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Abstract Drug resistance is vital for the poor prognosis of acute myeloid leukemia (AML) patients, but the underlying mechanism remains poorly understood. Given the unique microenvironment of bone marrow, we reasoned that drug resistance of AML might rely on distinct metabolic processes. Here, we identify succinate dehydrogenase (SDH) deficiency and over-cumulative succinate as typical features in AML, with a marked function in causing the resistance of AML cells to various anti-cancer therapies. Mechanistically, succinate promotes the accumulation of oncogenic proteins in a manner that precedes transcriptional activation. This function is mediated by succinate-triggered upregulation of ubiquitin-conjugating enzyme E2M (UBC12) phosphorylation, which impairs its E2 function in cullins neddylation. Notably, decreasing succinate by fludarabine can restore the sensitivity of anti-cancer drugs in SDH-deficient AML. Together, we uncover the function of succinate in driving drug resistance by regulating p-UBC12/cullin activity, and indicate reshaping succinate metabolism as a promising treatment for SDH-deficient AML.

Background Nonalcoholic fatty liver disease (NAFLD) is a common digestive system disease, which is often diagnosed by imaging methods in clinical work. At present, there is a lack of research on the effectiveness evaluation of imaging diagnostic methods with histology as the gold standard. Objective To study the consistency of imaging and histological diagnosis of NAFLD, and to analyze the influencing factors of gallstone disease (GD) complicated with NAFLD. Methods From January 2021 to July 2022, 53 patients with GD who underwent simple cholecystectomy and liver biopsy were selected from the Department of Hepatobiliary surgery, Nanjing Hospital affiliated to Nanjing University of traditional Chinese Medicine. The demographic characteristics, BMI, systolic blood pressure (SBP) and diastolic blood pressure (DBP) of the subjects were collected, and the laboratory indexes, imaging and histological results were collected. The consistency of imaging and histological diagnosis of NAFLD was evaluated by Kappa consistency test. According to the histological diagnostic criteria, the subjects were divided into NAFLD group (n=15) and non-NAFLD group (n=38). Multivariate Logistic regression analysis was used to explore the influencing factors of NAFLD in patients with GD. Results The imaging detection rate of NAFLD in GD patients was 20.7% (11/53), which was lower than that of histology (28.3%) (15/53) (Kappa=0.404, P=0.001). The sensitivity of imaging diagnosis was 60.0% (9/15), the specificity was 94.7% (36/38), and the rate of missed diagnosis was 40.0% (6/15). There were 8 cases of nonalcoholic fatty liver (NAFL), 7 cases of nonalcoholic steatohepatitis (NASH) and no NASH associated cirrhosis in 15 patients with histological manifestation of NAFLD. The proportion of fibrosis in the NASH group was higher than that in the NAFL group. There were significant differences in the levels of BMI, SBP, fasting blood glucose (FPG) and aspartate aminotransferase (AST) between NAFLD group and non-NAFLD group (P

Abstract Potassium-ion batteries (KIBs) are emerging as a promising alternative technology to lithium-ion batteries (LIBs) due to their significantly reduced dependency on critical minerals. KIBs may also present an opportunity for superior fast-charging compared to LIBs, with significantly faster K-ion electrolyte transport properties already demonstrated. In the absence of a viable K-ion electrolyte, a full-cell KIB rate model in commercial cell formats is required to determine the fast-charging potential for KIBs. However, a thorough and accurate characterisation of the critical electrode material properties determining rate performance—the solid state diffusivity and exchange current density—has not yet been conducted for the leading KIB electrode materials. Here, we accurately characterise the effective solid state diffusivities and exchange current densities of the graphite negative electrode and potassium manganese hexacyanoferrate $${{{{\rm{K}}}}}_{2}{{{\rm{Mn}}}}[{{{\rm{Fe}}}}{({{{\rm{CN}}}})}_{6}]$$ K 2 Mn [ Fe ( CN ) 6 ] (KMF) positive electrode, through a combination of optimised material design and state-of-the-art analysis. Finally, we present a Doyle-Fuller-Newman model of a KIB full cell with realistic geometry and loadings, identifying the critical materials properties that limit their rate capability.

Abstract Methanogenic hydrocarbon degradation can be carried out by archaea that couple alkane oxidation directly to methanogenesis, or by syntrophic associations of bacteria with methanogenic archaea. However, metagenomic analyses of methanogenic environments have revealed other archaea with potential for alkane degradation but apparent inability to form methane, suggesting the existence of other modes of syntrophic hydrocarbon degradation. Here, we provide experimental evidence supporting the existence of a third mode of methanogenic degradation of hydrocarbons, mediated by syntrophic cooperation between archaeal partners. We collected sediment samples from a hot spring sediment in Tengchong, China, and enriched Hadarchaeota under methanogenic conditions at 60 °C, using hexadecane as substrate. We named the enriched archaeon Candidatus Melinoarchaeum fermentans DL9YTT1. We used 13C-substrate incubations, metagenomic, metatranscriptomic and metabolomic analyses to show that Ca. Melinoarchaeum uses alkyl-coenzyme M reductases (ACRs) to activate hexadecane via alkyl-CoM formation. Ca. Melinoarchaeum likely degrades alkanes to carbon dioxide, hydrogen and acetate, which can be used as substrates by hydrogenotrophic and acetoclastic methanogens such as Methanothermobacter and Methanothrix.

This paper addresses the problem of high-resolution imaging of shadowed multiple-targets with limited labeled data, by proposing a transfer-learning-based method for through-the-wall radar imaging. First, a generative adversarial sub-network is developed to facilitate the migration of labeled simulation data to measured data, overcoming the difficulty of generating labeled data. This method incorporates an attention mechanism, adaptive residual blocks, and a multi-scale discriminator to improve the quality of image migration. It also incorporates a structural consistency loss function to minimize perceptual differences between images. Finally, the labeled data are used to train the through-the-wall radar target-imaging sub-network, achieving high-resolution imaging of multiple targets through walls. Experimental results show that the proposed method effectively reduces discrepancies between simulated and obtained images, and generates pseudo-measured images with labels. It systematically addresses issues such as side/grating ghost interference, target image defocusing, and multi-target mutual interference, significantly improving the multi-target imaging quality of the through-the-wall radar. The imaging accuracy achieved is 98.24%, 90.97% and 55.17% for single, double, and triple-target scenarios, respectively. Compared with CycleGAN, the imaging accuracy for the corresponding scenarios is improved by 2.29%, 40.28% and 15.51%, respectively.

Weekly artificial insemination (AI) is a common practice on commercial turkey breeder farms. The aim of this study was to determine changes in stress as well as oviduct and systemic immunity in response to weekly artificial inseminations through the laying cycle of turkey hens. Hens were divided into sham (extender only) and semen (extender + sperm) treatments. Blood, uterovaginal junction (UVJ), vagina, and spleen were collected at start of lay, peak lay, and end of lay (n = 8-12 /group for blood and 5 for tissues). The heterophil to lymphocyte ratio (H:L) was significantly higher in the semen-inseminated hens compared with the sham-inseminated hens at peak lay (n = 0.05). Immunohistochemistry revealed a higher number of CD3+ T cells in sperm storage tubules (SSTs) and UVJ submucosa at the end of lay compared with start and peak of lay across insemination treatments (n = 0.07 and 0.01, respectively). Within the end-of-lay group, semen-inseminated hens showed a higher number of CD3+ T cells in SSTs and UVJ submucosa (n = 0.04 and 0.1, respectively). The number of IgM+ B cells was significantly higher at start of lay compared with end of lay in SSTs and spleen (n = 0.01 and 0.0001, respectively) regardless of insemination treatment. In the vaginal submucosa, the number of IgM+ B cells was significantly higher in the semen group compared with the sham group at peak lay (n = 0.04). The number of IgA+ and IgY+ B cells were higher in the UVJ submucosa at the end of lay compared with start of lay, regardless of insemination treatment (n = 0.0001 and 0.03 respectively). In summary, the localization and number of adaptive immune cells change in response to the presence of sperm and laying cycle and depend on factors including immune cell type and tissue compartment. This suggests that the adaptive immune system of the oviduct plays an important role in responding to sperm based on the stage of the laying cycle. Modulating this immune response could improve reproductive performance.

KRAS mutations are associated with poor prognosis in colorectal cancer (CRC). Although the association between the gut microbiota and CRC has been extensively documented, it is unclear whether KRAS mutations can regulate the gut microbiota. Metagenomics has identified changes in the diversity of the gut microbiota in CRC due to KRAS mutations. Specifically, KRAS mutations positively correlate with the abundance of the bacteroides. Understanding how to regulate the classic carcinogenic bacterium within the bacteroides, such as enterotoxigenic bacteroides fragilis (ETBF), to enhance treatment efficacy of tumors is a key focus of research. Mechanistically, we found that the reduction of miR3655 is indispensable for KRAS mutation-promoted proliferation of CRC and the abundance of ETBF. miR3655 targets SURF6 to inhibit its transcription. Further transcriptomic sequencing revealed that SURF6 promotes intratumoral colonization of ETBF in CRC by inhibiting the nuclear translocation and transcription levels of the IRF7, affecting the activation of the IFNβ promoter. Regulating miR3655 and SURF6 can promote IFNβ secretion in CRC, directly killing ETBF. These data indicate that KRAS mutations affect the intratumoral colonization of ETBF in CRC through the miR3655/SURF6/IRF7/IFNβ axis. This provides new potential strategies for treating CRC associated with KRAS mutations or high levels of ETBF.

The majority of AI literacy studies have designed and developed self-reported questionnaires to assess AI learning and understanding. These studies assessed students' perceived AI capability rather than AI literacy because self-perceptions are seldom an accurate account of true measures. International assessment programs that use objective measures to assess science, mathematical, digital, and computational literacy back up this argument. Furthermore, because AI education research is still in its infancy, the current definition of AI literacy in the literature may not meet the needs of young students. Therefore, this study aims to develop and validate an AI literacy test for school students within the interdisciplinary project known as AI4future. Engineering and education researchers created and selected 25 multiple-choice questions to accomplish this goal, and school teachers validated them while developing an AI curriculum for middle schools. 2390 students in grades 7 to 9 took the test. We used a Rasch model to investigate the discrimination, reliability, and validity of the items. The results showed that the model met the unidimensionality assumption and demonstrated a set of reliable and valid items. They indicate the quality of the test items. The test enables AI education researchers and practitioners to appropriately evaluate their AI-related education interventions.

Abstract Background Intensive glycemic control is insufficient to reduce the risk of heart failure in patients with diabetes mellitus. While the hyperglycemic memory in the diabetic cardiomyopathy has been well documented, its underlying mechanisms are not fully understood. The present study tried to investigate whether the dysregulated proteins/biological pathways, which persistently altered in diabetic hearts during normoglycemia, participate in the hyperglycemic memory. Methods Hearts of streptozotocin‐induced diabetic mice, with or without intensive glycemic control using slow‐release insulin implants, were collected. Proteins from total heart samples and subcellular fractions were assessed by mass spectrometry, Western blotting, and KEGG pathway enrichment analysis. mRNA sequencing was used to determine whether the persistently altered proteins were regulated at the transcriptional or post‐transcriptional level. Results Western blot validation of several proteins with high pathophysiological importance, including MYH7, HMGCS2, PDK4, and BDH1, indicated that mass spectrometry was able to qualitatively, but not quantitatively, reflect the fold changes of certain proteins in diabetes. Pathway analysis revealed that the peroxisome, PPAR pathway, and fatty acid metabolism could be efficiently rescued by glycemic control. However, dysregulation of oxidative phosphorylation and reactive oxygen species persisted even after normalization of hyperglycemia. Notably, mRNA sequencing revealed that dysregulated proteins in the oxidative phosphorylation pathway were not accompanied by coordinated changes in mRNA levels, indicating post‐transcriptional regulation. Moreover, literature review and bioinformatics analysis suggested that hyperglycemia‐induced persistent alterations of miRNAs targeted genes from the persistently dysregulated oxidative phosphorylation pathway, whereas, oxidative phosphorylation dysfunction‐induced ROS regulated miRNA expression, which thereby might sustained the dysregulation of miRNAs. Conclusions Glycemic control cannot rescue hyperglycemia‐induced alterations of subcellular proteins in the diabetic heart, and persistently altered proteins are involved in multiple functional pathways, including oxidative phosphorylation. These findings might provide novel insights into hyperglycemic memory in diabetic cardiomyopathy.

Alcoholic liver disease is one of the main causes of global liver disease-related deaths, which has emerged as a major health concern for people. In this study, a peptide was prepared from Pinctada Martensii meat (named HPM-3), and its protective effect against alcohol-induced liver damage in mice was investigated. The results indicated that intervention of HPM-3 significantly decreased the levels of transaminase and lactate dehydrogenase in serum, and improved the antioxidant enzyme activities in the liver. Besides, HPM-3 could alleviate alcohol-induced liver injury by mediating Keap1/Nrf2 signaling pathway. Moreover, HPM-3 could preserve the diversity of the gut microbiota, and restore the relative abundance of some microbial communities that were impacted by alcohol intervention. HPM-3 intervention also affected the secretion of L-glutamine and other associated metabolites and mediated the related metabolic pathways. The results would help to clarify the mechanisms of protective effects of marine peptides against alcohol-induced liver injury.

Summary: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood and adolescence. The availability of appropriate and well-characterized preclinical models for RMS is limited, posing a challenge for investigating the molecular mechanisms and evaluating new targeted compounds in preclinical settings. Here, we collected 51 RMS specimens (referred to as ZJUCH-RMS cohort) and established 9 patient-derived cells (PDCs) and validated the identity of these cells by the expression of RMS-specific markers. Whole-transcriptome analysis identified high-confidence mutations in ZJUCH-RMS cohort including RAS, TP53, ARID1A, MYOD1, and MYCN. Further studies showed that RMS PDCs retained the genetic alterations and the expression of RMS hallmark and dependency genes in matched primary tumors and acted as valuable tools to assess drug responses and pharmacogenomic interactions. Our study provides unique PDCs that are available for preclinical studies of RMS and further advances the feasibility of RMS PDCs as valuable tools for developing personalized treatments for patients.

The value of Baijiu is affected by its flavor, age, and adulteration. Therefore, a simple and rapid identification method is crucial for the market. In this study, we present a rapid, non-intrusive identification technique for Baijiu utilizing the Tyndall effect combined with chemometrics analysis. Our experiment begins illuminating Baijiu with a 405 nm wavelength laser and recording the resulting bright light path due to the Tyndall effect. To further analyze the color and brightness information, Principal Component Analysis (PCA), Linear Discriminant Analysis (LDA), Hierarchical Cluster Analysis (HCA), and Multilayer Perceptron (MLP) were employed. This study establishes correlations between the brightness of the Tyndall light path and seven trace flavor compounds in Baijiu. The findings demonstrate that this method effectively identifies the flavor, age cellar, and adulteration of Baijiu and also quantitatively detects the concentrations of flavor compounds. Additionally, an analysis platform was developed to enable the rapid identification of Baijiu.

Abstract This study proposes an innovative deep learning algorithm for pose estimation based on point clouds, aimed at addressing the challenges of pose estimation for objects affected by the environment. Previous research on using deep learning for pose estimation has primarily been conducted using RGB-D data. This paper introduces an algorithm that utilizes point cloud data for deep learning-based pose computation. The algorithm builds upon previous work by integrating PointNet + + technology and the classical Point Pair Features algorithm, achieving accurate pose estimation for objects across different scene scales. Additionally, an adaptive parameter-density clustering method suitable for point clouds is introduced, effectively segmenting clusters in varying point cloud density environments. This resolves the complex issue of parameter determination for density clustering in different point cloud environments and enhances the robustness of clustering. Furthermore, the LineMod dataset is transformed into a point cloud dataset, and experiments are conducted on the transformed dataset to achieve promising results with our algorithm. Finally, experiments under both strong and weak lighting conditions demonstrate the algorithm's robustness.

Abstract Background The endothelial-to-hematopoietic transition (EHT) process during definitive hematopoiesis is highly conserved in vertebrates. Stage-specific expression of transposable elements (TEs) has been detected during zebrafish EHT and may promote hematopoietic stem cell (HSC) formation by activating inflammatory signaling. However, little is known about how TEs contribute to the EHT process in human and mouse. Results We reconstructed the single-cell EHT trajectories of human and mouse and resolved the dynamic expression patterns of TEs during EHT. Most TEs presented a transient co-upregulation pattern along the conserved EHT trajectories, coinciding with the temporal relaxation of epigenetic silencing systems. TE products can be sensed by multiple pattern recognition receptors, triggering inflammatory signaling to facilitate HSC emergence. Interestingly, we observed that hypoxia-related signals were enriched in cells with higher TE expression. Furthermore, we constructed the hematopoietic cis-regulatory network of accessible TEs and identified potential TE-derived enhancers that may boost the expression of specific EHT marker genes. Conclusions Our study provides a systematic vision of how TEs are dynamically controlled to promote the hematopoietic fate decisions through transcriptional and cis-regulatory networks, and pre-train the immunity of nascent HSCs.

Abstract A key strategy for minimizing our reliance on precious metals is to increase the fraction of surface atoms and improve the metal-support interface. In this work, we employ a solvent/ligand/counterion-free method to deposit copper in the atomic form directly onto a nanotextured surface of graphitized carbon nanofibers (GNFs). Our results demonstrate that under these conditions, copper atoms coalesce into nanoparticles securely anchored to the graphitic step edges, limiting their growth to 2–5 nm. The resultant hybrid Cu/GNF material displays high selectivity in the CO2 reduction reaction (CO2RR) for formate production with a faradaic efficiency of ~94% at -0.38 V vs RHE and a high turnover frequency of 2.78 × 106 h-1. The Cu nanoparticles adhered to the graphitic step edges significantly enhance electron transfer to CO2. Long-term CO2RR tests coupled with atomic-scale elucidation of changes in Cu/GNF reveal nanoparticles coarsening, and a simultaneous increase in the fraction of single Cu atoms. These changes in the catalyst structure make the onset of the CO2 reduction potential more negative, leading to less formate production at -0.38 V vs RHE, correlating with a less efficient competition of CO2 with H2O for adsorption on single Cu atoms on the graphitic surfaces, revealed by density functional theory calculations.

Abstract Background & aims Pyogenic liver abscess (PLA) is a common hepatobiliary infection that has been shown to have an increasing incidence, with biliary surgery being identified as a trigger. Our aim was to investigate the clinical characteristics and treatments of PLA patients with and without a history of biliary surgery (BS). Methods The study included a total of 353 patients with PLA who received treatment at our hospital between January 2014 and February 2023. These patients were categorized into two groups: the BS group (n = 91) and the non-BS group (n = 262). In the BS group, according to the anastomosis method, they were further divided into bilioenteric anastomoses group (BEA, n = 22) and non-bilioenteric anastomoses group (non-BEA, n = 69). Clinical characteristics were recorded and analyzed. Results The percentage of PLA patients with BS history was 25.78%. The BS group exhibited elevated levels of TBIL and activated APTT abnormalities (P = 0.009 and P = 0.041, respectively). Within the BS group, the BEA subgroup had a higher prevalence of diabetes mellitus (P

Abstract Background Our previous study found that crude polysaccharide extracted from Sargassum fusiforme (PSF) exhibited excellent anti-photoaging activity, but the composition responsible for this activity remained unknown. Results In this study, three fractions (P1, P2 and P3) obtained by hot water extraction and column chromatographic separation from PSF were structurally characterized. The anti-photoaging activities of these isolated polysaccharides were evaluated using HaCaT cells. The results showed that P1, P2 and P3 were acidic polysaccharides with 42.94%, 40.75% and 2.21% uronic acid. In addition, the contents of sulfate groups were 3.01%, 10.05% and 7.44%, respectively. Moreover, their content of reducing sugar was low, and none of the fractions had a triple-stranded helical structure. P1 had the largest average molecular weight of 208.89 kDa, while P2 and P3 had a relatively lower molecular weight of 154.09 and 151.71 kDa, respectively. Treatment with P2 effectively safeguarded the viability of HaCaT cells exposed to UVB irradiation. Additionally, it inhibited the secretion of MMP-1 and MMP-3 while elevating the content of hydroxyproline (HYP) in the cell supernatant. Methylation and NMR analysis suggested the main structure of P2 might be → [4)-β-ManA-(1]23 → 4)-β-ManA-(1 → 3)-β-d-Glcp-(1 → 4)-β-d-Glcp-(1 → 4)-β-d-Glcp-(1 → . The two terminal groups of β-ManA-(1 → and β-d-Glcp-(1 → were connected via the glycosidic bonds of → 3, 4)-O-3 in β-ManA-(1 → and O-6 in → 4, 6)-β-d-Glcp-(1 → , respectively. Conclusions These findings will open new avenues for exploring the potential use of Sargassum fusiforme polysaccharide, particularly P2, as a functional ingredient with anti-photoaging activity. Graphical Abstract

Abstract Ultralight dark photons constitute a well-motivated candidate for dark matter. A coherent electromagnetic wave is expected to be induced by dark photons when coupled with Standard-Model photons through kinetic mixing mechanism, and should be spatially correlated within the de Broglie wavelength of dark photons. Here we report the first search for correlated dark-photon signals using a long-baseline network of 15 atomic magnetometers, which are situated in two separated meter-scale shield rooms with a distance of about 1700 km. Both the network’s multiple sensors and the shields large size significantly enhance the expected dark-photon electromagnetic signals, and long-baseline measurements confidently reduce many local noise sources. Using this network, we constrain the kinetic mixing coefficient of dark photon dark matter over the mass range 4.1 feV-2.1 peV, which represents the most stringent constraints derived from any terrestrial experiments operating over the aforementioned mass range. Our prospect indicates that future data releases may go beyond the astrophysical constraints from the cosmic microwave background and the plasma heating.

The accurate simulation of regional-scale winter wheat yield is important for national food security and the balance of grain supply and demand in China. Presently, most remote sensing process models use the “biomass×harvest index (HI)” method to simulate regional-scale winter wheat yield. However, spatiotemporal differences in HI contribute to inaccuracies in yield simulation at the regional scale. Time-series dry matter partition coefficients (Fr) can dynamically reflect the dry matter partition of winter wheat. In this study, Fr equations were fitted for each organ of winter wheat using site-scale data. These equations were then coupled into a process-based and remote sensing-driven crop yield model for wheat (PRYM-Wheat) to improve the regional simulation of winter wheat yield over the North China Plain (NCP). The improved PRYM-Wheat model integrated with the fitted Fr equations (PRYM-Wheat-Fr) was validated using data obtained from provincial yearbooks. A 3-year (2000–2002) averaged validation showed that PRYM-Wheat-Fr had a higher coefficient of determination (R²=0.55) and lower root mean square error (RMSE=0.94 t ha–1) than PRYM-Wheat with a stable HI (abbreviated as PRYM-Wheat-HI), which had R² and RMSE values of 0.30 and 1.62 t ha–1, respectively. The PRYM-Wheat-Fr model also performed better than PRYM-Wheat-HI for simulating yield in verification years (2013–2015). In conclusion, the PRYM-Wheat-Fr model exhibited a better accuracy than the original PRYM-Wheat model, making it a useful tool for the simulation of regional winter wheat yield.

IntroductionPlants are inherently connected with the microbiome, which plays a crucial role in regulating various host plant biological processes, including immunity, nutrient acquisition, and resistance against abiotic and biotic stresses. Many factors affect the interaction between plants and microbiome.Methods and resultsIn this study, microbiome samples were collected from five niches (bulk soil, rhizoplane, root endosphere, phylloplane, and leaf endosphere) across four developmental stages (seedling, flowering, podding, and maturity) of various soybean varieties. Composition and structure of bacterial and fungal communities were analyzed using 16S rRNA gene and ITS (Internally Transcribed Spacer) region amplicon sequencing. It was observed that both niches and developmental stages significantly impact on the assembly and composition of soybean microbiome. However, variety, presence of a transgene, and glyphosate application had minimal effects on microbial communities. The dominant microbiome varied across the five niches, with most containing beneficial microbial communities capable of promoting plant growth or increasing disease resistance. Types and abundance of the dominant microbes affected network stability, potentially resulting in functional changes in different ecological niches.ConclusionThis study provides theoretical evidence for microbial protection of plants against diseases and demonstrates that systematic analysis of the composition and diversity of soybean microbiomes can contribute to the development of biological control technologies.

ABSTRACT: This experiment was conducted to investigate the effects of mulberry leaf extract (MLE) on alleviating fatty liver hemorrhagic syndrome (FLHS) in laying hens. The 576 Jing Fen laying hens of 56 weeks of age with good health and similar weights (1.76 ± 0.17 kg) were randomly divided into 6 groups, with 8 replicates in each group and 12 chickens in each replicate. The experiment lasted 56 d. The control group was fed a corn-soybean meal diet. The FLHS group was fed a high energy-low protein (HELP) diet, and the other four experimental groups were fed HELP diets supplemented with 0.04, 0.40, 0.80, and 1.20% MLE, respectively. The results showed that HELP treatment significantly induced liver injury, which indicated that the FLHS model was successfully established. MLE supplementation could alleviate the FLHS by reducing the liver index, abdominal fat percentage, total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and very low-density lipoprotein (VLDL) in the serum (P < 0.05), and subsequently increase the egg production rate (P < 0.05). The laying hens fed 0.8% MLE exhibited the greatest production performance (P < 0.05) and could improve serum lipid levels. In addition, the genes associated with fatty acid synthesis (ACC, HMGR and SREBP-1C) were downregulated (P < 0.05), and genes related to fatty acid oxidation (CPT1A, AMPK, and ATGL) were found to be upregulated (P < 0.05). Supplementation with 1.2% MLE significantly reduced the relative abundance of Firmicutes and Desulfurized Bacillus (P < 0.05) and significantly increased the relative abundance of Fecal Bacillus (P < 0.05). In conclusion, MLE may regulate the mRNA expression of lipid metabolism-related genes through the AMPK signaling pathway and improve cecal microbiota balance and serum lipid levels to alleviate FLHS in laying hens and subsequently improve egg production performance.

Heterosigma akashiwo is a harmful algal bloom species that causes significant detrimental effects on marine ecosystems worldwide. The algicidal bacterium Pseudalteromonas sp. LD-B1 has demonstrated potential effectiveness in mitigating these blooms. However, the molecular mechanisms underlying LD-B1’s inhibitory effects on H. akashiwo remain poorly understood. In this study, we employed the comprehensive methodology, including morphological observation, assessment of photosynthetic efficiency (Fv/Fm), and transcriptomic analysis, to investigate the response of H. akashiwo to LD-B1. Exposure to LD-B1 resulted in a rapid decline of H. akashiwo's Fv/Fm ratio, with cells transitioning to a rounded shape within 2 hours, subsequently undergoing structural collapse and cytoplasmic leakage. Transcriptomic data revealed sustained downregulation of photosynthetic genes, indicating impaired functionality of the photosynthetic system. Additionally, genes related to the respiratory electron transfer chain and antioxidant defenses were consistently downregulated, suggesting prolonged oxidative stress beyond the cellular antioxidative capacity. Notably, upregulation of autophagy-related genes was observed, indicating autophagic responses in the algal cells. This study elucidates the molecular basis of LD-B1's algicidal effects on H. akashiwo, advancing our understanding of algicidal mechanisms and contributing to the development of effective strategies for controlling harmful algal blooms.

Objective The mechanisms of intervertebral disc degeneration (IVDD) in low back pain (LBP) patients are multiples. In this study, we attempt to investigate whether melatonergic system plays a potential role in IVDD patients with LBP by analyzing their clinical specimens. The fucus will be given to the correlation between the melatonin receptor expression and intervertebral disc tissue apoptosis. Methods In this clinical study, 107 lumbar intervertebral disc nucleus pulposus (NP) specimens from patients with LBP were collected with patients’ consents. The disc height (DH) discrepancy ratio, range of motion and sagittal parameters of the pathological plane were measured and Pfirrmann grade was used to classified the grades of IVDD level. Discs at grades 1–3 were served as normal control and grades 4–5 were considered as IVDD. The expression levels of melatonin receptor 1A (MT1) and 1B (MT2) were measured by immunohistochemistry. The apoptosis of NP was assessed using TUNEL staining. Their potential associations among MT1/2, DH, apoptosis, sagittal parameters with IVDD and LBP were evaluated with statistical analysis. Results The incidence of IVDD was positively associated with age and negatively related to VAS scores for LBP (p

BackgroundThe protective role of gut microbiota and its metabolites against intestinal damage in sepsis patients remain unclear.MethodsFecal samples were acquired from patients categorized into sepsis and non-sepsis groups for analysis of microbial composition via 16S rRNA sequencing and untargeted metabolomics analysis. We assessed the impact of gut microbiota from sepsis patients on intestinal barriers in antibiotic-treated mice. Furthermore, We conducted spearman’s correlation analysis to examine the relationship between metabolites and the severity of sepsis. Additionally, we performed animal experiments to validate the functionality of identified metabolites.ResultsThe diversity of intestinal flora is decreased in patients with sepsis compared to the control group. Through fecal microbiota transplantation experiments, it was discovered that the gut microbiota derived from sepsis patients could induce intestinal damage in antibiotic-treated mice. Metabolomics analysis of the microbiota revealed a significant enrichment of the Valine, leucine, and isoleucine biosynthesis pathway. Further analysis showed a significant decrease in the abundance of L-valine in sepsis patients, which was negatively correlated with APACHE-II and SOFA scores. In sepsis mouse experiments, it was found that L-valine could alleviate sepsis-induced intestinal damage.ConclusionAlterations in microbial and metabolic features in the gut can affect the severity of sepsis. Furthermore, L-valine can protect against sepsis-induced intestinal injury.

Diabetic cardiomyopathy (DCM) is a major complication of diabetes and is characterized by left ventricular dysfunction. Currently, there is a lack of effective treatments for DCM. Ubiquitin-specific protease 7 (USP7) plays a key role in various diseases. However, whether USP7 is involved in DCM has not been established. In this study, we demonstrated that USP7 was upregulated in diabetic mouse hearts and NMCMs co-treated with HG+PA or H9c2 cells treated with PA. Abnormalities in diabetic heart morphology and function were reversed by USP7 silencing through conditional gene knockout or chemical inhibition. Proteomic analysis coupled with biochemical validation confirmed that PCG1β was one of the direct protein substrates of USP7 and aggravated myocardial damage through coactivation of the PPARα signaling pathway. USP7 silencing restored the expression of fatty acid metabolism-related proteins and restored mitochondrial homeostasis by inhibiting mitochondrial fission and promoting fusion events. Similar effects were also observed in vitro. Our data demonstrated that USP7 promoted cardiometabolic metabolism disorders and mitochondrial homeostasis dysfunction via stabilizing PCG1β and suggested that silencing USP7 may be a therapeutic strategy for DCM.

Abstract An understanding of the mechanisms regulating embryonic hematopoietic stem cell (HSC) development would facilitate their regeneration. The aorta-gonad-mesonephros region is the site for HSC production from hemogenic endothelial cells (HEC). While several distinct regulators are involved in this process, it is not yet known whether macroautophagy (autophagy) plays a role in hematopoiesis in the pre-liver stage. Here, we show that different states of autophagy exist in hematopoietic precursors and correlate with hematopoietic potential based on the LC3-RFP-EGFP mouse model. Deficiency of autophagy-related gene 5 (Atg5) specifically in endothelial cells disrupts endothelial to hematopoietic transition (EHT), by blocking the autophagic process. Using combined approaches, including single-cell RNA-sequencing (scRNA-seq), we have confirmed that Atg5 deletion interrupts developmental temporal order of EHT to further affect the pre-HSC I maturation, and that autophagy influences hemogenic potential of HEC and the formation of pre-HSC I likely via the nucleolin pathway. These findings demonstrate a role for autophagy in the formation/maturation of hematopoietic precursors.

Abstract Background Secondary immunodeficiency can arise from various clinical conditions that include HIV infection, chronic diseases, malignancy and long-term use of immunosuppressives, which makes the suffering patients susceptible to all types of pathogenic infections. Other than HIV infection, the possible pathogen profiles in other aetiology-induced secondary immunodeficiency are largely unknown. Methods Medical records of the patients with secondary immunodeficiency caused by various aetiologies were collected from the First Affiliated Hospital of Nanchang University, China. Based on these records, models were developed with the machine learning method to predict the potential infectious pathogens that may inflict the patients with secondary immunodeficiency caused by various disease conditions other than HIV infection. Results Several metrics were used to evaluate the models’ performance. A consistent conclusion can be drawn from all the metrics that Gradient Boosting Machine had the best performance with the highest accuracy at 91.01%, exceeding other models by 13.48, 7.14, and 4.49% respectively. Conclusions The models developed in our study enable the prediction of potential infectious pathogens that may affect the patients with secondary immunodeficiency caused by various aetiologies except for HIV infection, which will help clinicians make a timely decision on antibiotic use before microorganism culture results return.

Abstract Ageing exhibits common and distinct features in various tissues, making it critical to decipher the tissue-specific ageing mechanisms. MiRNAs are essential regulators in ageing and are recently highlighted as a class of intercellular messengers. However, little is known about the tissue-specific transcriptomic changes of miRNAs during ageing. C. elegans is a well-established model organism in ageing research. Here, we profile the age-dependent miRNAomic changes in five isolated worm tissues. Besides the diverse ageing-regulated miRNA expression across tissues, we discover numerous miRNAs in the tissues without their transcription. We further profile miRNAs in the extracellular vesicles and find that worm miRNAs undergo inter-tissue trafficking via these vesicles in an age-dependent manner. Using these datasets, we uncover the interaction between body wall muscle-derived mir-1 and DAF-16/FOXO in the intestine, suggesting mir-1 as a messenger in inter-tissue signalling. Taken together, we systematically investigate worm miRNAs in the somatic tissues and extracellular vesicles during ageing, providing a valuable resource to study tissue-autonomous and nonautonomous functions of miRNAs in ageing.

Abstract Background Oils are important sources of energy in pig diets. The combination of oils with different degree of saturation contributes to improve the utilization efficiency of the mixed oils and may reduce the cost of oil supplemented. An experiment was conducted to evaluate the effects of oils with different degree of saturation on the fat digestibility and corresponding additivity and bacterial community in growing pigs. Methods Eighteen crossbred (Duroc × Landrace × Yorkshire) barrows (initial body weight: 29.3 ± 2.8 kg) were surgically fitted with a T-cannula in the distal ileum. The experimental diets included a fat-free basal diet and 5 oil-added diets. The 5 oil-added diets were formulated by adding 6% oil with different ratio of unsaturated to saturated fatty acids (U:S) to the basal diet. The 5 oils were palm oil (U:S = 1.2), canola oil (U:S = 12.0), and palm oil and canola oil were mixed in different proportions to prepare a combination of U:S of 2.5, 3.5 and 4.5, respectively. Results The apparent and standardized ileal digestibility (AID and SID) of fat and fatty acids increased linearly (P