Quercetin (Que) has been proven to enhance the chemosensitivity of multiple cancers, including colon cancer (CC). However, whether the combination of Que and 5-fluorouracil (5-FU) has a synergistic effect on drug-resistant CC cells has not previously been reported. The effect of Que (5 and 10 μg/mL) on cell vitality and apoptosis of CC and CC drug-resistant cells was examined using a cell counting kit-8 (CCK-8) and flow cytometry. After cells were treated with 5-FU (10, 40 μg/mL), Que (10 μM, 40 μM), or 5-FU in combination with Que, cell proliferation, apoptosis, oxidative stress-related factors, reactive oxygen species (ROS), and nuclear factor erythroid 2-related factor (Nrf2)/heme oxygenase-1 (HO-1) pathway-related factors were examined by colony formation assay, flow cytometry, ELISA, ROS kit, immunofluorescence assay, and Western blot. The results showed that 5-FU reduced cell viability and induced apoptosis of CC as well as 5-FU-resistant CC cells. Que further restrained the proliferation, oxidative stress-related factors (SOD, CAT, GPx, and GR), ROS production, and induced apoptosis in CC cells and 5-FU-resistant CC cells induced by 5-FU. Moreover, the combination of Que and 5-FU attenuated the Nrf2/HO-1 pathway-related marker levels in CC cells and 5-FU-resistant CC cells. Therefore, our results suggest that Que reverses 5-FU resistance in CC cells via modulating the Nrf2/HO-1 pathway.

The function of macula densa nitric oxide synthase 1 (NOS1) in the regulation of renin release is controversial. This study was conducted to further elucidate the role of macula densa NOS1 in renin release and blood pressure regulation in response to salt challenges and hemorrhagic shock.

Bacteria-associated infections and thrombosis, particularly catheter-related bloodstream infections and catheter-related thrombosis, are life-threatening complications. Herein, we utilize a concise assembly of heparin sodium with organosilicon quaternary ammonium surfactant to fabricate a multifunctional coating complex. In contrast to conventional one-time coatings, the complex attaches to medical devices with arbitrary shapes and compositions through a facile dipping process and further forms robust coatings to treat catheter-related bloodstream infections and thrombosis simultaneously. Through their robustness and adaptively dissociation, coatings not only exhibit good stability under extreme conditions but also significantly reduce thrombus adhesion by 60%, and shows broad-spectrum antibacterial activity ( > 97%) in vitro and in vivo. Furthermore, an ex vivo rabbit model verifies that the coated catheter has the potential to prevent catheter-related bacteremia during implantation. This substrate-independent and portable long-lasting multifunctional coating can be employed to meet the increasing clinical demands for combating catheter-related bloodstream infections and thrombosis.

In order to improve the understanding of the environmental impacts of polymetallic nodule mining, ecotoxicological studies were conducted on the growth of model phytoplankton species Skeletonema costatum and Prorocentrum donghaiense using cobalt and nickel. This study evaluated various physiological and ecological indicators, such as cell proliferation, chlorophyll a, pigments, total protein, and antioxidant enzyme markers. The results show that the introduction of low amounts of cobalt or nickel increased the growth rate of phytoplankton. The phytoplankton benefited from low concentrations of cobalt and nickel stress. The increased protein levels and decreased activity of antioxidant enzymes considerably impacted physiological responses during the promotion of cell abundance. High concentrations of cobalt or nickel resulted in decreased light-absorbing pigments, increased photoprotective pigments, an inactive chlorophyll content, decreased total proteins, and maximal antioxidant enzyme activity in phytoplankton. Throughout the experiment, both the phytoplankton protein and enzyme activity declined with prolonged stress, and the cells underwent age-induced damage. Thus, seabed mining's repercussions on phytoplankton could result in both short-term growth promotion and long-term damage. These consequences depend on the impurity concentrations infiltrating the water, their duration, and the organism's physiological responses.

Identifying the ecological forces that structure root-associated microbial communities is an essential step toward more sustainable agriculture. Legumes are widely utilized as model plants to study selective forces and their functioning in plant-microbial interactions owing to their ability to establish mutualism with rhizobia. Root nodules act as symbiotic organs to optimize the cost-benefit balance in this mutualistic relationship by modulating the number of nodules. However, it is not known whether the number of nodules is related to the structure of root-associated bacterial communities. Here, the root-associated bacterial communities of soybean grown in native soil by means of soybean cultivars with super- or normal nodulation were investigated across four developmental stages. We compared ecological processes between communities and found decreased relative importance of neutral processes for super-nodulating soybean, although the overall structures resembled those of normal-nodulating soybean. We identified the generalist core bacterial populations in each root-associated compartment, that are shared across root-associated niches, and persist through developmental stages. Within core bacterial species, the relative abundances of bacterial species in the rhizosphere microbiome were linked to host-plant functional traits and can be used to predict these traits from microbes using machine learning algorithms. These findings broaden the comprehensive understanding of the ecological forces and associations of microbiotas in various root-associated compartments and provide novel insights to integrate beneficial plant microbiomes into agricultural production to enhance plant performance.

Activating humoral and cellular immunity in lymph nodes (LNs) of nanoparticle-based vaccines is critical to controlling tumors. However, how the physical properties of nanovaccine carriers orchestrate antigen capture, lymphatic delivery, antigen presentation and immune response in LNs is largely unclear. Here, we manufactured gold nanoparticles (AuNPs) with the same size but different shapes (cages, rods, and stars), and loaded tumor antigen as nanovaccines to explore their disparate characters on above four areas. Results revealed that star-shaped AuNPs captured and retained more repetitive antigen epitopes. On lymphatic delivery, both rods and star-shaped nanovaccines mainly drain into the LN follicles region while cage-shaped showed stronger paracortex retention. A surprising finding is that the star-shaped nanovaccines elicited potent humoral immunity, which is mediated by CD4+ T helper cell and follicle B cell cooperation significantly preventing tumor growth in the prophylactic study. Interestingly, cage-shaped nanovaccines preferentially presented peptide-MHC I complexes to evoke robust CD8+ T cell immunity and showed the strongest therapeutic efficacy when combined with the PD-1 checkpoint inhibitor in established tumor study. These results highlight the importance of nanoparticle shape on antigen delivery and presentation for immune response in LNs, and our findings support the notion that different design strategies are required for prophylactic and therapeutic vaccines.

Third-generation chimeric antigen receptor (CAR)-engineered T cells (CARTs) might improve clinical outcome of patients with B cell malignancies. This is the first report on a third-generation CART dose-escalating, phase-1/2 investigator-initiated trial treating adult patients with refractory and/or relapsed (r/r) acute lymphoblastic leukemia (ALL).

Houshiheisan (HSHS), a classic prescription in traditional Chinese medicine (TCM), has shown outstanding efficacy in treating stroke. This study investigated various therapeutic targets of HSHS for ischemic stroke using mRNA transcriptomics. Herein, rats were randomly separated into the sham, model, HSHS 5.25 g/kg (HSHS5.25), and HSHS 10.5 g/kg (HSHS10.5) groups. Rats suffering from stroke were induced by permanent middle cerebral artery occlusion (pMCAO). After seven days of HSHS treatment, behavioral tests were conducted, and histological damage was examined with hematoxylin-eosin (HE). The mRNA expression profiles were identified using microarray analysis and quantitative real-time PCR (qRT-PCR) validated gene expression changes. An analysis of gene ontology and pathway enrichment was conducted to analyze potential mechanisms confirmed using immunofluorescence and western blotting. HSHS5.25 and HSHS10.5 improved neurological deficits and pathological injury in pMCAO rats. The intersections of 666 differentially expressed genes (DEGs) were chosen using transcriptomics analysis in the sham, model, and HSHS10.5 groups. The enrichment analysis suggested that the therapeutic targets of HSHS might regulate the apoptotic process and ERK1/2 signaling pathway, which was related to neuronal survival. Moreover, TUNEL and immunofluorescence analysis indicated that HSHS inhibited apoptosis and enhanced neuronal survival in the ischemic lesion. Western blot and immunofluorescence assay indicated that HSHS10.5 decreased Bax/Bcl-2 ratio and suppressed caspase-3 activation, while the phosphorylation of ERK1/2 and CREB was upregulated in a stroke rat model after HSHS treatment. Effective inhibition of neuronal apoptosis by activating the ERK1/2-CREB signaling pathway may be a potential mechanism for HSHS in the treatment of ischemic stroke.

Osteoarthritis (OA) is the most prevalent joint disease characterized by the degeneration of articular cartilage and the remodeling of its underlying bones, resulting in pain and loss of function in the knees and hips. As far as we know, no curative treatments are available except for the joint replacement. The precise molecular mechanisms which are involved in the degradation of cartilage matrix and development of osteoarthritis are still unclear.

Jellyfish represent one of the most basal animal groups with complex life cycles. The polyp-to-medusa transition, termed strobilation, is the pivotal process that determines the switch in swimming behavior and jellyfish blooms. Their microbiota plays an essential role in strobilation. Here, we investigated microbiota-mediated host phenotype dynamics during strobilation in the jellyfish Aurelia coerulea via antibiotic-induced microbiome alteration. Microbial depletion delayed the initiation of strobilation and resulted in fewer segments and ephyrae, which could be restored via microbial recolonization. Jellyfish-associated cyanobacteria, which were eliminated by antibiotics in the polyp stage, had the potential to supply retinal and trigger the retinoic acid signaling cascade, which drove the strobilation process. The microbiota regulated nematocyte development and differentiation, influencing the feeding and growth of the jellyfish. The findings improve our understanding of jellyfish-microbe interactions and provide new insights into the role of the microbiota in shaping feeding behavior through nematocyte dynamics.

Recent advances in human blastoids have opened new avenues for modeling early human development and implantation. One limitation of our first protocol for human blastoid generation was relatively low efficiency. We now report an optimized protocol for the efficient generation of large quantities of high-fidelity human blastoids from naive pluripotent stem cells. This enabled proteomics analysis that identified phosphosite-specific signatures potentially involved in the derivation and/or maintenance of the signaling states in human blastoids. Additionally, we uncovered endometrial stromal effects in promoting trophoblast cell survival, proliferation, and syncytialization during co-culture with blastoids and blastocysts. Side-by-side single-cell RNA sequencing revealed similarities and differences in transcriptome profiles between pre-implantation blastoids and blastocysts, as well as post-implantation cultures, and uncovered a population resembling early migratory trophoblasts during co-culture with endometrial stromal cells. Our optimized protocol will facilitate broader use of human blastoids as an accessible, perturbable, scalable, and tractable model for human blastocysts.

Male sterility in plants provides valuable breeding tools in germplasm innovation and hybrid crop production. However, genetic resources for dominant genic male sterility, which hold great promise to facilitate breeding processes, are extremely rare in natural germplasm. Here we characterized the Sanming Dominant Genic Male Sterility in rice and identified the gene SDGMS using a map-based cloning approach. We found that spontaneous movement of a 1978-bp long terminal repeat (LTR) retrotransposon into the promoter region of the SDGMS gene activates its expression in anther tapetum, which causes abnormal programmed cell death of tapetal cells resulting in dominant male sterility. SDGMS encodes a ribosome inactivating protein showing N-glycosidase activity. The activation of SDGMS triggers transcription reprogramming of genes responsive to biotic stress leading to a hypersensitive response which causes sterility. The results demonstrate that an ectopic gene activation by transposon movement can give birth to a novel trait which enriches phenotypic diversity with practical utility.

Lung cancer brain metastases refer to intracranial space-occupying lesions formed by the metastasis of tumor cells from the lung to the brain parenchyma or dissemination in the meninges. The datasets GSE200563 and GSE126548 for lung cancer brain metastasis were obtained from gene expression omnibus database with the platform files GPL21697 and GPL16791. Differentially expressed genes analysis was conducted, followed by weighted gene co-expression network analysis, construction and analysis of protein-protein interaction networks, functional enrichment analysis, gene set enrichment analysis, comparative toxicogenomics database analysis. Five hundred differentially expressed genes were identified. According to gene ontology, they were mainly enriched in terms of fucosyltransferase activity, protein-DNA complex, cAMP signaling pathway, and transcriptional misregulation in cancer. Ten core genes (JUN, IL1A, VEGFA, MMP1, EDN1, SOCS3, NOD2, NCOR2, VDR, and HDAC2) were obtained. Comparative toxicogenomics database analysis revealed associations between core genes (JUN, IL1A, VEGFA, MMP1, EDN1, SOCS3, NOD2, NCOR2, VDR, and HDAC2) and tumor cell transformation, non-small cell carcinoma, lung neoplasms, tumor invasiveness, tumor metastasis, and inflammation. JUN and MMP1 are abnormally highly expressed in lung cancer brain metastasis tissues, which may be their molecular targets.

While conventional magnetic resonance imaging (MRI) in multiple sclerosis (MS) primarily evaluates focal lesions, the normal-appearing white matter (NAWM) encompasses brain tissue that appears radiologically normal but harbors subtle pathological changes that contribute to the overall disease burden. The aim of this study was to investigate the role of T1rho MRI in characterising distance-dependent microstructural changes in the perilesional NAWM in patients with relapsing-remitting multiple sclerosis (RRMS).

Intestinal ischemia‑reperfusion (I/R) injury is a clinical condition that leads to severe intestinal damage, inflammation and oxidative stress. While cathepsin B (CTSB) has been implicated in these pathophysiological processes, its precise role in mediating I/R‑induced injury remains poorly understood. The present study aimed to elucidate how CTSB knockdown influences oxidative stress, inflammatory responses and the integrity of the intestinal epithelial barrier in intestinal epithelial Caco‑2 cells subjected to I/R injury. To identify key genes implicated in I/R injury, a comprehensive analysis was conducted using differential expression profiling and protein‑protein interaction network analysis of the GSE37013 dataset. To simulate I/R damage in vitro, an oxygen‑glucose deprivation/reoxygenation (OGD/R) model was employed in Caco‑2 cells. Subsequently, inflammation was induced by stimulating the cells with lipopolysaccharide (LPS) and adenosine triphosphate (ATP). To investigate the role of CTSB in this context, small interfering RNA was utilized to knock down CTSB expression. In vitro assays were then performed to evaluate NLR family pyrin domain‑containing 3 (NLRP3) inflammasome activation, oxidative stress levels, inflammatory cytokine production and cell survival. The results revealed that intestinal tissues from the I/R group in the GSE37013 dataset showed markedly higher CTSB expression, and the Caco‑2 cells subjected to OGD/R model resulted in a considerable increase in CTSB expression. However, the expression levels of tight junction proteins were enhanced, cell survival was improved and lactate dehydrogenase release was reduced by CTSB knockdown. This reduction in CTSB levels also reduced malondialdehyde levels, and alleviated oxidative stress by increasing the activities of glutathione peroxidase and superoxide dismutase. Furthermore, pro‑inflammatory cytokine production was reduced, and NLRP3 inflammasome activation was inhibited by CTSB knockdown, although a modest increase was still observed after LPS + ATP stimulation. Notably, although CTSB knockdown significantly reduced the inflammatory response, LPS + ATP stimulation still elicited a modest reversal in cytokine levels, suggesting that a CTSB‑independent pathway of inflammatory activation may exist. In conclusion, CTSB knockdown effectively mitigates I/R injury by reducing inflammation, preserving barrier integrity and alleviating oxidative stress, positioning CTSB as a promising therapeutic target. Future work should validate these findings in in vivo models and explore CTSB‑targeted therapies to improve clinical outcomes in I/R‑related diseases.

This study aimed to analyze the molecular composition and physiological changes in the plasma of patients with convalescent coronavirus disease 2019 (COVID-19).

BACKGROUND: Inhibiting TNF-α signaling is an effective approach to prevent inflammation, which can mitigate the symptoms of autoimmune diseases. Activation of the ADAM17-TNFR1 signaling module using small-molecule protein disulfide isomerase (PDI) inhibitors effectively induces TNFR1 shedding and TNF-α signaling inhibition. However, it is not known whether tannic acid (TA), a verified PDI inhibitor with outstanding anti-inflammatory effects, could alleviate autoimmune diseases. OBJECTIVE: We set out to explore the anti-inflammatory mechanism of TA and whether it could be used to treat the classical autoimmune disease, psoriasis. METHODS: Molecular interactions were assessed using insulin reduction assays with full-length PDI and its domain fragments to identify TA binding sites. Non-covalent binding and conformational changes were evaluated using AMS-modified SDS-PAGE and ANS fluorescence. Molecular chaperone activity was measured using rhodanese refolding. Cellular assays included cytotoxicity, apoptosis, and NF-κB activation in L929 cells using CCK-8, flow cytometry, western blot, and RT-qPCR. PDI dependency was confirmed using CRISPR-Cas9 knockout. TNFR1 shedding was quantified using flow cytometry and ELISA. In vivo efficacy was tested in an imiquimod (IMQ)-induced psoriasis mouse model treated with TA ointment (5% and 10%), and the outcomes were evaluated using the psoriasis area and severity index (PASI), histopathology, blood routines, and blood biochemical examinations. RESULTS: TA selectively inhibited the reductase activity of the b’ domain of PDI and induced non-covalent conformational changes, reducing hydrophobicity and chaperone function. TA effectively suppressed TNF-α-induced apoptosis in cells, NF-κB activation, and inflammatory gene expression. PDI knockout abolished TA-induced TNFR1 shedding, confirming PDI dependence. In IMQ-induced psoriatic mice, 10% TA ointment significantly reduced the PASI scores and the incidence of histopathological features. TA also normalized blood inflammation and restored physical functions. CONCLUSIONS: In summary, our study showed that TA blocks TNF-α signaling by inhibiting PDI, and exhibits potential application value in combating autoimmune diseases, especially psoriasis.

Mechanical transmission is essential in force-related activities ranging from the daily tying of shoe laces1 to sophisticated surgical2 and robotic operations3,4. Modern machines and robots typically use complex electronic devices designed to sense and limit force5, some of which still face challenges when operating space is limited (for example, in minimally invasive surgeries)6 or when resources are scarce (for example, operations in remote areas without electricity). Here we describe an alternative slipknot-based mechanical transmission mechanism to control the intelligent operation of both human and robotic systems. Through topological design, slipknot tying and release can encode and deliver force with a consistency of 95.4% in repeating operations, which circumvents the need for additional sensors and controllers. When applied to surgical repair, this mechanism helped inexperienced surgeons to improve their knotting-force precision by 121%, enabling them to perform surgical knots as good as those of experienced surgeons. Moreover, blood supply and tissue healing after surgery were improved. The mechano-intelligence exhibited in slipknots may inspire investigations of knotted structures across multiple length scales. This slipknot-gauged mechanical transmission strategy can be widely deployed, opening up opportunities for resource-limited healthcare, science education and field exploration.

Aberrant glycogen metabolism drives lipid accumulation and adaptive lipid homeostasis reprogramming, a metabolic adaptation critical for sustaining malignant progression and chemoresistance in cholangiocarcinoma (CCA). While our prior study highlighted glycogen degradation as pivotal for CCA tumorigenesis, the molecular mechanisms governing lipogenesis and its therapeutic exploitation remain elusive.

Chronic kidney disease (CKD) is characterized by progressive renal fibrosis, which contributes to disease progression and ultimately leads to kidney failure. Circular RNAs (circRNAs) are key regulators in various fibrotic diseases, showing different expression patterns in different organs. However, the exact role and mechanisms of circRNAs in renal fibrosis are still not fully understood.