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Macrophages are widely distributed in tissues and function in homeostasis. During cancer development, tumor-associated macrophages (TAMs) dominatingly support disease progression and resistance to therapy by promoting tumor proliferation, angiogenesis, metastasis, and immunosuppression, thereby making TAMs a target for tumor immunotherapy. Here, we started with evidence that TAMs are highly plastic and heterogeneous in phenotype and function in response to microenvironmental cues. We pointed out that efforts to tear off the heterogeneous "camouflage" in TAMs conduce to target de facto protumoral TAMs efficiently. In particular, several fate-mapping models suggest that most tissue-resident macrophages (TRMs) are generated from embryonic progenitors, and new paradigms uncover the ontogeny of TAMs. First, TAMs from embryonic modeling of TRMs and circulating monocytes have distinct transcriptional profiling and function, suggesting that the ontogeny of TAMs is responsible for the functional heterogeneity of TAMs, in addition to microenvironmental cues. Second, metabolic remodeling helps determine the mechanism of phenotypic and functional characteristics in TAMs, including metabolic bias from macrophages' ontogeny in macrophages' functional plasticity under physiological and pathological conditions. Both models aim at dissecting the ontogeny-related metabolic regulation in the phenotypic and functional heterogeneity in TAMs. We argue that gleaning from the single-cell transcriptomics on subclonal TAMs' origins may help understand the classification of TAMs' population in subclonal evolution and their distinct roles in tumor development. We envision that TAM-subclone-specific metabolic reprogramming may round-up with future cancer therapies.

BACKGROUND: Radiation induces rapid bone loss and enhances bone resorption and adipogenesis, leading to an increased risk of bone fracture. There is still a lack of effective preventive or therapeutic method for irradiation-induced bone injury. Receptor activator of nuclear factor κB ligand (RANKL) provides the crucial signal to induce osteoclast differentiation and plays an important role in bone resorption. However, the mechanisms of radiation-induced osteoporosis are not fully understood. AIM: To investigate the role of CR6-interacting factor-1 (Crif1) in osteoclastogenesis after radiation and its possible mechanism. METHODS: C57BL/6 mice were exposed to Co-60 gamma rays and received 5 Gy of whole-body sublethal irradiation at a rate of 0.69 Gy/min. For in vitro study, mouse bone marrow mesenchymal stem/stromal cells (BM-MSCs) were irradiated with Co-60 at a single dose of 9 Gy. For osteoclast induction, monocyte-macrophage RAW264.7 cells were cocultured with mouse BM-MSCs for 7 d. ClusPro and InterProSurf were used to investigate the interaction interface in Crif1 and protein kinase cyclic adenosine monophosphate (cAMP)-activited catalytic subunit alpha complex. Virtual screening using 462608 compounds from the Life Chemicals database around His120 of Crif1 was carried out using the program Autodock_vina. A tetrazolium salt (WST-8) assay was carried out to study the toxicity of compounds to different cells, including human BM-MSCs, mouse BM-MSCs, and Vero cells. RESULTS: Crif1 expression increased in bone marrow cells after radiation in mice. Overexpression of Crif1 in mouse BM-MSCs and radiation exposure could increase RANKL secretion and promote osteoclastogenesis in vitro. Deletion of Crif1 in BM-MSCs could reduce both adipogenesis and RANKL expression, resulting in the inhibition of osteoclastogenesis. Deletion of Crif1 in RAW264.7 cells did not affect the receptor activator of nuclear factor κB expression or osteoclast differentiation. Following treatment with protein kinase A (PKA) agonist (forskolin) and inhibitor (H-89) in mouse BM-MSCs, Crif1 induced RANKL secretion via the cAMP/PKA pathway. Moreover, we identified the Crif1-protein kinase cyclic adenosine monophosphate-activited catalytic subunit alpha interaction interface by in silico studies and shortlisted interface inhibitors through virtual screening on Crif1. Five compounds dramatically suppressed RANKL secretion and adipogenesis by inhibiting the cAMP/PKA pathway. CONCLUSION: Crif1 promotes RANKL expression via the cAMP/PKA pathway, which induces osteoclastogenesis by binding to receptor activator of nuclear factor κB on monocytes-macrophages in the mouse model. These results suggest a role for Crif1 in modulating osteoclastogenesis and provide insights into potential therapeutic strategies targeting the balance between osteogenesis and adipogenesis for radiation-induced bone injury.

Flexible debris flow barriers are important engineering measures to prevent debris flow disasters. The existing prevention structures are mainly in the form of closed barriers, which are prone to blockage with poor regulation abilities. Therefore, we proposed open flexible debris flow barriers to overcome the above shortcomings. Based on theoretical analyses and physical model tests, the research on the regulation performance of the open flexible debris flow barriers was carried out, and the theoretical formulas for the velocity attenuation rate, run-up height, and blocking rate of debris flows were deduced. The results show that compared with the closed flexible debris flow barriers, the improved structure has a good self-cleaning effect and can effectively control the peak velocity of debris flows. The calculation results through the derived non-dimensional theoretical formulas are in good agreement with the physical test results. The velocity attenuation rate, run-up height, and blocking rate of debris flows are mainly controlled by the relative open height, dimensionless flow depth, relative density of debris flows, and the Froude number. The velocity attenuation rate and blocking rate are negatively correlated with the relative open height, and positively correlated with the relative density of debris flows. The run-up height is negatively correlated with both the relative open height and the relative density. The above research can provide theoretical and technical support for the application of open flexible barriers in debris flow prevention and control projects.

The rise of antibiotic resistance poses a significant public health crisis, particularly due to limited antimicrobial options for the treatment of infections with Gram‐negative pathogens. Here, an antimicrobial peptide (AMP) SR25 is characterized, which effectively kills both Gram‐negative and Gram‐positive bacteria through a unique dual‐targeting mechanism without detectable resistance. Meanwhile, an SR25‐functionalized hydrogel is developed for the efficient treatment of infected diabetic wounds. SR25 is obtained through genome mining from an uncultured bovine enteric actinomycete named Nonomuraea Jilinensis sp. nov. Investigations reveal that SR25 has two independent cellular targets, disrupting bacterial membrane integrity and restraining the activity of succinate:quinone oxidoreductase (SQR). In a diabetic mice wound infection model, the SR25‐incorporated hydrogel exhibits high efficacy against mixed infections of Escherichia coli (E. coli) and methicillin‐resistant Staphylococcus aureus (MRSA), accelerating wound healing. Overall, these findings demonstrate the therapeutic potential of SR25 and highlight the value of mining drugs with multiple mechanisms from uncultured animal commensals for combating challenging bacterial pathogens. [ABSTRACT FROM AUTHOR]

Antibiotic residues in milk powder are public focusing concerns relevant to food safety. Long term exposure to antibiotic residues will lead to drug resistant strains in human body, reduce body's immunity, and bring health hazards to consumers. Sulfonamides, (fluoro)quinolones and macrolides are high frequency detecting antibiotic residues in matrix of milk powder. Rapid screening analysis of these residues and simultaneous confirmation with high confidence are valuable in practical scenarios of investigation testing, special monitoring program and so on. The direct analysis in real time (DART) ion source is an emerging technology of ambient pressure desorption ionization, it can directly complete the analysis of sample ionization and injection at the ambient pressure and open experimental environment, without changing the properties of the analyte itself. It became possible to analyze samples directly with minimal sample preparation steps or even without any sample pretreatment procedure with DART ion source. A hybrid high resolution mass spectrotmety, quadrupole orbitrap high resolution mass spectrometry (Q-Orbitrap HRMS) is a powerful tool in veterinary drug residue analysis with superior specificity, accuracy and sensitivity. In present study, DART ion source was hyphenated to Q-Orbitrap HRMS to perform rapid screening analysis and simultaneously unambiguous identification of the above mentioned antibiotic residues in milk powder. Sample was diluted in water and fast purified by filtering solid phase extraction column and then the filtrate was subjected to DART QOrbitrap HRMS analysis. Several key parameters of the DART ion source, such as ionization type and temperature, as well as injection speed of DART ion source were optimized to enhance the performance of the method. Then, a QuickStrip (QS) Module was selected with the helium as carrier gas and ionization temperature as well as injection speed were set to 400 ℃ and 1 mm/s, respectively. The DART ion source with optimized settings coupled to Q-Orbitrap HRMS was finally applied to screening analysis. Results showed that 16 commonencountered antibiotic residues including sulfonamides, (fluoro)quinolones and macrolides can be effectively detected with the screening concentration of 100 μg/kg. Recoveries of the analytes ranged from 72.5% to 106.7% and the false negative rates were all less than 5%. Real life sample analysis was finally conducted by the proposed method with an expected method performance, evidencing the potency of the developed method in risk monitoring in milk powder for veterinary drug screening analysis. It should be mentioned here that the screening concentration of 100 μg/kg is a compromised concentration for the sake of some less sensitive analytes to provide reliable determination of the antibiotic residues with the proposed procedures. It is, however, quite meaningful concentration to indicate the existence of high risk level of corresponding antibiotic residues which need to take actions. In total, the proposed method can play a role in risk monitoring laboratories and relevant industry institutions.

Coronarin E is a main diterpene ever isolated from Hedychium yunnanense. With the aim to enlarge its potential application, four butenolide derivatives (compounds 4a, 4b, 5a and 5b) were obtained from coronarin E via synthetic method, and their antibacterial effects were also evaluated. It is noteworthy that compounds 5a and 5b exhibited stronger antibacterial activities against most of the tested bacterial strains than ampicillin and kanamycin, two first- and second-line antimicrobials in clinical. For example, minimum inhibitory concentration (MIC) of 5a, 5b, ampicillin and kanamycin against Acinetobacter baumanii were 2, 1, 8 and 4 μg/mL, respectively, and MIC of the four compounds mentioned above against Klebsiella pneumonia were 1, 0.5, 16 and 4 μg/mL, respectively. The current studies not only enrich the structural diversity of diterpenes derived from Hedychium genus, but also provide potent candidates for the development of antibacterial medicines. [ABSTRACT FROM AUTHOR]

Colletotrin A (1), a new 1,4-benzoxazine derivative, and eight known compounds, including two alkaloids (2-3), one acylamide (4), one benzaldehyde (5), and four sterols (6-9) were obtained from endophytic fungus Colletotrichum gloeosporioides B-142, which was isolated from Dracaena cochinchinensis. Among them, 1,2,3,4-tetrahydroquinoline-4,8-diol (2) was reported for the first time as natural product. The structure of compound 1 was elucidated with help of spectroscopic data including IR, UV, electronic circular dichroism (ECD) calculation, HRESIMS, 1D and 2D NMR (COSY, HSQC and HMBC). The antimicrobial activities were evaluated by disc diffusion method. [ABSTRACT FROM AUTHOR]

This study aimed to compare the current Essen rabies post-exposure immunization schedule (0-3-7-14-28) in China and the simple 4-dose schedule (0-3-7-14) newly recommended by the World Health Organization in terms of their safety, efficacy, and protection. Mice were vaccinated according to different immunization schedules, and blood was collected for detection of rabies virus neutralizing antibodies (RVNAs) on days 14, 21, 28, 35, and 120 after the first immunization. Additionally, different groups of mice were injected with lethal doses of the CVS-11 virus on day 0, subjected to different rabies immunization schedules, and assessed for morbidity and death status. In a clinical trial, 185 rabies-exposed individuals were selected for post-exposure vaccination according to the Essen schedule, and blood was collected for RVNAs detection on days 28 and 42 after the first immunization. A statistically significant difference in RVNAs between mice in the Essen and 0-3-7-14 schedule groups was observed on the 35th day (P < 0.05). The groups 0-3-7-14, 0-3-7-21, and 0-3-7-28 showed no statistically significant difference (P > 0.05) in RVNAs levels at any time point. The post-exposure immune protective test showed that the survival rate of mice in the control group was 20%, whereas that in the immunization groups was 40%. In the clinical trial, the RVNAs positive conversion rates on days 28 (14 days after 4 doses) and 42 (14 days after 5 doses) were both 100%, and no significant difference in RVNAs levels was observed (P > 0.05). The simple 4-dose schedule can produce sufficient RVNAs levels, with no significant effect of a delayed fourth vaccine dose (14–28 d) on the immunization potential. [ABSTRACT FROM AUTHOR]

Purpose: To characterize the cytokine profile of patients with severe fever with thrombocytopenia syndrome (SFTS) in relation to disease severity.Patients and Methods: 60 laboratory-confirmed SFTS patients and 12 healthy individuals from multi-centers in Shandong Province of China were included, and all patients were divided into fatal patients (9) and recovered patients (51) due to their final outcomes. Multiplex-microbead immunoassays were conducted to estimate levels of 27 cytokines in the sera of patients and controls.Results: The results showed that levels of IL-2, IL-4, IL-6, IL-7, IL-8, IL-15, IL-1RA, G-CSF, GM-CSF, IFN-γ, TNF-α, basic FGF, PDGF-BB, RANTES, IP-10, MIP-1α, MIP-1β, MCP-1, and Eotaxin differed significantly among the SFTS fatal patients, recovered patients, and the healthy controls (all p< 0.05). Compared to the healthy controls, the fatal patients and recovered patients had reduced levels of IL-2, IL-4, IL-7, PDGF-BB, RANTES, and Eotaxin, while the levels of PDGF-BB and RANTES were significantly lower in fatal patients compared to recovered patients. The increasing levels of IL-6, IL-8, IL-15, IL-1RA, G-CSF, GM-CSF, IFN-γ, TNF-α, basic FGF, IP-10, MIP-1α, MIP-1β, and MCP-1 were observed in fatal patients (all p< 0.05), and the levels of IL-6, IP-10, MIP-1α, and MCP-1 were significantly higher than other two groups. The Spearman correlation analysis indicated a positive correlation between platelet count and PDGF-BB levels (p< 0.05), while the white blood cell count had a negative correlation with MIP-1 level (p< 0.05).Conclusion: The research exhibited that the SFTS virus (SFTSV) caused an atypical manifestation of cytokines. The levels of IL-6, IP-10, MIP-1α, and MCP-1 had been observed a positive association with the severity of the illness. [ABSTRACT FROM AUTHOR]