Engineered CAR-NK cells with tolerance to H2O2 and hypoxia can suppress postoperative relapse of triple-negative breast cancers.

Surgical resection is a primary treatment option for triple-negative breast cancer (TNBC) patients, but it is associated with a high rate of postoperative local and metastatic relapse. Although chimeric antigen receptor-engineered natural killer (CAR-NK) cell therapy can specifically recognize and eradicate tumor cells, its therapeutic potency toward TNBCs is markedly suppressed by the hostile tumor microenvironment, which restricts the infiltration, survival and effector functions of CAR-NK cells inside the tumor masses. Herein, HER1-overexpressing TNBC-targeted CAR-NK (HER1-CAR-NK) cells were genetically engineered with catalase to endow them with tolerance toward the high levels of oxidative stress and hypoxia inside TNBC tumors through the catalytic decomposition of hydrogen peroxide, which is a principle reactive oxygen species inside tumors, into O2. We refer to these cells as HER1-CAR-CAT-NK cells. Upon intratumoral fixation with an injectable alginate hydrogel, HER1-CAR-CAT-NK cells enabled sustained tumor hypoxia attenuation and exhibited markedly enhanced persistence and effector functions inside TNBC tumors. As a result, locoregional HER1-CAR-CAT-NK cell therapy not only inhibited the growth of local primary residual tumors, but also elicited systemic antitumor activity to suppress the growth of distant tumors. This study highlights that genetic engineering of HER1-CAR-NK cells with catalase is a promising strategy to suppress the postoperative local and distant relapse of TNBC tumors.

A Mysterious Asian Firefly Genus, Oculogryphus Jeng, Engel & Yang (Coleoptera, Lampyridae): The First Complete Mitochondrial Genome and Its Phylogenetic Implications.

The firefly genus Oculogryphus Jeng, Engel & Yang, 2007 is a rare-species group endemic to Asia. Since its establishment, its position has been controversial but never rigorously tested. To address this perplexing issue, we are the first to present the complete mitochondrial sequence of Oculogryphus, using the material of O. chenghoiyanae Yiu & Jeng, 2018 determined through a comprehensive morphological identification. Our analyses demonstrate that its mitogenome exhibits similar characteristics to that of Stenocladius, including a rearranged gene order between trnC and trnW, and a long intergenic spacer (702 bp) between the two rearranged genes, within which six remnants (29 bp) of trnW were identified. Further, we incorporated this sequence into phylogenetic analyses of Lampyridae based on different molecular markers and datasets using ML and BI analyses. The results consistently place Oculogryphus within the same clade as Stenocladius in all topologies, and the gene rearrangement is a synapomorphy for this clade. It suggests that Oculogryphus should be classified together with Stenocladius in the subfamily Ototretinae at the moment. This study provides molecular evidence confirming the close relationship between Oculogryphus and Stenocladius and discovers a new phylogenetic marker helpful in clarifying the monophyly of Ototretinae, which also sheds a new light on firefly evolution.

Sodium tanshinone IIA sulfonate protects vascular relaxation in ApoE-knockout mice by inhibiting the SYK-NLRP3 inflammasome-MMP2/9 pathway.

BACKGROUND: Hyperlipidemia damages vascular wall and serves as a foundation for diseases such as atherosclerosis, hypertension and stiffness. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is implicated in vascular dysfunction associated with hyperlipidemia-induced vascular injury. Sodium tanshinone IIA sulfonate (STS), a well-established cardiovascular protective drug with recognized anti-inflammatory, antioxidant, and vasodilatory properties, is yet to be thoroughly investigated for its impact on vascular relaxant imbalance induced by hyperlipidemia. METHODS: In this study, we treated ApoE-knockout (ApoE-/-) mouse with STS and assessed the activation of the NLRP3 inflammasome, expression of MMP2/9, integrity of elastic fibers, and vascular constriction and relaxation. RESULTS: Our findings reveal that STS intervention effectively preserves elastic fibers, significantly restores aortic relaxation function in ApoE-/- mice, and reduces their excessive constriction. Furthermore, STS inhibits the phosphorylation of spleen tyrosine kinase (SYK), suppresses NLRP3 inflammasome activation, and reduces MMP2/9 expression. CONCLUSIONS: These results demonstrate that STS protects vascular relaxation against hyperlipidemia-induced damage through modulation of the SYK-NLRP3 inflammasome-MMP2/9 pathway. This research provides novel insights into the mechanisms underlying vascular relaxation impairment in a hyperlipidemic environment and uncovers a unique mechanism by which STS preserves vascular relaxation, offering valuable foundational research evidence for its clinical application in promoting vascular health.

Identification of DNase I hypersensitive sites in the human genome by multiple sequence descriptors.

DNase I hypersensitive sites (DHSs) are chromatin regions highly sensitive to DNase I enzymes. Studying DHSs is crucial for understanding complex transcriptional regulation mechanisms and localizing cis-regulatory elements (CREs). Numerous studies have indicated that disease-related loci are often enriched in DHSs regions, underscoring the importance of identifying DHSs. Although wet experiments exist for DHSs identification, they are often labor-intensive. Therefore, there is a strong need to develop computational methods for this purpose. In this study, we used experimental data to construct a benchmark dataset. Seven feature extraction methods were employed to capture information about human DHSs. The F-score was applied to filter the features. By comparing the prediction performance of various classification algorithms through five-fold cross-validation, random forest was proposed to perform the final model construction. The model could produce an overall prediction accuracy of 0.859 with an AUC value of 0.837. We hope that this model can assist scholars conducting DNase research in identifying these sites.

[Chemical composition and pharmacological effects of Cinnamomum camphora chvar. borneol essential oil: a review].

Cinnamomum camphora chvar. borneol, a rare camphor tree variant recently identified in China, is distinguished by its high concentration of D-borneol, also known as " plant gold" due to its significant value. The essential oil extracted from this variant,rich in monoterpenes and sesquiterpenes, demonstrates a broad spectrum of pharmacological activities, including analgesic, antiinflammatory, antioxidant, cognition-enhancing, anti-bacterial, and insecticidal effects. These properties, underscored by extensive research, highlight the oil's potential in the biomedical, chemical, and food sectors as a valuable commodity. Nonetheless, the safety profile of this valuable oil remains poorly characterized, with its chemical composition and therapeutic efficacy subject to variations in the factors like geographic origin, harvesting timing, part used for extraction, and processing techniques. Such variability poses challenges to its clinical application and hampers the efficient exploitation of this resource. This review synthesizes current studies on C. camphora chvar. borneol essential oil and provides a detailed examination of its chemical and pharmacological profiles. In this study, we discuss existing research gaps and propose strategies for advancing its clinical use and industrial application, aiming to provide a foundational reference for future investigations and the resolution of its commercial and therapeutic challenges.

Biomineralization-inspired synthesis of autologous cancer vaccines for personalized metallo-immunotherapy.

Autologous cancer vaccines represent a promising therapeutic approach against tumor relapse. Herein, a concise biomineralization strategy was developed to prepare an immunostimulatory autologous cancer vaccine through protein antigen-mediated growth of flower-like manganese phosphate (MnP) nanoparticles. In addition to inheriting the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING)-activating capacity of Mn2+, the resulting ovalbumin (OVA)-loaded MnP (OVA@MnP) nanoparticles with superior stability and pH-responsiveness enabled efficient priming of antigen-specific CD8+ T cell expansion through promoting the endo/lysosome escape and subsequent antigen cross-presentation of OVA. Resultantly, OVA@MnP vaccines upon subcutaneous vaccination elicited both prophylactic and therapeutic effects against OVA-expressing B16-F10 melanoma. Furthermore, the biomineralized autologous cancer vaccines prepared from the whole tumor cell lysates of the dissected tumors suppressed the growth of residual tumors, particularly in combination with anti-PD-1 immunotherapy. This study highlights a simple biomineralization approach for the controllable synthesis of cGAS-STING-activating autologous cancer vaccines to suppress postsurgical tumor relapse.

A novel OsGST gene encoding 9glutathione reductase negatively regulates cadmium accumulation in rice.

Cadmium (Cd) accumulates in rice and then moves up the food chain, causing serious health problems for humans. Glutathione S-transferase (GST) binds exogenous hazardous compounds to glutathione (GSH), which performs a variety of roles in plant responses to Cd stress. Here, Cd stimulated the transcripts of a novel OsGST gene, and the OsGST protein, which was localized in the nucleus and cytoplasm, was also induced by Cd. In OsGST deletion mutant lines generated by CRISPR/Cas9, more Cd was accumulated, and Cd hypersensitive phenotypes were observed, while transgenic lines overexpressing OsGST exhibited enhanced Cd tolerance and less Cd accumulation. Further analysis indicated that the osgst mutants exhibited considerably greater reactive oxygen species (ROS) and higher GSH level, and the antioxidant activity associated genes' expression were down-regulated, imply that OsGST controlled rice Cd accumulation and resistance through preserving the equilibrium of the GSH and redox in rice.

Evaluation of pathological response to neoadjuvant chemotherapy in locally advanced cervical cancer.

Neoadjuvant chemotherapy (NACT) is a viable therapeutic option for women diagnosed locally advanced cervical cancer (LACC). However, the factors influencing pathological response are still controversial. We collected pair specimens of 185 LACC patients before and after receiving NACT and conducted histological evaluation. 8 fresh tissues pre-treatment were selected from the entire cohort to conducted immune gene expression profiling. A novel pathological grading system was established by comprehensively assessing the percentages of viable tumor, inflammatory stroma, fibrotic stroma, and necrosis in the tumor bed. Then, 185 patients were categorized into either the good pathological response (GPR) group or the poor pathological response (PPR) group post-NACT, with 134 patients (72.4%, 134/185) achieving GPR. Increasing tumor-infiltrating lymphocytes (TILs) and tumor-infiltrating lymphocytes volume (TILV) pre-treatment were correlated with GPR, with TILV emerging as an independent predictive factor for GPR. Additionally, CIBERSORT analysis revealed noteworthy differences in the expression of immune makers between cPR and non-cPR group. Furthermore, a significantly heightened density of CD8 + T cells and a reduced density of FOXP3 + T cells were observed in GPR than PPR. Importantly, patients exhibiting GPR or inflammatory type demonstrated improved overall survival and disease-free survival. Notably, stromal type was an independent prognostic factor in multivariate analysis. Our study indicates the elevated TILV in pre-treatment specimens may predict a favorable response to NACT, while identifying stromal type in post-treatment specimens as an independent prognostic factor. Moreover, we proposed this pathological grading system in NACT patients, which may offer a more comprehensive understanding of treatment response and prognosis.

Dual protection by Bcp1 and Rkm1 ensures incorporation of uL14 into pre-60S ribosomal subunits.

Eukaryotic ribosomal proteins contain extended regions essential for translation coordination. Dedicated chaperones stabilize the associated ribosomal proteins. We identified Bcp1 as the chaperone of uL14 in Saccharomyces cerevisiae. Rkm1, the lysine methyltransferase of uL14, forms a ternary complex with Bcp1 and uL14 to protect uL14. Rkm1 is transported with uL14 by importins to the nucleus, and Bcp1 disassembles Rkm1 and importin from uL14 simultaneously in a RanGTP-independent manner. Molecular docking, guided by crosslinking mass spectrometry and validated by a low-resolution cryo-EM map, reveals the correlation between Bcp1, Rkm1, and uL14, demonstrating the protection model. In addition, the ternary complex also serves as a surveillance point, whereas incorrect uL14 is retained on Rkm1 and prevented from loading to the pre-60S ribosomal subunits. This study reveals the molecular mechanism of how uL14 is protected and quality checked by serial steps to ensure its safe delivery from the cytoplasm until its incorporation into the 60S ribosomal subunit.

Efficient Compressive Strength Prediction of Alkali-Activated Waste Materials Using Machine Learning.

This study explores the integration of machine learning (ML) techniques to predict and optimize the compressive strength of alkali-activated materials (AAMs) sourced from four industrial waste streams: blast furnace slag, fly ash, reducing slag, and waste glass. Aimed at mitigating the labor-intensive trial-and-error method in AAM formulation, ML models can predict the compressive strength and then streamline the mixture compositions. By leveraging a dataset of only 42 samples, the Random Forest (RF) model underwent fivefold cross-validation to ensure reliability. Despite challenges posed by the limited datasets, meticulous data processing steps facilitated the identification of pivotal features that influence compressive strength. Substantial enhancement in predicting compressive strength was achieved with the RF model, improving the model accuracy from 0.05 to 0.62. Experimental validation further confirmed the ML model's efficacy, as the formulations ultimately achieved the desired strength threshold, with a significant 59.65% improvement over the initial experiments. Additionally, the fact that the recommended formulations using ML methods only required about 5 min underscores the transformative potential of ML in reshaping AAM design paradigms and expediting the development process.

Taking Advantage of Potential Coincidence Region: Insights into Gas Production Behavior in Advanced Self-Activated Hydrazine-Assisted Alkaline Seawater Electrolysis.

Water electrolysis assisted by hydrazine has emerged as a prospective energy conversion method for achieving efficient hydrogen generation. Due to the potential coincidence region (PCR) between the hydrogen evolution reaction (HER) and the electro-oxidation of hydrazine, the hydrazine oxidation reaction (HzOR) offers distinct advantages in terms of strategy amalgamation, device architecture, and the broadening of application horizons. Herein, we report a bifunctional electrocatalyst of interfacial heterogeneous Fe2P/Co2P microspheres supported on Ni foam (FeCoP/NF). Benefiting from the strong interfacial coupling effect between Fe2P and Co2P and the three-dimensional microsphere structure, FeCoP/NF exhibits outstanding bifunctional electrocatalytic performance, achieving 10 mA cm-2 with low overpotentials of 10 and 203 mV for HER and HzOR, respectively. Utilizing FeCoP/NF for both electrodes in HzOR-assisted water electrolysis results in significantly reduced potentials of 820 mV for 1 A cm-2 in contrast to the electro-oxidation of alternative chemical substrates. The presence of a potential coincidence region makes the application of self-activated seawater electrolysis realistic. The gas production behavior at different current densities in this interesting hydrogen production system is discussed, and some rules that are distinguished from conventional water electrolysis are summarized. Furthermore, a new self-powered hydrogen production system with a direct hydrazine fuel cell, rechargeable Zn-hydrazine battery, and hydrazine-assisted seawater electrolysis is proposed, emphasizing the distinct benefits of HzOR and its potential role in electrochemical energy conversion technologies powered by renewable sources.

Covalent Bonding of Salen Metal Complexes with Pyrene Chromophores to Porous Polymers for Photocatalytic Hydrogen Evolution.

The development of low-cost and efficient photocatalysts to achieve water splitting to hydrogen (H2) is highly desirable but remains challenging. Herein, we design and synthesize two porous polymers (Co-Salen-P and Fe-Salen-P) by covalent bonding of salen metal complexes and pyrene chromophores for photocatalytic H2 evolution. The catalytic results demonstrate that the two polymers exhibit excellent catalytic performance for H2 generation in the absence of additional noble-metal photosensitizers and cocatalysts. Particularly, the H2 generation rate of Co-Salen-P reaches as high as 542.5 µmol g-1 h-1, which is not only 6 times higher than that of Fe-Salen-P but also higher than a large amount of reported Pt-assisted photocatalytic systems. Systematic studies show that Co-Salen-P displays faster charge separation and transfer efficiencies, thereby accounting for the significantly improved photocatalytic activity. This study provides a facile and efficient way to fabricate high-performance photocatalysts for H2 production.

Microwave Radiation Caused Dynamic Metabolic Fluctuations in the Mammalian Hippocampus.

To investigate the dynamic changes in hippocampal metabolism after microwave radiation using liquid chromatography in tandem with mass spectrometry/mass spectrometry (LC-MS/MS) and to identify potential biomarkers. Wistar rats were randomly assigned to a sham group and a microwave radiation group. The rats in the microwave radiation group were exposed to 2.856 GHz for 15 min for three times, with 5 min intervals. The rats in the sham group were not exposed. Transmission electron microscope revealed blurring of the synaptic cleft and postsynaptic dense thickening in hippocampal neurons after microwave radiation. Metabolomic analysis revealed 38, 24, and 39 differentially abundant metabolites at 3, 7, and 14 days after radiation, respectively, and the abundance of 9 metabolites, such as argininosuccinic acid, was continuously decreased. After microwave radiation, the abundance of metabolites such as argininosuccinic acid was successively decreased, indicating that these metabolites could be potential biomarkers for hippocampal tissue injury.

Natural products for Gut-X axis: pharmacology, toxicology and microbiology in mycotoxin-caused diseases.

Introduction: The gastrointestinal tract is integral to defending against external contaminants, featuring a complex array of immunological, physical, chemical, and microbial barriers. Mycotoxins, which are toxic metabolites from fungi, are pervasive in both animal feed and human food, presenting substantial health risks. Methods: This review examines the pharmacological, toxicological, and microbiological impacts of natural products on mycotoxicosis, with a particular focus on the gut-x axis. The analysis synthesizes current understanding and explores the role of natural products rich in polysaccharides, polyphenols, flavonoids, and saponins. Results: The review highlights that mycotoxins can disrupt intestinal integrity, alter inflammatory responses, damage the mucus layer, and disturb the bacterial balance. The toxins' effects are extensive, potentially harming the immune system, liver, kidneys, and skin, and are associated with serious conditions such as cancer, hormonal changes, genetic mutations, bleeding, birth defects, and neurological issues. Natural products have shown potential anticancer, anti-tumor, antioxidant, immunomodulatory, and antitoxic properties. Discussion: The review underscores the emerging therapeutic strategy of targeting gut microbial modulation. It identifies knowledge gaps and suggests future research directions to deepen our understanding of natural products' role in gut-x axis health and to mitigate the global health impact of mycotoxin-induced diseases.

Engineered droplet-forming peptide as photocontrollable phase modulator for fused in sarcoma protein.

The assembly and disassembly of biomolecular condensates are crucial for the subcellular compartmentalization of biomolecules in the control of cellular reactions. Recently, a correlation has been discovered between the phase transition of condensates and their maturation (aggregation) process in diseases. Therefore, modulating the phase of condensates to unravel the roles of condensation has become a matter of interest. Here, we create a peptide-based phase modulator, JSF1, which forms droplets in the dark and transforms into amyloid-like fibrils upon photoinitiation, as evidenced by their distinctive nanomechanical and dynamic properties. JSF1 is found to effectively enhance the condensation of purified fused in sarcoma (FUS) protein and, upon light exposure, induce its fibrilization. We also use JSF1 to modulate the biophysical states of FUS condensates in live cells and elucidate the relationship between FUS phase transition and FUS proteinopathy, thereby shedding light on the effect of protein phase transition on cellular function and malfunction.

Neurosyphilis Presenting as Psychiatric Symptoms at Younger Age: A Case Report.

Neurosyphilis is a central nervous system infection caused by Treponema pallidum that imitates various neurological and mental disorders. Therefore, patients with this disease are prone to misdiagnoses. Here, we report a case of neurosyphilis with a psychotic disorder as the main manifestation. A young girl exhibited mental and behavioural abnormalities after a heartbreak, which manifested as alternating low mood, emotional irritability, and a lack of interest in social relations, followed by memory loss. The cerebrospinal fluid protein - Treponema pallidum particle agglutination test was positive, the toluidine red unheated serum test titre was 1:4, the white blood cell count was 5 × 10^6/L, the cerebrospinal fluid protein level was 0.97 g/L, and the brain CT was abnormal. After admission, the possibility of neurosyphilis was considered and the patient received intravenous penicillin G treatment. The patient's clinical symptom ms improved. This case emphasises that doctors should maintain clinical suspicion of Treponema pallidum infection in adolescent patients with mental abnormalities.

CD47-SIRPα Blockade Sensitizes Head and Neck Squamous Cell Carcinoma to Cetuximab by Enhancing Macrophage Adhesion to Cancer Cells.

Developing effective treatments for patients with head and neck squamous cell carcinoma (HNSCC) is a significant challenge. Cetuximab, a first-line targeted therapy for HNSCC, exhibits limited efficacy. Here, we used pooled CRISPR screening to find targets that can synergize with cetuximab and identified CD47 as the leading candidate. Rather than inhibiting cancer cell proliferation, CD47 inhibition promoted cetuximab-triggered antibody-dependent cellular phagocytosis (ADCP), thereby enhancing macrophage-mediated cancer cell removal. The combination of CD47-SIRPα blockade and cetuximab demonstrated strong anticancer activity in vivo. In addition to blocking the phagocytosis checkpoint, CD47-SIRPα inhibition upregulated CD11b/CD18 on the surface of macrophages, which accelerated intercellular adhesion between macrophages and cancer cells to enhance subsequent phagocytosis. Inhibition of the interaction between macrophage CD11b/CD18 and cancer cell ICAM1 eliminated the intercellular adhesion and phagocytosis induced by CD47-SIRPα blockade. Thus, CD47-SIRPα blockade enhances ADCP through CD11b/CD18-ICAM1-mediated intercellular adhesion and sensitizes HNSCC to cetuximab.

ASFV infection induces macrophage necroptosis and releases proinflammatory cytokine by ZBP1-RIPK3-MLKL necrosome activation.

African swine fever (ASF) is an infectious disease characterized by hemorrhagic fever, which is highly pathogenic and causes severe mortality in domestic pigs. It is caused by the African swine fever virus (ASFV). ASFV is a large DNA virus and primarily infects porcine monocyte macrophages. The interaction between ASFV and host macrophages is the major reason for gross pathological lesions caused by ASFV. Necroptosis is an inflammatory programmed cell death and plays an important immune role during virus infection. However, whether and how ASFV induces macrophage necroptosis and the effect of necroptosis signaling on host immunity and ASFV infection remains unknown. This study uncovered that ASFV infection activates the necroptosis signaling in vivo and macrophage necroptosis in vitro. Further evidence showed that ASFV infection upregulates the expression of ZBP1 and RIPK3 to consist of the ZBP1-RIPK3-MLKL necrosome and further activates macrophage necroptosis. Subsequently, multiple Z-DNA sequences were predicted to be present in the ASFV genome. The Z-DNA signals were further confirmed to be present and colocalized with ZBP1 in the cytoplasm and nucleus of ASFV-infected cells. Moreover, ZBP1-mediated macrophage necroptosis provoked the extracellular release of proinflammatory cytokines, including TNF-α and IL-1ß induced by ASFV infection. Finally, we demonstrated that ZBP1-mediated necroptosis signaling inhibits ASFV replication in host macrophages. Our findings uncovered a novel mechanism by which ASFV induces macrophage necroptosis by facilitating Z-DNA accumulation and ZBP1 necrosome assembly, providing significant insights into the pathogenesis of ASFV infection.

Atomically Resolved Defect-Engineering Scattering Potential in 2D Semiconductors.

Engineering atomic-scale defects has become an important strategy for the future application of transition metal dichalcogenide (TMD) materials in next-generation electronic technologies. Thus, providing an atomic understanding of the electron-defect interactions and supporting defect engineering development to improve carrier transport is crucial to future TMDs technologies. In this work, we utilize low-temperature scanning tunneling microscopy/spectroscopy (LT-STM/S) to elicit how distinct types of defects bring forth scattering potential engineering based on intervalley quantum quasiparticle interference (QPI) in TMDs. Furthermore, quantifying the energy-dependent phase variation of the QPI standing wave reveals the detailed electron-defect interaction between the substitution-induced scattering potential and the carrier transport mechanism. By exploring the intrinsic electronic behavior of atomic-level defects to further understand how defects affect carrier transport in low-dimensional semiconductors, we offer potential technological applications that may contribute to the future expansion of TMDs.