Brain glymphatic dysfunction is involved in the pathologic process of acute ischemic stroke (IS). The relationship between brain glymphatic activity and dysfunction in subacute IS has not been fully elucidated. Diffusion tensor image analysis along the perivascular space (DTI-ALPS) index was used in this study to explore whether glymphatic activity was related to motor dysfunction in subacute IS patients.

Bone marrow mesenchymal stem cells (BM MSCs) play a tumor-supportive role in promoting drug resistance and disease relapse in multiple myeloma (MM). Recent studies have discovered a sub-population of MSCs, known as inflammatory MSCs (iMSCs), exclusive to the MM BM microenvironment and implicated in drug resistance. Through a sophisticated analysis of public expression data from unexpanded BM MSCs, we uncovered a positive association between iMSC signature expression and minimal residual disease. While in vitro expansion generally results in the loss of the iMSC signature, our meta-analysis of additional public expression data demonstrated that cytokine stimulation, including IL1-β and TNF-α, as well as immune cells such as neutrophils, macrophages, and MM cells, can reactivate the signature expression of iMSCs to varying extents. These findings underscore the importance and potential utility of cytokine stimulation in mimicking the gene expression signature of early passage of iMSCs for functional characterizations of their tumor-supportive roles in MM.

Sesame is an ancient oilseed crop with high oil content and quality. However, the evolutionary history and genetic mechanisms of its valuable agronomic traits remain unclear. Here, we report chromosome-scale genomes of cultivated sesame (Sesamum indicum L.) and six wild Sesamum species, representing all three karyotypes within this genus. Karyotyping and genome-based phylogenic analysis revealed the evolutionary route of Sesamum species from n = 13 to n = 16 and revealed that allotetraploidization occurred in the wild species Sesamum radiatum. Early divergence of the Sesamum genus (48.5-19.7 million years ago) during the Tertiary period and its ancient phylogenic position within eudicots were observed. Pan-genome analysis revealed 9164 core gene families in the 7 Sesamum species. These families are significantly enriched in various metabolic pathways, including fatty acid (FA) metabolism and FA biosynthesis. Structural variations in SiPT1 and SiDT1 within the phosphatidyl ethanolamine-binding protein gene family lead to the genomic evolution of plant-architecture and inflorescence-development phenotypes in Sesamum. A genome-wide association study (GWAS) of an interspecific population and genome comparisons revealed a long terminal repeat insertion and a sequence deletion in DIR genes of wild Sesamum angustifolium and cultivated sesame, respectively; both variations independently cause high susceptibility to Fusarium wilt disease. A GWAS of 560 sesame accessions combined with an overexpression study confirmed that the NAC1 and PPO genes play an important role in upregulating oil content of sesame. Our study provides high-quality genomic resources for cultivated and wild Sesamum species and insights that can improve molecular breeding strategies for sesame and other oilseed crops.

Endoplasmic reticulum (ER) stress is a crucial factor in the pathogenesis of intestinal diseases. Soybean antigenic proteins (β-conglycinin and soy glycinin) induce hypersensitivity reactions and intestinal barrier damage. However, whether this damage is associated with ER stress, autophagy, and the gut microbiome is largely unclear. Therefore, in this study, we aimed to investigate the effect of dietary supplementation with soy glycinin (11S glycinin) and β-conglycinin (7S glycinin) on intestinal ER stress, autophagy, and flora in weaned piglets. Thirty healthy 21-day-old weaned "Duroc × Long White × Yorkshire" piglets were randomly divided into three groups and fed a basic, 7S-supplemented, or 11S-supplemented diet for one week. The results indicated that 7S/11S glycinin disrupted growth performance, damaged intestinal barrier integrity, and impaired goblet cell function in piglets (p < 0.05). Moreover, 7S/11S glycinin induced ER stress and blocked autophagic flux in the jejunum (p < 0.05) and increased the relative abundance of pathogenic flora (p < 0.01) and decreased that of beneficial flora (p < 0.05). In conclusion, 7S/11S glycinin induces intestinal ER stress, autophagic flux blockage, microbiota imbalance, and intestinal barrier damage in piglets.

Background and Objective: Transjugular intrahepatic portal shunt (TIPS) insertion could promote weight gain and muscle and fat mass increase in patients with cirrhosis. However, few studies have focused on metabolic changes after TIPS. This study aims to explore metabolic changes after TIPS and potential biomarkers of adverse events. Methods: Peripheral and portal serum samples were collected before and after TIPS insertion. Untargeted metabolomics was performed using ultra-high-performance liquid chromatography-mass spectrometry. Spearman's correlation analysis was used to determine the relationship between metabolites and clinical parameters. Metabolite set enrichment analysis was performed to explore enriched pathways. The predictive value of the metabolites was calculated by receiver operating characteristic curve (ROC) analysis. Results: Metabolites in the peripheral and portal serum significantly changed early after TIPS. Some lipid metabolites were significantly correlated with liver function parameters. Both elevated and depleted metabolites were mainly enriched in amino acid metabolism. Nine and 12 portal metabolites have moderate predictive value in post-TIPS liver function decline and hepatic encephalopathy (HE), separately (area under curve >0.7). Conclusion: Metabolites in the peripheral and portal veins significantly changed after TIPS. Some metabolic changes might be ascribed to liver function decline early after TIPS. Nine and 12 portal metabolites might be potential biomarkers in prediction of liver function decline and HE, separately.

Blastocystis hominis (Bh) is zoonotic parasitic pathogen with a high prevalent globally, causing opportunistic infections and diarrhea disease. Human immunodeficiency virus (HIV) infection disrupts the immune system by depleting CD4+ T lymphocyte (CD4+ T) cell counts, thereby increasing Bh infection risk among persons living with HIV (PLWH). However, the precise association between Bh infection risk and HIV-related biological markers and treatment processes remains poorly understood. Hence, the purpose of the study was to explore the association between Bh infection risk and CD4+ T cell counts, HIV viral load (VL), and duration of interruption in antiviral therapy among PLWH.

Rheumatoid arthritis (RA) is a common chronic inflammatory autoimmune disease with a multifactorial etiology. Peripheral blood is the main channel of the immune system, and peripheral blood mononuclear cells (PBMCs) are the immune cells that initiate the autoimmune inflammatory process. However, there are few reports on the mechanisms of peripheral blood immunity in RA.

Three-dimensional (3D) bioprinted cartilage-mimicking substitutes for full-thickness articular cartilage defect repair have emerged as alternatives to in situ defect repair models. However, there has been very limited breakthrough in cartilage regeneration based on 3D bioprinting owing to the lack of ideal bioinks with printability, biocompatibility, bioactivity, and suitable physicochemical properties. In contrast to animal-derived natural polymers or acellular matrices, human-derived Wharton's jelly is biocompatible and hypoimmunogenic with an abundant source. Although acellular Wharton's jelly can mimic the chondrogenic microenvironment, it remains challenging to prepare both printable and biologically active bioinks from this material. Here, we firstly prepared methacryloyl-modified acellular Wharton's jelly (AWJMA) using a previously established photo-crosslinking strategy. Subsequently, we combined methacryloyl-modified gelatin with AWJMA to obtain a hybrid hydrogel that exhibited both physicochemical properties and biological activities that were suitable for 3D bioprinting. Moreover, bone marrow mesenchymal stem cell-loaded 3D-bioprinted cartilage-mimicking substitutes had superior advantages for the survival, proliferation, spreading, and chondrogenic differentiation of bone marrow mesenchymal stem cells, which enabled satisfactory repair of a model of full-thickness articular cartilage defect in the rabbit knee joint. The current study provides a novel strategy based on 3D bioprinting of cartilage-mimicking substitutes for full-thickness articular cartilage defect repair.

Nuclease is a type of protein that degrades nucleic acids, which plays an important role in biological processes, including RNA interference efficiency and antiviral immunity. However, no evidence of a link between nuclease and Bombyx mori nucleopolyhedrovirus (BmNPV) infection in silkworm B. mori has been found. In this study, a protein asteroid (BmAst) containing the PIN domain and XPG domain was identified in silkworm B. mori. BmAst gene was highest expressed in hemocytes and fat body of the 5th instar larvae, and high expression in the pupa stage. The transcriptional levels of the BmAst gene in 5th instar larvae were significantly induced by BmNPV or dsRNA. After knocking down BmAst gene expression by specific dsRNA, the proliferation of BmNPV in B. mori was increased significantly, whereas the survival rate of larvae was significantly lower when compared with the control. Our findings indicate that BmAst is involved in silkworm resistance to BmNPV infection.

Lung cancer is the most common malignant tumor worldwide. In recent years, the incidence of lung adenocarcinoma (LAD) has increased significantly, with an unfavorable 5-year survival rate. Long non-coding RNAs (lncRNAs) have been shown to play a significant role in the emergence, growth, and metastasis of tumors. However, the functional role and mechanism of LINC00943 in LAD progression have not yet been investigated. Aberrant expressions of LINC00943, miR-1252-5p, and YWHAH were determined by RT-qPCR and Western blot analyses. The binding relationship between miR-1252-5p and LINC00943 or YWHAH was examined by Pearson's correlation analysis, RNA pull-down, and dual-luciferase reporter assays. MTT assay was conducted to measure cell viability and colony formation assay was performed to evaluate cell proliferation potential. Transwell assay was used to investigate cell migration and invasion and flow cytometry was applied to evaluate cell apoptosis. We found that LINC00943 was highly expressed in LAD tissue samples and cell lines and was a reliable biomarker with high sensitivity, and specificity (P < 0.0001; AUC: 0.8966) for LAD detection. LINC00943 was mainly localized in the cytoplasm. In vitro, LINC00943 promoted LAD cell proliferation, migration, and invasion; however, silencing LINC00943 inhibited LAD tumor metastasis. Mechanistically, LINC00943 was competitively bound with miR-1252-5p to enhance YWHAH expression. Moreover, LINC00943 silencing sponged miR-1252-5p to inhibit YWHAH, thereby retraining LAD cell malignant behaviors. In summary, LINC00943 facilitates LAD cell malignancy through sponging miR-1252-5p to upregulate YWHAH. LINC00943 is a novel lncRNA that serves as an oncogene and might be used as a prognostic biomarker for LAD.

As a classical regulating formula, Guominkang (GMK) has been extensively employed in clinical practice to treat the allergic asthma (AA) and alleviate allergy symptoms, however, the underlying mechanism remains elusive. The aim of this study was to explored the mechanism of action through which GMK combats AA.

The impact of ZnO as a feed additive on growth-performance and intestinal function of Enterotoxigenic Escherichia coli (ETEC) K88-infected piglets remains unclear. Fecal scores of piglets in ETEC group were significantly increased compared to control group. ETEC K88 significantly damages the small intestine, including a reduction in villus height in the jejunum, duodenum, and ileum, and a decrease in total superoxide dismutase activity in the jejunum and catalase activity in the ileum and jejunum. Compared to control group, ETEC K88 infection significantly elevated the mRNA level of gene IL-1β and the level of ileal epithelial cell apoptosis. ZnO administration significantly alleviated these negative effects and improved the antioxidative capability of the ileum. Moreover, ZnO supplementation alleviated the imbalance of gut microbiota by restoring the reduced amount of Enterococcus and Lactobacillus in the jejunum, Clostridium in the ileum, and Lactobacillus in the cecum, as well as the increased amount of total eubacteria in the ileum and Enterococcus in the cecum induced by the ETEC K88 infection. In conclusion, ZnO administration can reduce the diarrhea of piglets infected with ETEC K88 by reducing the structural damage of the intestine, attenuating intestinal oxidative stress and epithelial cell apoptosis, and modulating the gut microbiota.

Accurate prediction of microbe-drug associations is essential for drug development and disease diagnosis. However, existing methods often struggle to capture complex nonlinear relationships, effectively model long-range dependencies, and distinguish subtle similarities between microbes and drugs. To address these challenges, this paper introduces a new model for microbe-drug association prediction, CLMT. The proposed model differs from previous approaches in three key ways. Firstly, unlike conventional GCN-based models, CLMT leverages a Graph Transformer network with an attention mechanism to model high-order dependencies in the microbe-drug interaction graph, enhancing its ability to capture long-range associations. Then, we introduce graph contrastive learning, generating multiple augmented views through node perturbation and edge dropout. By optimizing a contrastive loss, CLMT distinguishes subtle structural variations, making the learned embeddings more robust and generalizable. By integrating multi-view contrastive learning and Transformer-based encoding, CLMT effectively mitigates data sparsity issues, significantly outperforming existing methods. Experimental results on three publicly available datasets demonstrate that CLMT achieves state-of-the-art performance, particularly in handling sparse data and nonlinear microbe-drug interactions, confirming its effectiveness for real-world biomedical applications. On the MDAD, aBiofilm, and Drug Virus datasets, CLMT outperforms the previously best model in terms of Accuracy by 4.3%, 3.5%, and 2.8%, respectively.

Phosphorylase kinase (PhK) regulates the degradation of glycogen by integrating diverse signals, providing energy to the organism. Dysfunctional mutations may directly lead to Glycogen Storage Disease type IX (GSD IX), whereas the abnormal expression of PhK is also associated with tumors. Here, we use cryo-electron microscopy (cryo-EM) to resolve its near-atomic structures in the inactive and active states. These structures reveal the interactions and relative locations of the four subunits (αβγδ) within the PhK complex. Phosphorylated α and β subunits induce PhK to present a more compact state, while Ca2+ causes sliding of the δ subunit along the helix of the γ subunit. Both actions synergistically activate PhK by enabling the de-inhibition of the γ subunit. We also identified different binding modes between PhK and its substrate, glycogen phosphorylase (GP), in two distinct states, using cross-linking mass spectrometry (XL-MS). This study provides valuable insights into the regulatory mechanisms of PhK, thereby enhancing our understanding of GSD IX and its implications in tumorigenesis.

To address the clinical challenges posed by symbiotic drug-resistant bacterial infections and tumor microenvironments, this study designed and synthesized novel carbazole/benzindole-based photosensitizers A1-A4, systematically evaluating their antitumor and antibacterial therapeutic potential through chemo-photodynamic therapy. Especially, compound A4 demonstrated potent Type I/II reactive oxygen species (ROS) generation capabilities. In vitro experiments revealed that A4 concentration-dependently inhibited HT-29 cells under hypoxic conditions (IC50 = 0.89 μM) with a prominent photodynamic index (PI > 9.23), and substantially promoted cancer cell programmed death. In antibacterial evaluations, A4 achieved the complete eradication of dermal MRSA infections within 7 days through ROS-mediated membrane disruption under illumination. In the HT-29 xenograft model, the PDT-chemotherapy synergy strategy achieved a tumor suppression rate of 96%. This work establishes an innovative strategy for the combinatorial management of multidrug-resistant infections and solid tumors.

Emerging evidence has indicated that the complex interactions between tumor microenvironment (TME) and cancer cells play a pivotal role in driving tumor initiation and metastasis. Cancer associated fibroblasts (CAFs), major cell components in the TME, exert significant effects on malignant behaviors of various cancers. Triple negative breast cancer (TNBC) is the most malignant subtype of breast cancer with a high metastatic potential and poorer prognosis. However, the underlying mechanism by which CAFs promote TNBC development has not been sufficiently studied.

Alpine treelines ecotones are critical ecological transition zones and are highly sensitive to global warming. However, the impact of climate on the distribution of treeline trees is not yet fully understood as this distribution may also be affected by other factors. Here, we used high-resolution satellite images with climatic and topographic variables to study changes in treeline tree distribution in the alpine treeline ecotone of the Changbai Mountain for the years 2002, 2010, 2017, and 2021. This study employed the Geodetector method to analyze how interactions between climatic and topographic factors influence the expansion of Betula ermanii on different aspect slopes. Over the past 20 years, B. ermanii, the only tree species in the Changbai Mountain tundra zone, had its highest expansion rate from 2017 to 2021 across all the years studied, approaching 2.38% per year. In 2021, B. ermanii reached its uppermost elevations of 2224 m on the western aspects and 2223 m on the northern aspects, which are the predominant aspects it occupies. We also observed a notable increase in the distribution of B. ermanii on steeper slopes (> 15°) between 2002 and 2021. Moreover, we found that interactions between climate and topographic factors played a more significant role in B. ermanii's expansion than any single dominant factor. Our results suggest that the interaction between topographic wetness index and the coldest month precipitation (Pre1), contributing 91% of the observed variability, primarily drove the expansion on the southern aspect by maintaining soil moisture, providing snowpack thermal insulation which enhanced soil temperatures, decomposition, and nutrient release in harsh conditions. On the northern aspect, the interaction between elevation and mean temperature of the warmest month explained 80% of the expansion. Meanwhile, the interaction between Pre1 and mean temperature of the growing season explained 73% of the expansion on the western aspect. This study revealed that dominant factors driving treeline upward movement vary across different mountain aspects. Climate and topography play significant roles in determining tree distribution in the alpine treeline ecotone. This knowledge helps better understand and forecast treeline dynamics in response to global climate change.

Renal cell carcinoma (RCC) is a heterogeneous malignancy with diverse gene expression patterns, molecular landscapes, and differentiation characteristics of tumor cells. It is imperative to develop molecular RCC classification based on tumor cell differentiation for precise risk stratification and personalized therapy.

Advanced colorectal cancer (CRC) exhibits weak responses to multiple therapies, primarily due to the presence of cancer stem cells (CSCs), which drive high recurrence rates, metastasis, and drug resistance. We have previously systematically conducted CSC-targeted compound discovery and evaluation studies to inhibit CSC-mediated tumorigenesis and metastasis. Here, we identified ZSH-512, a novel synthetic retinoid that selectively targets retinoic acid receptor (RAR)γ, demonstrating its ability to effectively inhibit CRC-CSCs and patient-derived organoids (PDOs) in vitro and significantly reduce CSC-mediated tumor formation and liver metastasis in mouse models without noticeable toxicity. Mechanistically, integrated analysis of Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq) and RNA sequencing (RNA-seq) revealed that ZSH-512 exerted its effect by modulating the RARγ-KDM3A axis to mediate epigenetic reprogramming and broadly suppress stemness-related signaling pathways, including Wnt, Hippo, and Hedgehog. ZSH-512 efficiently inhibited tumorigenesis in CRC-patient-derived tumor xenografts (PDXs) with high KDM3A expression, suggesting KDM3A as a potential predictive biomarker. Collectively, ZSH-512 is a promising therapeutic candidate for targeting CRC-CSCs with high efficacy.

Recently, a growing body of research has shown that microRNAs (miRNAs) are crucial in the pathophysiological mechanisms of brain disorders, miR-210 is one of the significant miRNAs implicated in these disorders, and its function in intracerebral hemorrhage (ICH) is not yet fully understood. Research the impact of miR-210 on intracerebral hemorrhage and probe into its working mechanism. The ICH model was established by injecting collagenase into the basal ganglia of male C57/BL6 mice (n = 142). Firstly, the mice were divided into sham group (n = 6) and ICH group (n = 30) (3 h, 6 h, 12 h, 24 h, 72 h), the samples of the sham group were collected at 48 h after operation, the brain tissues of the left and right basal ganglia were collected in each groupand. qPCR was used to detect the level of miR-210 in each group. Then, LV-miR-210 was injected into the lateral ventricle to establish a model of miR-210 overexpression, and NS injection was set as a comparison, which was divided into sham group (n = 15), ICH group (n = 15), ICH + NS group (n = 15), and ICH + LV-miR-210 group (n = 15). Water maze training was started on the 2 d after surgery. qPCR was used to detect the levels of miR-210, iNOS, IL-1β, IL-6, TNF-α, and IL-10 in each group at 3 d after operation. Western blotting was used to detect the levels of p-AMPK/AMPK, p-mTOR/mTOR, Beclin 1, Bax, Bcl-2, and LC3 II/I in each group. Immunofluorescence was used to detect the expression of lentivirus-mediated miR-210 in mouse brain. Water maze was used to evaluate the learning and memory function of the mice. The dry-wet method was used to evaluate brain edema, TUNEL was used to detect the apoptosis of brain cells in each group. Then, Rapamycin and AICAR were used to intervene p-AMPK/AMPK and p-mTOR/mTOR, and they were divided into sham group (n = 6), ICH group (n = 6), ICH + LV-miR-210 group (n = 6), ICH + LV-miR-210 + AICAR group (n = 6), and ICH + LV-miR-210 + Rapamycin group (n = 6). The levels of miR-210 in each group were detected by qPCR at 3 d after operation, and the levels of p-AMPK/AMPK, p-mTOR/mTOR, Beclin 1, Bax, Bcl-2, and LC3 II/I in each group were detected by WB. Finally, HT22 cells were stimulated with Hemin to construct an in vitro intracerebral hemorrhage model, and the time gradient was set (control group, 3 h, 6 h, 12 h, and 24 h). qPCR was used to detect the expression of miR-210 in each group. Then HT22 cells were transfected with lentivirus, and rapamycin and AICAR were used to interfere with p-AMPK/AMPK and p-mTOR/mTOR. Control group, Hemin group, Hemin + LV-miR-210 group, Hemin + LV-miR-210 + AICAR group, and Hemin + LV-miR-210 + Rapamycin group. qPCR was used to detect the level of miR-210 in each group. The levels of p-AMPK/AMPK, p-mTOR/mTOR, Beclin 1, Bax, Bcl-2, and LC3 II/I in each group were detected by Western blotting. miR-210 is significantly increased in a short time after intracerebral hemorrhage in mice. miR-210 can alleviate secondary injury of ICH by improving neurological deficit and reducing brain edema. In addition, upregulation of miR-210 expression inhibited autophagy and alleviated apoptosis and inflammation. In our study, we found that miR-210 significantly inhibited the activation of AMPK/ mTOR pathway triggered by ICH, and the neuroprotective effect of miR-210 was partially reversed when Rapamycin and AICAR reversed this inhibition. At the mechanistic level, miR-210 exerts its function by regulating AMPK/mTOR signaling pathway, thereby inhibiting autophagy and reducing apoptosis and inflammation. Further studies at the cellular level were basically consistent with the above results. miR-210 is up-regulated after ICH and can play a neuroprotective role by regulating the AMPK/mTOR signaling pathway mediated by autophagy, suggesting that it may become a therapeutic target for reducing nerve injury after ICH.