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Through hot compression and subsequent heat treatment experiments on GH4079 superalloy, the influence of different hot deformation and heat treatment conditions on the evolution of GH4079 superalloy microstructure was studied. The evolution of grains and γ′ phases under different thermomechanical conditions was investigated. The results indicate that at deformation temperatures above 1100 °C and strain rates ranging from 0.01 to 0.1 s−1, the primary mechanism of dynamic softening in the alloy is discontinuous dynamic recrystallization (DDRX). When the deformation temperature is below 1100 °C and strain rates range from 0.01 to 0.1 s−1, both continuous dynamic recrystallization (CDRX) and DDRX are the main dynamic softening mechanisms. Due to high strain energy accumulation, the samples deformed at lower temperatures (below 1100 °C) and then solution-treated at 1120 °C for 8 h exhibit significant increases in recrystallization volume fraction and recrystallization grain size. Conversely, the samples deformed at higher temperatures (above 1100 °C) and then solution-treated at 1120 °C for 8 h show minimal changes in recrystallization volume fraction and recrystallization grain size. After solution treatment at 1140 °C, the grain size of the alloy significantly increases. The samples deformed at higher strain rates exhibit the evolution of fine γ′ phases into elongated rod shapes during solution treatment, while larger γ′ phases undergo splitting processes.

Abstract Background Mesenchymal stem cells (MSCs) are multipotent stem cells that are under investigation for use in clinical trials because they are capable of self-renewal and differentiating into different cell types under defined conditions. Nonetheless, the therapeutic effects of MSCs have been constrained by low engraftment rates, cell fusion, and cell survival. Various strategies have been explored to improve the therapeutic efficacy of MSCs, with platelet-derived growth factor (PDGF)-BB emerging as a promising candidate. To enhance our comprehension of the impact of PDGF-BB on the gene expression profile and chromosomal accessibility of MSCs, RNA-sequencing and analysis of chromatin accessibility profiles were conducted on three human primary MSCs in culture, both with and without stimulation by PDGF-BB. Results Integrative analysis of gene expression and chromatin accessibility demonstrated that PDGF-BB treatment modified the chromatin accessibility landscape, marking regions for activation or repression through the AP-1 family transcription factors TEAD, CEBP, and RUNX2. These changes in AP-1 transcription factor expression, in turn, led to cell proliferation and differentiation potential towards osteoblasts, adipocytes, or chondrocytes. The degree of MSC differentiation varies among cells isolated from different donors. The presence of an enrichment of exosome-related genes is also noted among all the differentially expressed genes. Conclusions In conclusion, the observed changes in AP-1 transcription factor expression not only induced cellular proliferation and differentiation, but also revealed variations in the degree of MSC differentiation based on donor-specific differences. Moreover, the enrichment of exosome-related genes among differentially expressed genes suggests a potential significant role for PDGF-BB in facilitating intercellular communication.

ABSTRACT: Inhibition of methyl-coenzyme M reductase can suppress the activity of ruminal methanogens, thereby reducing enteric methane emissions of ruminants. However, developing specific and environmentally friendly inhibitors is a challenging endeavor. To identify a natural and effective methane inhibitor that specifically targets methyl-coenzyme M reductase, molecular docking technology was employed to screen a library of phytogenic compounds. A total of 52 candidate compounds were obtained through molecular docking technique. Rosmarinic acid (RA) was one of the compounds that could traverse a narrow channel and bind to the active sites of methyl-coenzyme M reductase, with a calculated binding free energy of −9.355 kcal/mol. Furthermore, the effects of RA supplementation on methane production, rumen fermentation, and the microorganism community in dairy cows were investigated through in vitro rumen fermentation simulations according to a random design. Supplementation of RA resulted in a 15% decrease in methane production compared with the control. In addition, RA increased the molar proportion of acetate and propionate, whereas the sum of acetate and butyrate divided by propionate was decreased. At the bacterial level, the relative abundance of Rikenellaceae RC9 gut group, Christensenellaceae R7 group, Candidatus Saccharimonas, Desulfovibrio, and Lachnospiraceae FE2018 group decreased with RA supplementation. Conversely, the addition of RA significantly increased the relative abundance of DNF00809 (a genus from Eggerthellaceae), Denitrobacterium, an unclassified genus from Eggerthellaceae, an unclassified genus from Bacteroidales, and an unclassified genus from Atopobiaceae. At the archaeal level, the relative abundance of Methanobrevibacter decreased, whereas that of Methanosphaera increased with RA supplementation. These findings suggested that RA has the potential to be used as a novel natural additive for inhibiting ruminal methane production.

This work systematically investigated the coarsening, dissolution, and morphological evolution behavior of γ′ precipitates in GH4742 superalloy through carefully designed heat treatment experiments. During long-term aging processes at 650 °C, 750 °C, and 850 °C, the coarsening model of γ′ precipitates followed the classic function of r3 vs. t, consistent with the classical Lifshitz-Slyozov-Wagner (LSW) coarsening model (diffusion-controlled). Due to higher diffusion coefficients of γ′ forming elements at higher temperatures, the coarsening rate K increased with aging temperature. The dynamical models for the dissolution of primary γ′ precipitates were established during sub-solvus (1080 °C) and super-solvus (1120 °C) heat treatment processes. The results indicated rapid dissolution of primary γ′ precipitates in the initial stages of solution heat treatment, with the dissolution rate gradually decreasing as the treatment time extended, approaching the γ′ precipitate size at thermodynamic equilibrium. During subsequent slow cooling at 14 °C/min after super-solvus (1120 °C) heat treatment, irregular-shaped γ′ precipitates formed through “aggregation” of adjacent γ′ precipitates, followed by “splitting” into smaller γ′ precipitates during growing up. Conversely, during subsequent slow cooling at 14 °C/min after sub-solvus (1080 °C) heat treatment, irregular-shaped γ′ precipitates were mainly controlled by unstable growth and “splitting” of cubic-shaped γ′ precipitates. For individual γ′ precipitates, the portion undergoing unstable growth (protrusions) did not undergo further splitting.

Abstract Background In prior research employing iTRAQ (Isobaric Tags for Relative and Absolute Quantitation) technology, we identified a range of proteins in breast cancer tissues exhibiting high levels of acetylation. Despite this advancement, the specific functions and implications of these acetylated proteins in the context of cancer biology have yet to be elucidated. This study aims to systematically investigate the functional roles of these acetylated proteins with the objective of identifying potential therapeutic targets within breast cancer pathophysiology. Methods Acetylated targets were identified through bioinformatics, with their expression and acetylation subsequently confirmed. Proteomic analysis and validation studies identified potential acetyltransferases and deacetylases. We evaluated metabolic functions via assays for catalytic activity, glucose consumption, ATP levels, and lactate production. Cell proliferation and metastasis were assessed through viability, cycle analysis, clonogenic assays, PCNA uptake, wound healing, Transwell assays, and MMP/EMT marker detection. Results Acetylated proteins in breast cancer were primarily involved in metabolism, significantly impacting glycolysis and the tricarboxylic acid cycle. Notably, PGK1 showed the highest acetylation at lysine 323 and exhibited increased expression and acetylation across breast cancer tissues, particularly in T47D and MCF-7 cells. Notably, 18 varieties acetyltransferases or deacetylases were identified in T47D cells, among which p300 and Sirtuin3 were validated for their interaction with PGK1. Acetylation at 323 K enhanced PGK1's metabolic role by boosting its activity, glucose uptake, ATP production, and lactate output. This modification also promoted cell proliferation, as evidenced by increased viability, S phase ratio, clonality, and PCNA levels. Furthermore, PGK1-323 K acetylation facilitated metastasis, improving wound healing, cell invasion, and upregulating MMP2, MMP9, N-cadherin, and Vimentin while downregulating E-cadherin. Conclusion PGK1-323 K acetylation was significantly elevated in T47D and MCF-7 luminal A breast cancer cells and this acetylation could be regulated by p300 and Sirtuin3. PGK1-323 K acetylation promoted cell glycolysis, proliferation, and metastasis, highlighting novel epigenetic targets for breast cancer therapy.

Abstract Tumor-associated macrophages play a crucial role in the tumor microenvironment. Tripartite motif 59 (TRIM59), a member of the tripartite motif (TRIM) family, is known to be associated with immunological diseases and macrophage activation. The functional and molecular mechanisms by which TRIM59 affects the occurrence and development of colorectal cancer (CRC) through macrophages are still not well understood. To address this, we generated macrophage-specific TRIM59 conditional knockout mice and utilized these mice to establish colitis-associated cancer and MC38 transplanted CRC models for further investigation. We found that the deficiency of TRIM59 in macrophages inhibited colorectal tumorigenesis in mice. This tumor-suppressive effect was achieved by promoting the activation of M1 macrophages via STAT1 signaling pathway. Further mechanistic studies revealed that TRIM59 could regulate macrophage polarization by ubiquitinating and degrading STAT1. These findings provide evidence that TRIM59 deficiency promotes M1 macrophage activation and inhibits CRC through the STAT1 signaling pathway, suggesting that the TRIM59/STAT1 signaling pathway may be a promising target for CRC.

Abstract Climate changes significantly impact greenhouse gas emissions from wetland soil. Specifically, wetland soil may be exposed to oxygen (O2) during droughts, or to sulfate (SO4 2-) as a result of sea level rise. How these stressors – separately and together – impact microbial food webs driving carbon cycling in the wetlands is still not understood. To investigate this, we integrated geochemical analysis, proteogenomics, and stoichiometric modeling to characterize the impact of elevated SO4 2- and O2 levels on microbial methane (CH4) and carbon dioxide (CO2) emissions. The results uncovered the adaptive responses of this community to changes in SO4 2- and O2 availability and identified altered microbial guilds and metabolic processes driving CH4 and CO2 emissions. Elevated SO4 2- reduced CH4 emissions, with hydrogenotrophic methanogenesis more suppressed than acetoclastic. Elevated O2 shifted the greenhouse gas emissions from CH4 to CO2. The metabolic effects of combined SO4 2- and O2 exposures on CH4 and CO2 emissions were similar to those of O2 exposure alone. The reduction in CH4 emission by increased SO4 2- and O2 was much greater than the concomitant increase in CO2 emission. Thus, greater SO4 2- and O2 exposure in wetlands is expected to reduce the aggregate warming effect of CH4 and CO2. Metaproteomics and stoichiometric modeling revealed a unique subnetwork involving carbon metabolism that converts lactate and SO4 2- to produce acetate, H2S, and CO2 when SO4 2- is elevated under oxic conditions. This study provides greater quantitative resolution of key metabolic processes necessary for the prediction of CH4 and CO2 emissions from wetlands under future climate scenarios.

As a strong human disturbance, coal mining has affected the ecosystem service function and economic value on mining area. However, there is a lack on the comparing for the long-term spatial scale evolution of landscape ecological risk after mining development based on different landforms in the same climate environment. Therefore, the spatial and temporal evolution characteristics of landscape ecological risk were explored on loess hilly and sandy land in the Yushenfu Mining Area based on the Landsat data from 1995—2021 with the construction of landscape ecological risk index and spatial statistical analysis methods. The results showed that: ① There was no significant changing between loess hilly and sandy land for the ecological risk pattern from 1995 to 2000. From 2000 to 2010, the low level ecological risk area changed to a higher level in the loess hilly region. In 2010, the proportion of medium-high, medium and medium-low ecological risk areas was 70% in the loess hilly area, while the high ecological risk area in the sand-covered area increased but not significant, and it was still dominated by medium-low ecological risk and account for 31%. Since 2010, the landscape ecological pattern tended to homogenization, and the landscape ecological risk gradually stabilized to a low-medium, medium and high-medium on loess hilly area, and the proportion of these three risk levels was 74% in 2021. The sandy landscape also formed a low, medium and low-medium ecological risk, and the proportion of the three risk levels was 77%, and decreased and stabilized gradually. ② From 1995 to 2021, the landscape ecological risks showed obvious spatially clustered distribution characteristics, and presented a clear hotspots and coldspots in Yushenfu Mining Area. The ecological risk hotspots were mainly located in the loess hilly area in the northeast and southeast of the study area where coal has been developed for a long time and the geological environment has been seriously damaged, and the ecological risk coldspots were mainly located in the sand-covered areas in the central part of study area which are still under resource exploration and survey. ③ Human disturbance was the most important factor affecting the landscape ecological risk in Yushenfu Mining Area, the determining force of q values in the loess area and the sand-covered area were 0.49−0.72 and 0.38−0.55, respectively, followed by vegetation coverage and temperature in the loess hilly area, and vegetation coverage and air temperature had a similar effects on landscape ecological risk in the sand-covered area, and the least factor was elevation for ecological risk on both landforms, the q values were less than 0.10. ④ The results of spatial and temporal landscape ecological risk indicated that the landscape pattern should be optimized according to the characteristics of different landforms in the process of ecological restoration in Yushenfu Mining Area, and the mining scheme should be optimized to reduce the surface ecological damage and the active restoration strategy should be actively carried out in the loess hilly area. Whilethe natural restorationcan be implemented to ensure the ecological stability on the sand-covered mining area.

Summary: Home information profoundly influences behavioral states in both humans and animals. However, how “home” is represented in the brain and its role in driving diverse related behaviors remain elusive. Here, we demonstrate that home bedding contains sufficient home information to modulate affective behaviors, including aversion responses, defensive aggression, and mating behaviors. These varied responses to home information are mediated by gama-aminobutyric acid (GABA)ergic neurons in the lateral hypothalamus (LHGABA). Inhibiting LHGABA abolishes, while activating mimics, the effects of home bedding on these behaviors across different contexts. Specifically, projections from LHGABA to the ventral tegmental area (VTA) mediate the relaxation of aversive emotion, while projections to the periaqueductal gray (PAG) initiate defensive concerns. Thus, our data suggest that home information in different contexts converges to activate distinct subgroups of the LHGABA, which, in turn, elicit appropriate affective behaviors in relieving aversion, fighting intruders, or enhancing mating through involving distinct downstream projections.

ObjectiveTo explore the relationship between serum calcium levels and the prognosis of severe acute osteomyelitis, and to assess the effectiveness of calcium levels in prognostic evaluation.MethodsRelevant patient records of individuals diagnosed with severe acute osteomyelitis were obtained for this retrospective study from the Medical Information Mart for Intensive Care (MIMIC-IV). The study aimed to assess the impact of different indicators on prognosis by utilizing COX regression analysis. To enhance prognostic prediction for critically ill patients, a nomogram was developed. The discriminatory capacity of the nomogram was evaluated using the Area Under the Curve (AUC) of the Receiver Operating Characteristic (ROC) curve, in addition to the calibration curve.ResultThe study analyzed a total of 1,133 cases of severe acute osteomyelitis, divided into the survivor group (1,025 cases) and the non-survivor group (108 cases). Significant differences were observed between the two groups in terms of age, hypertension, sepsis, renal injury, and various laboratory indicators, including WBC, PLT, Ca2+, CRP, hemoglobin, albumin, and creatinine (P0.05). To predict the survival time, a nomogram was developed using the aforementioned indicators and achieved an AUC of 0.841. The accuracy of the nomogram was further confirmed by the ROC curve and calibration curve.ConclusionAccording to the findings, this study establishes that a reduction in serum calcium levels serves as a distinct and standalone predictor of mortality among individuals diagnosed with severe acute osteomyelitis during their stay in the Intensive Care Unit (ICU) within a span of two years.

Summary: Most cells in solid tumors are exposed to oxygen levels between 0.5% and 5%. We developed an approach that allows collection, processing, and evaluation of cancer and non-cancer cells under physioxia, while preventing exposure to ambient air. This aided comparison of baseline and drug-induced changes in signaling pathways under physioxia and ambient oxygen. Using tumor cells from transgenic models of breast cancer and cells from breast tissues of clinically breast cancer-free women, we demonstrate oxygen-dependent differences in cell preference for epidermal growth factor receptor (EGFR) or platelet-derived growth factor receptor beta (PDGFRβ) signaling. Physioxia caused PDGFRβ-mediated activation of AKT and extracellular regulated kinase (ERK) that reduced sensitivity to EGFR and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) inhibition and maintained PDGFRβ+ epithelial-mesenchymal hybrid cells with potential cancer stem cell (CSC) properties. Cells in ambient air displayed differential EGFR activation and were more sensitive to targeted therapies. Our data emphasize the importance of oxygen considerations in preclinical cancer research to identify effective drug targets and develop combination therapy regimens.

In semi-arid areas, underground coal mining could cause ecological and environmental problems such as surface subsidence, which can increase soil erosion intensity and damage vegetation habitats. In these ecological damages, the effect of mining ground fissures development on the seedling banks still needs to be studied further for its important role in plant restoration. In this study, the density, composition, and diversity characteristics of seedling banks were clarified at different horizontal distances (0-1 m, 1-2 m, and 2-5 m) from the mining ground fissuresin the Yushenfu mining area. Then the spatial variability of driving factors affecting seedling establishment were explored by combining soil factors, aboveground vegetation communities and litters characterization. Finally, the species similarity model was used to explore the effects of seedling banks on the natural vegetation regeneration in different areas from the ground fissures. The results showed that: ① In the control site without fissures development, the composition of the seedling bank was dominated by perennial grasses (57%), but after fissures development, the proportion of perennial herbs decreased to 30% and 35% in the 0-1 m and 1-2 m area from the fissures, respectively. Compared with the control sites, the seedling density increased significantly by 92% and 68% in 0-1 m and 1-2 m area, the Margalef richness index, Shannon-Wiener diversity index, and Simpson dominance index of the seedling bank increased by 42% and 24%, 62% and 40%, and 33% and 18%, but Pielou evenness index was reduced by 55% and 38%, respectively. However, there were no significant differences in the composition, density and diversity of seedling bank in 2-5 m area from the ground fissures compared to the control area. Therefore, the impact of ground fissures development on the characteristics of the seedling bank was within the range of 2 meters. ② After the development of ground fissures, the same factors affected seedling establishment were soil moisture content, soil organic matter content and litter thickness in the 0-1 m and 1-2 m areas from the ground fissures. In addition to the above factors, seedling establishing factors in 0-1 m area also included litter cover, soil crust cover and thickness, aboveground vegetation cover and biomass. With increasing distance from ground fissures, the key factors limiting seedling establishment were reduced in the 2-5 m area, and were similar to those in the control area, which included soil moisture content, aboveground vegetation cover, and litter cover. ③ In 0-1 m and1-2 m areas from ground fissures, the annual herbaceous species composition were less similar to that of above-ground vegetation species which dominated by the perennial herbs, the species similarity is only 0.42 and 0.48, respectively. Considering the weak contribution of annuals to plant community succession, it can be concluded that the contribution of the seedling bank is limited for vegetation restoration with in the 0-2 m areas from the ground fissures which is greatly disturbed by the fissure. In the 2-5 m area and control area, the species similarity between the seedling bank and aboveground vegetation was 0.67 and 0.68, which indicate that the recovery potential of the vegetation community is not affected by the development of ground fissures in this area.

Phytoplankton are an important part of aquatic ecosystems and substantially contribute to primary productivity. Under certain conditions, phytoplankton can grow or cluster in large numbers, resulting in enormous economic losses and serious threats to human life and health. In this study, complex causative species of algal blooms were examined and regulatory factors were determined in a reservoir formed by harbor construction. The reservoir is isolated from the harbor by sluice gates, forming a separate water region. Twelve species of phytoplankton, including normally and abnormally blooming species, were identified to be causing blooms in this continuous water. Different from the areas where simple algae caused blooms, multiple bloom-causative species, which were completely different, occurred at several stations. In this study area, whereas the abundance of algal cells was above 10 million cells/L, the total phosphorus concentration was higher than 0.2 mg/L. When the total phosphorus concentration was lower than 0.2 mg/L, there was no algal bloom. In waters with total algal cell abundance over 10 million, the N/P ratios were all

ObjectiveElastic stable intramedullary nail (ESIN) is a commonly used method for treating diaphyseal fractures of the tibia, but its application in Distal Tibial Diaphyseal Metaphyseal Junction (DTDMJ) fractures has been a subject of controversy. This study aims to evaluate the clinical efficacy of the Elastic stable intramedullary nail-Kirschner wire (E-K) technique in treating pediatric DTDMJ fractures, providing better clinical decision-making for clinicians in diagnosing and treating such fractures.MethodsWe conducted a retrospective analysis of patients aged 3–9 years who received treatment at our hospital from January 2019–January 2021 for distal tibial diaphyseal metaphyseal junction (DTDMJ) fractures. Based on their surgical procedures, they were categorized into the Elastic Stable Intramedullary Nail—Kirschner wire group (E-K) and the ESIN group. Demographic data, surgical duration, clinical outcomes, complications, and imaging data were recorded.ResultsThe study included a total of 57 patients, with 24 cases in the E-K group and 33 cases in the ESIN group. There were 30 males and 27 females. The average age was (6.25 ± 1.59) years in the E-K group and (6.27 ± 1.48) years in the ESIN group. There were no significant differences between the two groups in terms of gender, age, weight, time from injury to surgery, follow-up time, side of injury, associated injuries, nail site infection, deep infection, and nail removal time (P > 0.05). Neither group experienced nonunion or refracture. The E-K group exhibited significantly lower coronal and sagittal plane angular values at the final follow-up compared to the ESIN group (P

Abstract Many Chinese universities are implementing an educational reform to transform their general English courses into academic English courses. Accordingly, how to assess students’ English ability should also be reformed. In this test review, we introduce a school-based general academic English summative test developed by English instructors. An argument-based approach was adopted to analyze the test validity by obtaining students’ test data and their reflective responses to the test. This review can provide a practical reference for the development of a valid general academic English summative test by including practices of course instructors and voices of students, two important test stakeholders, in test design.

Given the importance of peroxisome proliferator-activated receptor (PPAR)-gamma in epidermal inflammation and carcinogenesis, we analyzed the transcriptomic changes observed in epidermal PPARγ-deficient mice (Pparg-/-epi). A gene set enrichment analysis revealed a close association with epithelial malignancy, inflammatory cell chemotaxis, and cell survival. Single-cell sequencing of Pparg-/-epi mice verified changes to the stromal compartment, including increased inflammatory cell infiltrates, particularly neutrophils, and an increase in fibroblasts expressing myofibroblast marker genes. A comparison of transcriptomic data from Pparg-/-epi and publicly available human and/or mouse actinic keratoses (AKs) and cutaneous squamous cell carcinomas (SCCs) revealed a strong correlation between the datasets. Importantly, PPAR signaling was the top common inhibited canonical pathway in AKs and SCCs. Both AKs and SCCs also had significantly reduced PPARG expression and PPARγ activity z-scores. Smaller reductions in PPARA expression and PPARα activity and increased PPARD expression but reduced PPARδ activation were also observed. Reduced PPAR activity was also associated with reduced PPARα/RXRα activity, while LPS/IL1-mediated inhibition of RXR activity was significantly activated in the tumor datasets. Notably, these changes were not observed in normal sun-exposed skin relative to non-exposed skin. Finally, Ppara and Pparg were heavily expressed in sebocytes, while Ppard was highly expressed in myofibroblasts, suggesting that PPARδ has a role in myofibroblast differentiation. In conclusion, these data provide strong evidence that PPARγ and possibly PPARα represent key tumor suppressors by acting as master inhibitors of the inflammatory changes found in AKs and SCCs.

Abstract The establishment of left–right patterning in mice occurs at a transient structure called the embryonic node or left–right organizer (LRO). Previous analysis of the LRO has proven challenging due to the small cell number and transient nature of this structure. Here, we seek to overcome these difficulties to define the transcriptome of the LRO. Specifically, we used single cell RNA sequencing of 0–1 somite embryos to identify LRO enriched genes which were compared to bulk RNA sequencing of LRO cells isolated by fluorescent activated cell sorting. Gene ontology analysis indicated an enrichment of genes associated with cilia and laterality terms. Furthermore, comparison to previously identified LRO genes identified 127 novel LRO genes, including Ttll3, Syne1 and Sparcl1, for which the expression patterns were validated using whole mount in situ hybridization. This list of novel LRO genes will be a useful resource for further studies on LRO morphogenesis, the establishment of laterality and the genetic causes of heterotaxy.

This paper starts with the importance and basic physical phenomena of underwater explosion, explaining the background and significance of ship damage and protection research under underwater explosion loads, research progress and status, as well as key challenges. To address these challenges, the paper elaborates on popular underwater explosion theories, models and methods. In terms of theoretical and computational research, a unified theory of bubble dynamics is presented, as well as a transient strong non-linear gas-liquid-solid fully coupled model and numerical method for underwater explosion, which have been used to develop a fundamental industrial software FSLAB capable of solving practical problems in fluid-structure interaction. In terms of experimental research, underwater explosion surrogate experimental methods and model testing methods are elaborated. Based on this, theoretical analysis, computational and experimental results in the field of ship damage and protection under underwater explosion loads are presented and discussed, aiming to provide references for underwater explosion-related research.

The principle of acupoint stimulation efficacy is based on traditional meridian theory. However, the molecular mechanisms underlying the therapeutic effects of acupoints in treating diseases remain unclear in modern scientific understanding. In this study, we selected the ST36 acupoint for investigation and summarized all relevant literature from the PubMed database over the past 10 years. The results indicate that stimulation of ST36 single acupoints has therapeutic effects mainly in models of respiratory, neurological, digestive, endocrine and immune system diseases. And it can affect the inflammatory state, oxidative stress, respiratory mucus secretion, intestinal flora, immune cell function, neurotransmitter transmission, hormone secretion, the network of Interstitial Cells of Cajal (ICC) and glucose metabolism of the organism in these pathological states. Among them, acupuncture at the ST36 single point has the most prominent function in regulating the inflammatory state, which can mainly affect the activation of MAPK signaling pathway and drive the ''molecular-cellular'' mode involving macrophages, T-lymphocytes, mast cells (MCs) and neuroglial cells as the core to trigger the molecular level changes of the acupuncture point locally or in the target organ tissues, thereby establishing a multi-system, multi-target, multi-level molecular regulating mechanism. This article provides a comprehensive summary and discussion of the molecular mechanisms and effects of acupuncture at the ST36 acupoint, laying the groundwork for future in-depth research on acupuncture point theory.

ObjectiveThis study aims to identify factors influencing university students' participation in time banking volunteer services for older adults and provides evidence to promote the involvement.MethodsConducted in November 2022, we utilized a convenience sampling method to recruit students from the School of Aging Service and Management at Nanjing University of Chinese Medicine, China. Data was collected through an online questionnaire focusing on various aspects related to time banking volunteer services for older adults. Factor analysis was employed to extract variables, and logistic regression was applied to identify key determinants.ResultsA significant majority (82.67%) of participants expressed willingness to engage in volunteer services for older adults. Factor analysis uncovered six influential factors explaining 62.55% of the variance. Logistic regression highlighted four key determinants of students' willingness: value judgment (OR = 4.392, CI = 2.897–6.658), social support (OR = 1.262, CI = 0.938–1.975), social influence (OR = 1.777, CI = 1.598–3.799), and socioeconomic conditions (OR = 1.174, CI = 1.891–3.046).ConclusionTo foster sustainability and continuous time banking among university students majoring in aging service and management, a multifaceted support involving governmental, social, and university is recommended.

The introduction of mobile edge computing (MEC) technology in rail transit which has the characteristics of complex environment, high densities of passengers, and high-speed mobility can meet the low latency, mobility, and massive connection requirements of rail transit.However, MEC not only improves the performance of rail transit communication network but also brings security challenges.Firstly, an overview of rail transit communication network and MEC was given.Then the value of introducing MEC into rail transit and the architecture of rail transit edge computing network were discussed.After that, the security threats faced by rail transit edge computing network was analyzed and protection scheme was proposed.Finally, some open questions were proposed, which was expected to provide ideas for future research.

Abstract Computing‐in‐memory (CIM) is a promising technique for solving the ‘memory wall’ and ‘power consumption wall’ problems. However, calculations in the analog domain are limited in terms of accuracy and sensitivity to process, voltage, and temperature changes. In this study, the authors proposed a CIM multiply‐and‐accumulate (MAC) circuit in which the MAC result was reflected by the pulse edge and converted into the final digital output using a dual‐edge counter quantization circuit, thereby improving the accuracy of the MAC operation and reducing the difficulty of quantization. The performance of the proposed CIM circuit was evaluated using a 28‐nm process. It could achieve 4‐bit multiplication without errors, with an energy efficiency of 24.38 to 670.86 TOPS/W.

Summary: Lysine succinylation is a subtype of protein acylation associated with metabolic regulation of succinyl-CoA in the tricarboxylic acid cycle. Deficiency of succinyl-CoA synthetase (SCS), the tricarboxylic acid cycle enzyme catalyzing the interconversion of succinyl-CoA to succinate, results in mitochondrial encephalomyopathy in humans. This report presents a conditional forebrain-specific knockout (KO) mouse model of Sucla2, the gene encoding the ATP-specific beta isoform of SCS, resulting in postnatal deficiency of the entire SCS complex. Results demonstrate that accumulation of succinyl-CoA in the absence of SCS leads to hypersuccinylation within the murine cerebral cortex. Specifically, increased succinylation is associated with functionally significant reduced activity of respiratory chain complex I and widescale alterations in chromatin landscape and gene expression. Integrative analysis of the transcriptomic data also reveals perturbations in regulatory networks of neuronal transcription in the KO forebrain. Together, these findings provide evidence that protein succinylation plays a significant role in the pathogenesis of SCS deficiency.

Here, the authors report on the discovery of physiological vasculogenic fibroblasts capable of forming functional blood vessels. In vivo tissue reprogramming triggered by topical tissue nanotransfection (TNT) of a single anti-miR-200b oligonucleotide achieved therapeutic tissue vascularization.

Market drugs, such as Food and Drug Administration (FDA) or European Medicines Agency (EMA)-approved drugs for specific indications provide opportunities for repurposing for newer therapeutics. This potentially saves resources invested in clinical trials that verify drug safety and tolerance in humans prior to alternative indication approval. Protein arginine methyltransferase 5 (PRMT5) overexpression has been linked to promoting the tumor phenotype in several cancers, including pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and breast cancer (BC), making PRMT5 an important target for cancer therapy. Previously, we showed that PRMT5-mediated methylation of the nuclear factor (NF)-κB, partially contributes to its constitutive activation observed in cancers. In this study, we utilized an AlphaLISA-based high-throughput screening method adapted in our lab, and identified one FDA-approved drug, Candesartan cilexetil (Can, used in hypertension treatment) and one EMA-approved drug, Cloperastine hydrochloride (Clo, used in cough treatment) that had significant PRMT5-inhibitory activity, and their anti-tumor properties were validated using cancer phenotypic assays in vitro. Furthermore, PRMT5 selective inhibition of methyltransferase activity was confirmed by reduction of both NF-κB methylation and its subsequent activation upon drug treatment. Using in silico prediction, we identified critical residues on PRMT5 targeted by these drugs that may interfere with its enzymatic activity. Finally, Clo and Can treatment have exhibited marked reduction in tumor growth in vivo. Overall, we provide basis for pursuing repurposing Clo and Can as anti-PRMT5 cancer therapies. Our study offers potential safe and fast repurposing of previously unknown PRMT5 inhibitors into clinical practice.

Abstract Alternative splicing plays a pivotal role in tumorigenesis and proliferation. However, its pattern and pathogenic role has not been systematically analyzed in multiple myeloma or its subtypes. Alternative splicing profiles for 598 newly diagnosed myeloma patients with comprehensive genomic annotation identified primary translocations, 1q amplification, and DIS3 events to have more differentially spliced events than those without. Splicing levels were correlated with expression of splicing factors. Moreover, the non-homologous end joining pathway was an independent factor that was highly associated with splicing frequency as well as an increased number of structural variants. We therefore identify an axis of high-risk disease encompassing expression of the non-homologous end joining pathway, increase structural variants, and increased alternative splicing that are linked together. This indicates a joint pathogenic role for DNA damage response and alternative RNA processing in myeloma.

Abstract Osteocytes act within a hypoxic environment to control key steps in bone formation. FGF23, a critical phosphate-regulating hormone, is stimulated by low oxygen/iron in acute and chronic diseases, however the molecular mechanisms directing this process remain unclear. Our goal was to identify the osteocyte factors responsible for FGF23 production driven by changes in oxygen/iron utilization. Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHI) which stabilize HIF transcription factors, increased Fgf23 in normal mice, as well as in osteocyte-like cells; in mice with conditional osteocyte Fgf23 deletion, circulating iFGF23 was suppressed. An inducible MSC cell line (‘MPC2’) underwent FG-4592 treatment and ATACseq/RNAseq, and demonstrated that differentiated osteocytes significantly increased HIF genomic accessibility versus progenitor cells. Integrative genomics also revealed increased prolyl hydroxylase Egln1 (Phd2) chromatin accessibility and expression, which was positively associated with osteocyte differentiation. In mice with chronic kidney disease (CKD), Phd1-3 enzymes were suppressed, consistent with FGF23 upregulation in this model. Conditional loss of Phd2 from osteocytes in vivo resulted in upregulated Fgf23, in line with our findings that the MPC2 cell line lacking Phd2 (CRISPR Phd2-KO cells) constitutively activated Fgf23 that was abolished by HIF1α blockade. In vitro, Phd2-KO cells lost iron-mediated suppression of Fgf23 and this activity was not compensated for by Phd1 or −3. In sum, osteocytes become adapted to oxygen/iron sensing during differentiation and are directly sensitive to bioavailable iron. Further, Phd2 is a critical mediator of osteocyte FGF23 production, thus our collective studies may provide new therapeutic targets for skeletal diseases involving disturbed oxygen/iron sensing.

Transportation not only provides support for economic and social development, but also has an important impact on emissions. Based on the DPSIR model, the constraint index system of transportation carbon emissions in the Pearl River Delta under ‘Dual carbon’ is constructed, and the hierarchical structure model is constructed by using the DEMATEL-ISM integration method. The constraint mechanism of transportation carbon emission in the Pearl River Delta is analyzed from the three dimensions of the correlation and importance, system hierarchical structure and constraint path of the constraints. The study found that there are six levels of constraints. The economic development level, carbon emission scale and the ‘Dual carbon’ goals are the core factors of the entire system. Developing public transport and intelligent transportation and increasing investment in new energy infrastructure and technology are conducive to the development of transportation in the Pearl River Delta and the realization of ‘double carbon’ goals.

ObjectivesThis paper aims to address the numerical simulation problems of the dynamic response of ships subject to near-, medium- and far-field underwater explosions by establishing several numerical methods and calculation models. MethodsFirst, load and fluid-structure interaction models are established on the basis of the Eulerian finite element method and acoustic finite element method using the field-split technique, and FSLAB fluid-structure interaction software is developed. Next, near-, medium- and far-field underwater explosions are numerically simulated respectively. The shock wave propagation law, bubble shape and load evolution characteristics of near free-surface and near-wall underwater explosions are obtained, and the shock response characteristics of a spherical shell and ship subject to far-field underwater explosions are analyzed. Finally, the FSLAB software results are compared with the analytical solutions, reference solutions and experimental data. ResultsThe results show that the FSLAB fluid-structure interaction software developed in this paper is effective and accurate in simulating the impact damage of underwater explosions on warships. ConclusionThis study can provide a basis and support for the power assessment of underwater anti-explosion and shock design of warships.

Abstract The Penrose process of an extremal braneworld black hole is studied. We analyze the Penrose process by two massive spinning particles colliding near the horizon. By calculating the maximum energy extraction efficiency of this process, it turns out that the maximal efficiency increases as the tidal charge parameter d of the braneworld blackhole decreases. Interestingly, for the negative value of d, the efficiency can be even larger than the Kerr case.

Abstract Background Melatonin (MEL), an endogenous hormone, has been widely investigated in neurological diseases. Microglia (MG), a resident immunocyte localizing in central nervous system is reported to play important functions in the animal model of temporal lobe epilepsy (TLE). Some evidence showed that MEL influenced activation of MG, but the detailed model of action that MEL plays in remains uncertain. Methods In this study, we established a model of TLE in mice by stereotactic injection of kainic acid (KA). We treated the mice with MEL. Lipopolysaccharide, ROCK2‐knockdown (ROCK‐KD) and ‐overexpression (ROCK‐OE) of lentivirus‐treated cells were used in cell experiments to simulate an in vitro inflammatory model. Results The results of electrophysiological tests showed that MEL reduced frequency and severity of seizure. The results of behavioral tests indicated MEL improved cognition, learning, and memory ability. Histological evidences demonstrated a significant reduction of neuronal death in the hippocampus. In vivo study showed that MEL changed the polarization status of MG from a proinflammatory M1 phenotype to an anti‐inflammatory M2 phenotype by inversely regulating the RhoA/ROCK signaling pathway. In cytological study, we found that MEL had a significant protective effect in LPS‐treated BV‐2 cells and ROCK‐KD cells, while the protective effect of MEL was significantly attenuated in ROCK‐OE cells. Conclusion MEL played an antiepileptic role in the KA‐induced TLE modeling mice both in behavioral and histological levels, and changed MG polarization status by regulating the RhoA/ROCK signaling pathway.

N6-methyladenine (6mA) of DNA is an emerging epigenetic mark in the genomes of Chlamydomonas, Caenorhabditis elegans, and mammals recently. Levels of 6mA undergo drastic fluctuation and thus affect fertility during meiosis and early embryogenesis. Here, we showed three complex structures of 6mA demethylase C. elegans NMAD-1A, a canonical isoform of NMAD-1 (F09F7.7). Biochemical results revealed that NMAD-1A prefers 6mA Bubble or Bulge DNAs. Structural studies of NMAD-1A revealed an unexpected “stretch-out” conformation of its Flip2 region, a conserved element that is usually bent over the catalytic center to facilitate substrate base flipping in other DNA demethylases. Moreover, the wide channel between the Flip1 and Flip2 of the NMAD-1A explained the observed preference of NMAD-1A for unpairing substrates, of which the flipped 6mA was primed for catalysis. Structural analysis and mutagenesis studies confirmed that key elements such as carboxy-terminal domain (CTD) and hypothetical zinc finger domain (ZFD) critically contributed to structural integrity, catalytic activity, and nucleosome binding. Collectively, our biochemical and structural studies suggest that NMAD-1A prefers to regulate 6mA in the unpairing regions and is thus possibly associated with dynamic chromosome regulation and meiosis regulation.

Flexible organic light-emitting diodes (FOLEDs) have promising potential for future wearable applications because of their exceptional mechanical flexibility. Silver nanowire (Ag NW) networks are the most promising candidates to replace indium tin oxide (ITO), which is limited by its poor bendability. In this study, three different methods including methanol impregnation, argon plasma treatment, and ultraviolet radiation were used to reduce the junction resistance of Ag NWs to optimize the flexible transparent electrodes (FTEs); which were prepared using Ag NWs and poly(3,4-ethylenedioxythiophene): poly(styrenesulfonate) (PEDOT: PSS). Then, the optoelectronic properties of the FTEs were further improved by using a co-doped system of silver nanowires and silver nanoparticles (Ag NPs), the structure of which consisted of PET/Ag NWs: Ag NPs/PEDOT: PSS/DMSO. The largest FOM value of 1.42 × 10−2 ohm−1 and a low sheet resistance value of 13.86 ohm/sq were obtained using the optimized FTEs. The prepared FOLED based on the optimized FTEs had a luminous efficiency of 6.04 cd/A and a maximum EQE of 1.92%, and exhibited no observed decline in efficiency when reaching maximum luminance. After 500 bending tests, the luminance still reached 82% of the original value. It is demonstrated that the FTEs prepared via the co-doped system have excellent optoelectronic properties as well as high mechanical stability.

Organic light-emitting diodes (OLEDs) are widely recognized as the forefront technology for displays and lighting technology. Now, the global OLED market is nearly mature, driven by the rising demand for superior displays in smartphones. In recent years, numerous strategies have been introduced and demonstrated to optimize the hole injection layer to further enhance the efficiency of OLEDs. In this paper, different methods of optimizing the hole injection layer were elucidated, including using a suitable hole injection material to minimize the hole injection barrier and match the energy level with the emission layer, exploring new preparation methods to optimize the structure of hole injection layer, and so on. Meanwhile, this article can help people to understand the current research progress and the challenges still faced in relation to the hole injection layer in OLEDs, providing future research directions to enhance the properties of OLEDs.

We aimed to improve the detection accuracy of laser methane sensors in expansive temperature application environments. In this paper, a large-scale dataset of the measured concentration of the sensor at different temperatures is established, and a temperature compensation model based on the ISSA-BP neural network is proposed. On the data side, a large-scale dataset of 15,810 sets of laser methane sensors with different temperatures and concentrations was established, and an Improved Isolation Forest algorithm was used to clean the large-scale data and remove the outliers in the dataset. On the modeling framework, a temperature compensation model based on the ISSA-BP neural network is proposed. The quasi-reflective learning, chameleon swarm algorithm, Lévy flight, and artificial rabbits optimization are utilized to improve the initialization of the sparrow population, explorer position, anti-predator position, and position of individual sparrows in each generation, respectively, to improve the global optimization seeking ability of the standard sparrow search algorithm. The ISSA-BP temperature compensation model far outperforms the four models, SVM, RF, BP, and PSO-BP, in model evaluation metrics such as MAE, MAPE, RMSE, and R-square for both the training and test sets. The results show that the algorithm in this paper can significantly improve the detection accuracy of the laser methane sensor under the wide temperature application environment.

Abstract Background Cachexia is frequent, deadly, and untreatable for patients with pancreatic ductal adenocarcinoma (PDAC). The reproductive hormone and cytokine Activin is a mediator of PDAC cachexia, and Activin receptor targeting was clinically tested for cancer cachexia therapy. However, sex‐specific manifestations and mechanisms are poorly understood, constraining development of effective treatments. Methods Cachexia phenotypes, muscle gene/protein expression, and effects of the Activin blocker ACVR2B/Fc were assessed in LSL‐KrasG12D/+, LSL‐Trp53R172H/+, and Pdx‐1‐Cre (KPC) mice with autochthonic PDAC. Effects of PDAC and sex hormones were modelled by treating C2C12 myotubes with KPC‐cell conditioned medium (CM) and estradiol. Muscle gene expression by RNAseq and change in muscle from serial CT scans were measured in patients with PDAC. Results Despite equivalent tumour latency (median 17 weeks) and mortality (24.5 weeks), male KPC mice showed earlier and more severe cachexia than females. In early PDAC, male gastrocnemius, quadriceps, and tibialis anterior muscles were reduced (−21.7%, −18.9%, and −20.8%, respectively, all P

Abstract MicroRNAs (miRNAs) are small RNAs integral in the regulation of gene expression. Analysis of circulating miRNA levels may identify patients with coronary artery disease (CAD) at risk for recurrent myocardial infarction (MI) after percutaneous coronary interventions (PCIs). Subjects with CAD were selected from the GENCATH cardiac catheterization biobank. Subjects with recurrent MI after PCI were compared with those without recurrent MI during follow‐up in the initial (n = 48) and replication cohort (n = 67). Next generation MiRNA sequencing was performed on plasma samples and whole blood samples fixed with PAXGENE tubes upon collection. Overall, 164 miRNAs derived from whole blood were differentially expressed in the replication cohort between subjects with and without recurrent MI events (p

The role of IL-9 in the tumor microenvironment and its effects on macrophages remains unclear. Here, the authors show that IL-9 promotes the expansion of pulmonary macrophages and that targeting the IL-9R/arginase 1 axis restricts tumor growth, thus identifying this cytokine pathway as a potential therapeutic target.

Abstract Genome-wide association studies (GWAS) in admixed populations such as African Americans (AA) have limited sample sizes, resulting in poor performance of polygenic risk scores (PRS). Based on the observations that many disease-causing genes are shared between AA and European ancestry (EA) populations, and some disease-causing variants are located within the boundaries of these genes, we proposed a novel gene-based PRS framework (PRSgene) by using variants located within disease-associated genes. Using the AA GWAS of alcohol use disorder (AUD) from the Million Veteran Program and the EA GWAS of problematic alcohol use as the discovery GWAS, we identified 858 variants from 410 genes that were AUD-related in both AA and EA. PRSgene calculated using these variants were significantly associated with AUD in three AA target datasets (P-values ranged from 7.61E−05 to 6.27E−03; Betas ranged from 0.15 to 0.21) and outperformed PRS calculated using all variants (P-values ranged from 7.28E−03 to 0.16; Betas ranged from 0.06 to 0.18). PRSgene were also associated with AUD in an EA target dataset (P-value = 0.02, Beta = 0.11). In AA, individuals in the highest PRSgene decile had an odds ratio of 1.76 (95% CI: 1.32–2.34) to develop AUD compared to those in the lowest decile. The 410 genes were enriched in 54 Gene Ontology biological processes, including ethanol oxidation and processes involving the synaptic system, which are known to be AUD-related. In addition, 26 genes were targets of drugs used to treat AUD or other diseases that might be considered for repurposing to treat AUD. Our study demonstrated that the gene-based PRS had improved performance in evaluating AUD risk in AA and provided new insight into AUD genetics.

Abstract Hydrogel is frequently used as a solid electrolyte for all solid‐state supercapacitors (SCs) because of its liquid‐like ion‐transport property and high conformability. However, due to the higher water content, the hydrogel electrolyte undergoes inevitable freezing and/or dehydration with climate change. Herein, polypyrrole/carbon all‐solid‐state SCs (PCSCs) were developed based on a hierarchical polypyrrole/carbon nanotube electrode and a highly stretchable double‐network polymer hydrogel electrolyte with LiCl/ethylene glycol as a mixed solvent. The PCSCs showed excellent electrochemical performance and cycle stability with a wide operating temperature. The specific capacitances could reach 202.2 and 112.3 mF cm−2 at current densities of 0.5 and 3.0 mA cm−2, respectively. Meanwhile, the PCSCs showed outstanding mechanical properties in maintaining a high areal capacitance under deformations of bending and tension. The excellent water retention of the device also ensured the stable electrochemical performance of PCSCs in a wide temperature range (30–80°C), which could potentially represent a reliable application in various harsh environments.

Tomographic Synthetic Aperture Radar (TomoSAR) is an advanced technology for three-dimensional (3D) mountain reconstruction. However, the TomoSAR mountain point clouds have a significant location error in the elevation direction, making high-precision 3D reconstruction of mountains difficult. A geometry constrained Moving Least Squares (MLS)-based high-precision 3D reconstruction method is addressed in this issue. This method not only has the benefits of the traditional MLS in that it uses the local subspace principle for fitting complex surface structures but also fully uses the TomoSAR point cloud characteristic of monotonically increasing elevation with ground distance for reconstruction error correction. The point clouds are first projected onto a new azimuth-ground-elevation domain. Subsequently, the suggested iterative solution-based geometry constrained MLS performs location error correction in the elevation direction. Finally, the projection transformation is used to generate 3D reconstruction results of mountains. The simulation and measurement of airborne array TomoSAR mountain data, AW3D30 DSM data, and 1:10,000 DEM data validate the effectiveness of the proposed method and demonstrate the feasibility and superiority of airborne array TomoSAR for applications such as high-precision 3D mountain reconstruction.

Colitis-associated cancer (CAC) is closely related to chronic inflammation, whose underlying molecular mechanism, however, has not been elaborated comprehensively. In the current study, an investigation was conducted on the role of autophagy in the initiation and progression of azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colon tumors, a mouse model for CAC in humans. Mice with the intestinal epithelial cell (IEC)-specific deletion of the autophagy-related gene 7 (Atg7) saw a significant decrease in tumor number, burden, and risk of high-grade dysplasia. The autophagy deficiency of IECs resulted in the accumulation of T cells, especially CD8+ T lymphocytes in colon lamina propria. Furthermore, it was found that autophagy protects against DSS-induced intestinal injury through maintaining epithelial barrier function and promoting the survival and proliferation of IECs. Mechanistically, autophagy in IECs enhanced the activation of epithelial STAT3/ERK to promote the survival and proliferation of colonic epithelial cells during the development of CAC. Therefore, the findings unveil the essential role of autophagy in activating the processes of colonic protection, regeneration, and tumorigenesis.

Summary: Skeletal muscle dysfunction or reprogramming due to the effects of the cancer secretome is observed in multiple malignancies. Although mouse models are routinely used to study skeletal muscle defects in cancer, because of species specificity of certain cytokines/chemokines in the secretome, a human model system is required. Here, we establish simplified multiple skeletal muscle stem cell lines (hMuSCs), which can be differentiated into myotubes. Using single nuclei ATAC-seq (snATAC-seq) and RNA-seq (snRNA-seq), we document chromatin accessibility and transcriptomic changes associated with the transition of hMuSCs to myotubes. Cancer secretome accelerated stem to myotube differentiation, altered the alternative splicing machinery and increased inflammatory, glucocorticoid receptor, and wound healing pathways in hMuSCs. Additionally, cancer secretome reduced metabolic and survival pathway associated miR-486, AKT, and p53 signaling in hMuSCs. hMuSCs underwent myotube differentiation when engrafted into NSG mice and thus providing a humanized in vivo skeletal muscle model system to study cancer cachexia.

Most circulating endothelial cells are apoptotic, but rare circulating endothelial colony-forming cells (C-ECFCs), also known as blood outgrowth endothelial cells, with proliferative and vasculogenic activity can be cultured; however, the origin and naive function of these C-ECFCs remains obscure. Herein, detailed lineage tracing revealed murine C-ECFCs emerged in the early postnatal period, displayed high vasculogenic potential with enriched frequency of clonal proliferative cells compared with tissue-resident ECFCs, and were not committed to or derived from the BM hematopoietic system but from tissue-resident ECFCs. In humans, C-ECFCs were present in the CD34bright cord blood mononuclear subset, possessed proliferative potential and in vivo vasculogenic function in a naive or cultured state, and displayed a single cell transcriptome sharing some umbilical venous endothelial cell features, such as a higher protein C receptor and extracellular matrix gene expression. This study provides an advance for the field by identifying the origin, naive function, and antigens to prospectively isolate C-ECFCs for translational studies.

Aeromonas hydrophila is a kind of zoonotic pathogen, which can cause bacterial septicemia in fish and bring huge economic losses to global aquaculture. Outer membrane proteins (Omps) are conserved antigens of Aeromonas hydrophila, which can be developed as subunit vaccines. To evaluate the protective efficacy of inactivated vaccine and recombinant outer membrane protein A (OmpA) subunit vaccine against A. hydrophila in juvenile Megalobrama amblycephala, the present study investigated the immunogenicity and protective effects of both vaccines, as well as the non-specific and specific immune response of M. amblycephala. Compared with the non-vaccinated group, both inactivated and OmpA subunit vaccines improved the survival rate of M. amblycephala upon infection. The protective effects of OmpA vaccine groups were better than that of the inactivated vaccine groups, which should be attributed to the reduced bacterial load and enhanced host immunity in the vaccinated fish. ELISA assay showed that the titer of serum immunoglobulin M (IgM) specific to A. hydrophila up-regulated significantly in the OmpA subunit vaccine groups at 14 d post infection (dpi), which should contribute to better immune protective effects. In addition, vaccination enhanced host bactericidal abilities might also attribute to the regulation of the activities of hepatic and serum antimicrobial enzymes. Moreover, the expression of immune-related genes (SAA, iNOS, IL-1 β, IL-6, IL-10, TNF α, C3, MHC I, MHC II, CD4, CD8, TCR α, IgM, IgD and IgZ) increased in all groups post infection, which was more significant in the vaccinated groups. Furthermore, the number of immunopositive cells exhibiting different epitopes (CD8, IgM, IgD and IgZ) that were detected by immunohistochemical assay had increased in the vaccinated groups post infection. These results show that vaccination effectively stimulated host immune response (especially OmpA vaccine groups). In conclusion, these results indicated that both the inactivated vaccine and OmpA subunit vaccine could protect juvenile M. amblycephala against A. hydrophila infection, of which OmpA subunit vaccine provided more effective immune protection and can be used as an ideal candidate for the A. hydrophila vaccine.

Fucoidan and laminarin are polymolecular compounds that extracted from seaweed. As functional polysaccharides, they possess various biological functions such as immunomodulatory, anti-inflammatory, antiviral and antioxidant bioactivities. Fucoidan and laminarin modulate host immune responses by activating immune cells (macrophages, neutrophils, T lymphocytes) and inducing the expression of cytokines (TNFα, IL-1β, IL-6, IL-8, NF-κB). Intelectin is a novel lectin that plays important roles in bacterial agglutination and bactericidal effects by recognizing the polysaccharide components on the cell surface of pathogens, which can also enhance the phagocytosis of macrophages. The present study intends to explore the immunomodulatory effects of fucoidan, laminarin and intelectin on the macrophages of Megalobrama amblycephala. The results showed that the incubation of both fucoidan and laminarin at the concentration of 100 μg/mL for 4 h could enhance the phagocytic capacity of M. amblycephala macrophages, which also showed remodeled cytoskeleton with extended pseudopodia. In addition, fucoidan and laminarin could induce the expression of M. amblycephala intelectin (MaINTL) in the primary hepatocytes and macrophages, and the recombinant MaINTL (rMaINTL) could bind with fucoidan and laminarin. Furthermore, fucoidan and laminarin induced the expression of cytoskeletal remodeling related genes in the primary M. amblycephala macrophages, such as Rac1 and WASP, which should contribute to the enhancement of seaweed polysaccharides (fucoidan and laminarin) and MaINTL on the phagocytosis of M. amblycephala macrophages. However, even though fucoidan and laminarin could induced the expression of CXCL8, while the chemotaxis of M. amblycephala macrophages on neutrophils was not affected by them. These findings suggested that fucoidan and laminarin enhanced the phagocytic capacity of M. amblycephala macrophages via activation of MaINTL and up-regulation of the expression of downstream cytoskeletal remodeling related genes Rac1 and WASP. Therefore, fucoidan and laminarin could be used as immune enhancers to improve host immunity and disease resistance in M. amblycephala, which provided novel insights into the prevention and protection of fish bacterial diseases.

Abstract Background Colorectal cancer (CRC) consensus molecular subtypes (CMS) have different immunological, stromal cell, and clinicopathological characteristics. Single-cell characterization of CMS subtype tumor microenvironments is required to elucidate mechanisms of tumor and stroma cell contributions to pathogenesis which may advance subtype-specific therapeutic development. We interrogate racially diverse human CRC samples and analyze multiple independent external cohorts for a total of 487,829 single cells enabling high-resolution depiction of the cellular diversity and heterogeneity within the tumor and microenvironmental cells. Results Tumor cells recapitulate individual CMS subgroups yet exhibit significant intratumoral CMS heterogeneity. Both CMS1 microsatellite instability (MSI-H) CRCs and microsatellite stable (MSS) CRC demonstrate similar pathway activations at the tumor epithelial level. However, CD8+ cytotoxic T cell phenotype infiltration in MSI-H CRCs may explain why these tumors respond to immune checkpoint inhibitors. Cellular transcriptomic profiles in CRC exist in a tumor immune stromal continuum in contrast to discrete subtypes proposed by studies utilizing bulk transcriptomics. We note a dichotomy in tumor microenvironments across CMS subgroups exists by which patients with high cancer-associated fibroblasts (CAFs) and C1Q+TAM content exhibit poor outcomes, providing a higher level of personalization and precision than would distinct subtypes. Additionally, we discover CAF subtypes known to be associated with immunotherapy resistance. Conclusions Distinct CAFs and C1Q+ TAMs are sufficient to explain CMS predictive ability and a simpler signature based on these cellular phenotypes could stratify CRC patient prognosis with greater precision. Therapeutically targeting specific CAF subtypes and C1Q + TAMs may promote immunotherapy responses in CRC patients.

Elevated levels of atmospheric CO2 (eCO2) promote rice growth and increase methane (CH4) emissions from rice paddies, because increased input of plant photosynthate to soil stimulates methanogenic archae. However, temporal trends in the effects of eCO2 on rice growth and CH4 emissions are still unclear. To investigate changes in the effects of eCO2 over time, we conducted a two-season pot experiment in a walk-in growth chamber. Positive effects of eCO2 on rice leaf photosynthetic rate, biomass, and grain yield were similar between growing seasons. However, the effects of eCO2 on CH4 emissions decreased over time. Elevated CO2 increased CH4 emissions by 48%–101% in the first growing season, but only by 28%–30% in the second growing season. We also identified the microbial process underlying the acclimation of CH4 emissions to atmospheric CO2 enrichment: eCO2 stimulated the abundance of methanotrophs more strongly in soils that had been previously exposed to eCO2 than in soils that had not been. These results emphasize the need for long-term eCO2 experiments for accurate predictions of terrestrial feedbacks.