway, and AMPK signaling pathway were enriched in the UV-WSSV trained groups. Further study found that histone monomethylation and trimethylation at H3K4 (H3K4me1 and H3K4me3) were involved in the trained immunity. Our data suggest that the UV-WSSV induced trained immunity leads to metabolism reprogramming in the shrimp and provide insights for WSSV control in shrimp aquaculture.

Abstract Background The recent emergence and dissemination of high-level mobile tigecycline resistance Tet(X) challenge the clinical effectiveness of tigecycline, one of the last-resort therapeutic options for complicated infections caused by multidrug-resistant Gram-negative and Gram-positive pathogens. Although tet(X) has been found in various bacterial species, less is known about phylogeographic distribution and phenotypic variance of different genetic variants. Methods Herein, we conducted a multiregional whole-genome sequencing study of tet(X)-positive Acinetobacter isolates from human, animal, and their surrounding environmental sources in China. The molecular and enzymatic features of tet(X) variants were characterized by clonal expression, microbial degradation, reverse transcription, and gene transfer experiments, while the tet(X) genetic diversity and molecular evolution were explored by comparative genomic and Bayesian evolutionary analyses. Results We identified 193 tet(X)-positive isolates from 3846 samples, with the prevalence ranging from 2.3 to 25.3% in nine provinces in China. The tet(X) was broadly distributed in 12 Acinetobacter species, including six novel species firstly described here. Besides tet(X3) (n = 188) and tet(X4) (n = 5), two tet(X5) variants, tet(X5.2) (n = 36) and tet(X5.3) (n = 4), were also found together with tet(X3) or tet(X4) but without additive effects on tetracyclines. These tet(X)-positive Acinetobacter spp. isolates exhibited 100% resistance rates to tigecycline and tetracycline, as well as high minimum inhibitory concentrations to eravacycline (2–8 μg/mL) and omadacycline (8–16 μg/mL). Genetic analysis revealed that different tet(X) variants shared an analogous ISCR2-mediated transposon structure. The molecular evolutionary analysis indicated that Tet(X) variants likely shared the same common ancestor with the chromosomal monooxygenases that are found in environmental Flavobacteriaceae bacteria, but sequence divergence suggested separation ~ 9900 years ago (7887 BC), presumably associated with the mobilization of tet(X)-like genes through horizontal transfer. Conclusions Four tet(X) variants were identified in this study, and they were widely distributed in multiple Acinetobacter spp. strains from various ecological niches across China. Our research also highlighted the crucial role of ISCR2 in mobilizing tet(X)-like genes between different Acinetobacter species and explored the evolutionary history of Tet(X)-like monooxygenases. Further studies are needed to evaluate the clinical impact of these mobile tigecycline resistance genes.

Objective To investigate the regulation mechanism of miR-107 on proliferation, migration and invasion of glioma cells. Methods RT-qPCR was used to detect the expression of miR-107 and FOXK1 in human normal astrocytes NHA, glioma cell lines U87, A172 and U251. miR-NC(miR-NC group), miR-107 mimics(miR-107 group), si-NC(si-NC group), si-FOXK1(si-FOXK1 group), miR-107+pcDNA3.1(miR-107 mimics and pcDNA3.1 group), miR-107 +pcDNA3.1-FOXK1(miR-107 mimics and pcDNA3.1-FOXK1 group), were transfected respectively into U87 cells by liposome method. The proliferation of the cells was detected by CCK-8 method.The migration and invasion of the cells were detected by Transwell chamber assay. The protein expression of FOXK1 in the cells was detected by Western blot.The fluorescence activity of the cells was detected by the dual luciferase reporter assay. Results Compared with normal astrocyte NHA, the expression of miR-107 was down-regulated and the expression of FOXK1 was up-regulated in glioma cell lines U87, A172 and U251(P＜0.05). Over-expression of miR-107 and knockdown of FOXK1 inhibited U87 cell proliferation, migration and invasion. MiR-107 can inhibit the cytosolic activity of wild-type FOXK1 and negatively regulate the expression of FOXK1; over-expression of FOXK1 can reverse the inhibitory effect of miR-107 on proliferation and migration of U87 cells. Conclusions The mechanism of miR-107 inhibiting proliferation, migration and invasion of glioma cells may be related to the targeted negative regulation of FOXK1, which will provide a basis for the diagnosis and targeted therapy of glioma.

Pigment production is a unique character of melanocytes. Numerous factors are linked with melanin production, including genetics, ultraviolet radiation (UVR) and inflammation. Understanding the mechanism of melanogenesis is crucial to identify new preventive and therapeutic strategies in the treatment of melanoma. Here, we reviewed the current available literatures on the mechanisms of melanogenesis, including the signaling pathways of UVR-induced pigment production, MC1R’s central determinant roles and MITF as a master transcriptional regulator in melanogenesis. Moreover, we further highlighted the role of targeting BRAF, NRAS and MC1R in melanoma prevention and treatment. The combination therapeutics of immunotherapy and targeted kinase inhibitors are becoming the newest therapeutic option in advanced melanoma.

Hypoxia is a common biological condition in many malignant solid tumors that plays an imperative role in regulating tumor growth and impacting the treatment’s therapeutic effect. Therefore, the hypoxia assessment is of great significance in predicting tumor development and evaluating its prognosis. Among the plenty of existing tumor diagnosis techniques, magnetic resonance imaging (MRI) offers certain distinctive features, such as being free of ionizing radiation and providing images with a high spatial resolution. In this study, we develop a fluorescent traceable and hypoxia-sensitive T1-weighted MRI probe (Fe3O4-Met-Cy5.5) via conjugating notable hypoxia-sensitive metronidazole moiety and Cy5.5 dye with ultrasmall iron oxide (Fe3O4) nanoparticles. The results of in vitro and in vivo experiments show that Fe3O4-Met-Cy5.5 has excellent performance in relaxivity, biocompatibility, and hypoxia specificity. More importantly, the obvious signal enhancement in hypoxic areas indicates that the probe has great feasibility for sensing tumor hypoxia via T1-weighted MRI. These promising results may unlock the potential of Fe3O4 nanoparticles as T1-weighted contrast agents for the development of clinical hypoxia probes.

Aiming at the optimization of truss structure, a wolf pack algorithm based onchaos and improved search strategy was proposed. The mathematical model of truss optimization was constructed, and the classical truss structure was optimized. The results were compared with those of other optimization algorithms. When selecting and updating the initial position of wolves, chaos idea was used to distribute the initial value evenly in the solution space; phase factor was introduced to optimize the formula of wolf detection; information interaction between wolves is increased and the number of runs is reduced.The numerical results show that the improved wolf pack algorithm has the characteristics of fewer parameters, simple programming, easy implementation, fast convergence speed, and can quickly find the optimal solution. It is suitable forthe optimization design of the section size of space truss structures.

Iron oxide nanoparticles (IONPs) as magnetic resonance imaging (MRI) contrast agents have received considerable interest due to their superior magnetic properties. To increase the biocompatibility and blood circulation time, polyethylene glycol (PEG) is usually chosen to decorate IONPs. Although the surface effect induced by the PEGylation has an impact on the relaxometric properties of IONPs and can subsequently affect the imaging results, the occurrence of particle aggregation has troubled researchers to deeply explore this correlation. To shed light on this relationship, three diphosphonate PEGs with molecular weights of 1000, 2000, and 5000 Da were used to replace the hydrophobic oleate ligands of 3.6 nm and 10.9 nm IONPs. Then, the contrast enhancement properties of the resultant “aggregation-free” nanoparticles were carefully evaluated. Moreover, related theories were adopted to predict certain properties of IONPs and to compare with the experimental data, as well as obtain profound knowledge about the impacts of the PEG chain length on transverse relaxivity (r2) and longitudinal relaxivity (r1). It was found that r2 and the saturated magnetization of the IONPs, independent of particle size, was closely related to the chain length of PEG. The results unveiled the correlation between the chain length of the coated PEG and the relaxometric properties of IONPs, providing valuable information which might hold great promise in designing optimized, high-performance IONPs for MRI-related applications.

The newly emerged tigecycline-inactivating enzymes Tet(X3) and Tet(X4), which are associated with high-level tigecycline resistance, demonstrated significantly higher activities in comparison to that of the prototypical Tet(X) enzyme, threatening the clinical efficacy of tigecycline as a last-resort antibiotic to treat multidrug-resistant (MDR) Gram-negative bacterial infections. However, the molecular mechanisms leading to high-level tigecycline resistance remain elusive.

Invertebrates rely on innate immunity, including humoral and cellular immunity, to resist pathogenic infection. Previous studies showed that forkhead box transcription factor O (FOXO) participates in mucosal immune responses of mammals and the gut humoral immune regulation of invertebrates. However, whether FOXO is involved in systemic and cellular immunity regulation in invertebrates remains unknown. In the present study, we identified a FOXO from shrimp (Marsupenaeus japonicus) and found that it was expressed at relatively basal levels in normal shrimp, but was upregulated significantly in shrimp challenged by Vibrio anguillarum. FOXO played a critical role in maintaining hemolymph and intestinal microbiota homeostasis by promoting the expression of Relish, the transcription factor of the immune deficiency (IMD) pathway for expression of antimicrobial peptides (AMPs) in shrimp. We also found that pathogen infection activated FOXO and induced its nuclear translocation by reducing serine/threonine kinase AKT activity. In the nucleus, activated FOXO directly regulated the expression of its target Amp and Relish genes against bacterial infection. Furthermore, FOXO was identified as being involved in cellular immunity by promoting the phagocytosis of hemocytes through upregulating the expression of the phagocytotic receptor scavenger receptor C (Src), and two small GTPases, Rab5 and Rab7, which are related to phagosome trafficking to the lysosome in the cytoplasm. Taken together, our results indicated that FOXO exerts its effects on homeostasis of hemolymph and the enteric microbiota by activating the IMD pathway in normal shrimp, and directly or indirectly promoting AMP expression and enhancing phagocytosis of hemocytes against pathogens in bacteria-infected shrimp. This study revealed the different functions of FOXO in the mucosal (local) and systemic antibacterial immunity of invertebrates.

Circular RNAs (circRNAs) are evolutionarily conserved and abundant non-coding RNAs whose functions and regulatory mechanisms remain largely unknown. Here, we identify and characterize an epigenomically distinct group of circRNAs (TAH-circRNAs), which are transcribed to a higher level than their host genes. By integrative analysis of cistromic and transcriptomic data, we find that compared with other circRNAs, TAH-circRNAs are expressed more abundantly and have more transcription factors (TFs) binding sites and lower DNA methylation levels. Concordantly, TAH-circRNAs are enriched in open and active chromatin regions. Importantly, ChIA-PET results showed that 23–52% of transcription start sites (TSSs) of TAH-circRNAs have direct interactions with cis-regulatory regions, strongly suggesting their independent transcriptional regulation from host genes. In addition, we characterize molecular features of super-enhancer-driven circRNAs in cancer biology. Together, this study comprehensively analyzes epigenomic characteristics of circRNAs and identifies a distinct group of TAH-circRNAs that are independently transcribed via enhancers and super-enhancers by TFs. These findings substantially advance our understanding of the regulatory mechanism of circRNAs and may have important implications for future investigations of this class of non-coding RNAs.