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Abstract Natural products have long been a viable source of therapeutic agents, providing unique structures and mechanisms that may be beneficial for cancer treatment. Herein we first report on the anticancer activity OST-01, a natural product from Baccharis Coridifolia, on breast cancer cells, including triple-negative breast cancer (TNBC). OST-01 significantly inhibited cell proliferation and oncogenic activities of TNBC cells in vitro. OST-01 also markedly inhibited TNBC tumor growth in vivo, with > 50% reduction in tumor size compared to vehicle control treatment in different in vivo models, i.e., cell line-derived (CDX), patient-derived (PDX), and mammary fat pad xenografts. Mechanistically, OST-01 induces ferroptosis by downregulating LRP8-regulated selenoproteins, i.e., GPX4. A shift from a basal-mesenchymal to a luminal-epithelial state of breast cancer stem cells (BCSCs) as supported by the downregulation of stemness (e.g., CD44) and mesenchymal (e.g., FN1 and vimentin) markers, along with the upregulation of differentiation markers (e.g., CD24) and luminal-epithelial markers (e.g., CK19), was also observed.

Endothelial dysfunction is one of the early triggers of vascular remodeling during pulmonary hypertension (PH) with complex predisposing mechanisms, mainly via an unbalanced generation of vasoactive factors, increased expression of growth factors, prothrombotic elements, and inflammatory markers. Conventional treatment regimens are restricted to a single therapeutic pathway, which usually leads to limited clinical outcomes. Combination therapies targeting multiple cells and several signaling pathways are increasingly adopted in PH treatment. Herein, inspired by the cocrystal pleomorphism theory, we prepared rod-shaped nanococrystals of the endothelin-1 (ET-1) receptor antagonist (bosentan, BST) and the anti-inflammatory drug (andrographolide, AG) for targeting the pulmonary endothelium and alleviating PH. The 525 nm-sized co-delivery system displayed a rod-like morphology, preferentially accumulated in the pulmonary endothelium and alleviated pulmonary artery (PA) remodeling. A three-week treatment with the preparation significantly alleviated the monocrotaline (MCT)- or Sugen 5416/hypoxia (SuHx)-induced PH by reducing the pulmonary artery pressure, increasing the survival rate, improving the hemodynamics, and inhibiting vascular remodeling. Mechanistically, the nanococrystals collaboratively repaired endothelial dysfunction by suppressing the pathways of ET-1/NF-κB/ICAM-1/TNF-α/IL-6. In conclusion, the cocrystal-based strategy offers a promising approach for constructing co-delivery systems. The developed rod-shaped nanococrystals effectively target the pulmonary endothelium and relieve experimental PH.

Currently, 6G technology is at a pivotal stage for research and standardization, with the next three to five years being crucial for achieving technological breakthroughs and fostering industrial development. 6G is anticipated to support a broader spectrum of application scenarios, lead us into a more intelligent and interconnected future. The applications and use cases of 6G serve as a vital link between technological innovation and user demands, laying the groundwork for key network performance indicators, functional design, and service capability planning, and paving the way for its future commercialization. The forward-looking exploration and identification of potential 6G use cases, particularly those with high development prospects, can offer strategic guidance for technological research and development. This study introduces an innovative 6G Use Case Potential Matrix, designed from dual perspectives of innovation and business viability. It assesses application innovation through the volume and trends of invention patents and evaluates business potential using market outlook analyses. Based on these insights, typical 6G use cases are categorized into four groups: leading use cases, use cases to be broken through, use cases to be excavated, and use cases to be cultivated. We select 23 typical 6G use cases with consensus for empirical analysis, and recommendations for the development and layout of 6G use cases are given. The findings of this research aim to offer fresh perspectives for the systematic planning of 6G applications development pathways and to support decision-making on aligning technology research directions with network requirements definitions.

Abstract This study investigated whether honesty is a stable trait or varies depending on situational factors. Using a coin flip guessing paradigm with monetary rewards, 33 participants completed trials with rewards ranging from 0.01 to 3 yuan. Modeling of behavioral data showed individuals have varying “honesty thresholds” where they switch from honest to dishonest behavior. EEG analysis revealed increased P300 amplitude when resisting greater monetary temptation, and individuals with higher honesty thresholds had lower P300 amplitudes for the same rewards. A late positive component indicated greater cognitive conflict when the reward amount neared an individual’s honesty threshold. These findings challenge the conception of honesty as a stable trait, instead demonstrating it varies based on contextual factors like reward size. Computational modeling and EEG provide insight into the cognitive processes underlying contextual shifts in honest behavior.

The Sn-1.0Ag-0.5Cu-xBi solder joints with different Bi content were prepared by reflow soldering. The shear strength, intermetallic compound layer, and fatigue evolution in solder joints were then investigated under thermal aging and thermal fatigue. During isothermal aging, the size of Sn grain and intermetallic compound (IMC) thickness in solder joints were greatly decreased due to the addition of Bi, especially with 5 wt% addition because the atomic migration to produce IMC layer was hindered by the Bi diffusion layer formed at the IMC interface, which means that Bi can play a role in refining the grains. Meanwhile, the shear strength of Sn-1.0Ag-0.5Cu-xBi solder joints was greatly improved through solid solution strengthening. During thermal cycling, electron backscatter diffraction analysis showed that Bi addition increased the tendency of grains to slip, as indicated by a higher Schmid factor. The thermal fatigue failure modes of micro solder joints with various Bi contents were different. In the absence of Bi addition, the fracture mode of the solder joint was typical transgranular fracture mode. With the addition ofBi element, the solder joints showed an intergranular fracture mode. The addition of Bi provides more heterogeneous nucleation sites for fine recrystallized grains, and the fracture mode was changed due to the formation of a high number of recrystallized grains. The recrystallized grains evolved from the continuous recrystallization process of sub-grain rotation under the influence of thermal-mechanical stress and the discontinuous recrystallization process of deformation storage.

Pear (Pyrus bretschneideri) fruit stone cells are primarily composed of lignin and have strongly lignified cell walls. The presence of stone cells has a negative influence on fruit texture and taste, and thus the reduction of stone cell content in pear fruit is a key goal of breeding efforts. However, research into the key transcription factors and regulatory networks associated with pear fruit stone cell formation have been limited. We here used a combination of co-expression network and expression quantitative trait locus (eQTL) analyses in 206 pear cultivars with different stone cell contents to identify relevant genes; these analyses uncovered the gene PbrMYB4, a R2R3 MYB transcription factor gene. There was a strong positive correlation between relative PbrMYB4 expression levels in the fruit flesh and stone cell/lignin contents. Overexpression of PbrMYB4 significantly increased the lignin contents, whereas silencing of PbrMYB4 had the opposite effect, decreasing the contents of lignin. PbrMYB4 overexpression in pear calli significantly promoted lignin biosynthesis. In Arabidopsis thaliana, PbrMYB4 overexpression resulted in increasing lignin deposition, cell wall thickness of vessels and xylary fiber, and accelerating expression level of lignin biosynthetic genes. PbrMYB4 was found to activate 4-Coumarate:Coenzyme A Ligase (Pbr4CL1) by binding to AC-I elements in the promoter regions, as demonstrated with dual-luciferase reporter assays and a yeast one-hybrid assay. These results demonstrated that PbrMYB4 positively regulated lignin biosynthesis in pear fruit stone cells by activating lignin biosynthesis genes. This study improves our understanding of the gene regulatory networks associated with stone cell formation in pear fruit, providing guidance for molecular breeding of pear varieties with low stone cell content.

Abstract The paper addresses the economic operation optimization problem of photovoltaic charging-swapping-storage integrated stations (PCSSIS) in high-penetration distribution networks. It proposes a dual-layer optimization scheduling model for PCSSIS clusters and distribution network systems. Firstly, a master–slave game model is constructed. The upper layer takes the high-penetration distribution network as the decision-making entity and aims to maximize its own revenue while considering the energy trading of PCSSIS. The lower layer takes PCSSIS as the decision-making entity, and PCSSIS adjusts energy flow and optimizes revenue based on the internal electricity price provided by the upper-layer distribution network. Secondly, the differential evolution algorithm and GUROBI solver are used to solve for the maximum revenue, internal electricity price, and electricity consumption of PCSSIS and the distribution network. Finally, the effectiveness of the proposed strategy is verified through case studies and simulations.

Abstract Carbyne-related materials permit exploring the potentially extraordinary properties of this long-sought but still elusive carbon allotrope. However, accurate understanding of these materials is challenging. Here we report the crystal structure of a Au-pseudocarbyne, a representative of a possible new family of materials consisting of sp-hybridized carbon chains and stabilizing metal atoms. Au-pseudocarbyne(C6), the representative pseudocarbyne containing six-membered carbon chains, has space group P6/mmm191 and unit-cell parameters a = b = 0.60 nm, c = 0.896 nm, α = β = 90°, γ = 120°. Its long-range structure can be understood as intimately intergrown bundles, each consisting of six parallel, infinite carbon chains surrounding a column of gold atoms. This compound, together with its eight-membered counterpart Au-pseudocarbyne(C8), shows that interesting new materials resembling the carbyne structure and sharing some of its properties can be designed and developed. The current work raises serious questions regarding recent reports of carbyne synthesis.

Abstract Chronic allodynia stemming from peripheral stump neuromas can persist for extended periods, significantly compromising patients’ quality of life. Conventional managements for nerve stumps have demonstrated limited effectiveness in ensuring their orderly termination. In this study, we present a spatially confined conduit strategy, designed to enhance the self-organization of regenerating nerves after truncation. This innovative approach elegantly enables the autonomous slowing of axonal outgrowth in response to the gradually constricting space, concurrently suppressing neuroinflammation through YAP-mediated mechanotransduction activation. Meanwhile, the decelerating axons exhibit excellent alignment and remyelination, thereby helping to prevent failure modes in nerve self-organization, such as axonal twisting in congested regions and overgrowth beyond the conduit’s capacity. Additionally, proteins associated with mechanical allodynia, including TRPA1 and CGRP, exhibit a gradual reduction in expression as spatial constraints tighten, a trend inversely validated by the administration of the YAP-targeted inhibitor Verteporfin. This spatially confined conduit strategy significantly alleviates allodynia, thus preventing autotomy behavior and reducing pain-induced gait alterations.

The genome tagging project (GTP) plays a pivotal role in addressing a critical gap in the understanding of protein functions. Within this framework, we successfully generated a human influenza hemagglutinin-tagged sperm-specific protein 411 (HA-tagged Ssp411) mouse model. This model is instrumental in probing the expression and function of Ssp411. Our research revealed that Ssp411 is expressed in the round spermatids, elongating spermatids, elongated spermatids, and epididymal spermatozoa. The comprehensive examination of the distribution of Ssp411 in these germ cells offers new perspectives on its involvement in spermiogenesis. Nevertheless, rigorous further inquiry is imperative to elucidate the precise mechanistic underpinnings of these functions. Ssp411 is not detectable in metaphase II (MII) oocytes, zygotes, or 2-cell stage embryos, highlighting its intricate role in early embryonic development. These findings not only advance our understanding of the role of Ssp411 in reproductive physiology but also significantly contribute to the overarching goals of the GTP, fostering groundbreaking advancements in the fields of spermiogenesis and reproductive biology.

Sinarella Bryk, 1949 (Erebidae, Herminiinae) is a medium-sized, frail-bodied genus of moths that externally resembles other genera in the Zanclognatha generic complex. All known larvae of this genus feed on fresh leaves of moss. This genus is widely distributed from the Himalayas to Southeast Asia, Japan, Borneo, Sulawesi and New Guinea.A new species of the genus Sinarella Bryk, 1949, S. jinggangshana sp. nov., is described from Jinggangshan National Nature Reserve, Jiangxi Province, China. This species is morphologically similar to S. takasago Wu, Fu & Owada, 2013, S. cristulalis (Staudinger, 1892), S. formosensis Wu, Fu & Owada, 2013 and S. japonica (Butler, 1881), but differs in both external and male genitalia characters. Images of the male adults and their genitalia are provided.

Abstract Background The benefits of intravenous thrombolysis in patients with acute minor stroke remain controversial. For the aim of providing a better therapeutic strategy, high-quality trials are required to validate the efficacy of thrombolytic medicine other than intravenous recombinant tissue plasminogen and tenecteplase. In the trial, we evaluate the efficacy and safety of urokinase (UK) in acute minor stroke. Methods This multicenter, open-label, blinded-endpoint, randomized controlled clinical trial enrolled patients with minor stroke within 6 h of symptom onset, with a NIHSS score ≤ 5. The trial was conducted at 25 hospitals in China between October 2020 and February 2023. Eligible patients were randomized to the UK group (1,000,000 U) or the best medicine treatment group. The responsible investigator recommended and implemented the best medicine treatment based on guidelines. The primary endpoint was an excellent functional outcome, defined as a modified Rankin scale (mRS) score of 0–1 at 90 days. The primary safety outcome was symptomatic intracranial hemorrhage (sICH) within 36 h. Results A total of 999 patients were enrolled in the trial, the median age was 64 years, 371 (36.9%) were women; the median (IQR) NIHSS score was 3 (2–4). At 90 days, the primary endpoint was observed in 427 patients (84.9%) in the UK group and 425 patients (85.7%) in the control group (adjusted risk ratio [RR] 1.00, 95% CI 0.96–1.05, p = 0.87). A total of 3 patients in the UK-treated (0.6%) group experienced sICH compared to 1 patient (0.2%) in the control group (RR 1.83, 95% CI 0.16–20.27, p = 0.62). Conclusions For patients with acute minor stroke treated within 6 h of symptom onset, UK intravenous thrombolysis treatment was not found to be beneficial in terms of excellent functional outcome at 90 days, whereas it was safe. Trial registration ClinicalTrials.gov Identifier: NCT04420351.

Abstract In this paper, the light-front wave functions (LFWFs) of the $$\rho $$ ρ meson are evaluated in the framework of the Nambu–Jona-Lasinio model using the proper time regularization scheme. The transverse momentum-dependent parton distributions (TMDs) of the $$\rho $$ ρ meson are derived from the overlap representations of the LFWFs. We investigate the $$\varvec{k}_{\perp }$$ k ⊥ -weighted moments and the x-dependent average transverse momentum $$\langle k_{\perp }^n(x)\rangle _{\alpha }$$ ⟨ k ⊥ n ( x ) ⟩ α of $$\rho $$ ρ meson TMDs. The $$\langle k_{\perp }^n(x)\rangle _{\alpha }$$ ⟨ k ⊥ n ( x ) ⟩ α shows the typical transverse momenta of quark TMDs in our model. Our findings indicate that the average transverse momenta of $$\langle k_{\perp }(x)\rangle _{\alpha }$$ ⟨ k ⊥ ( x ) ⟩ α fall within the range of [0.3, 0.45] GeV, while $$\langle k_{\perp }^2(x)\rangle _{\alpha }$$ ⟨ k ⊥ 2 ( x ) ⟩ α are in the region of [0.15, 0.30] $$GeV^2$$ G e V 2 . Our TMDs and parton distribution functions (PDFs) exhibit excellent adherence to positive constraints. The investigation of spin densities within the $$\rho $$ ρ meson in transverse momentum space reveals axially symmetric distributions for quarks and targets polarized in either the longitudinal or transverse direction. Conversely, unpolarized symmetric distributions occur when the quark is longitudinally polarized and the target is transversely polarized, while exhibiting dipolar distortions in the opposite scenario. A comparison between TMDs from LFWFs and those from a covariant approach demonstrates that TMDs from LFWFs more effectively satisfy positive constraints than their counterparts from the covariant approach. Furthermore, the x-moments of $$\rho $$ ρ meson PDFs indicate that $$\langle x\rangle _{g_L}$$ ⟨ x ⟩ g L is larger using LFWFs than with the covariant approach. Additionally, analysis of quark spin densities within the $$\rho $$ ρ meson reveals that $$\rho _{\uparrow \downarrow }\left( k_x,k_y\right) =f-g_L-\frac{1}{3}f_{LL}$$ ρ ↑ ↓ k x , k y = f - g L - 1 3 f LL yields a negative result using the covariant approach, whereas $$\rho _{\uparrow \downarrow }\left( k_x,k_y\right) $$ ρ ↑ ↓ k x , k y derived from LFWFs produces a positive outcome.

Acute lung injury (ALI) or its more severe form, acute respiratory distress syndrome, is a life-threatening disease closely associated with an imbalance of M1/M2 macrophage polarization. However, current therapeutic strategies for ALI are controversial due to their side effects, restricted administration routes, or poor targeted delivery. The development of herbal medicine has uncovered numerous anti-inflammatory compounds potentially beneficial for ALI therapy. One such compound is the bergapten, a coumarin, which has been isolated from Ficus simplicissima Lour. However, it's been used as an anti-cancer drug and it's effects on ALI remain unexplored. The poor solubility and biodistribution of bergapten heavily limit its application. In this timely report, we developed a bioactive and lung-targeting lipid-nanomedicine by integrating bergapten and DPPC liposome, named as Ber-lipo. A comprehensive series of in vitro experiments confirmed the anti-inflammatory effects of Ber-lipo and its protective roles in maintaining the homeostasis of macrophage polarization and epithelial–endothelial integrity. In a lipopolysaccharide (LPS)-induced ALI mouse model, Ber-lipo can target inflamed lungs and significantly improve lung edema, tissue injury, and pulmonary function, relieve body weight loss, pulmonary permeability, and proinflammatory status, and especially maintain a balance of M1/M2 macrophage polarization. Furthermore, RNA sequencing analysis showed Ber-lipo's potential in effectively treating inflammatory lung diseases such as pneumonia, inhibiting proinflammatory signals, and altering the transcriptome of M1/M2 macrophages-associated genes in lung tissues. Molecular docking and Western blot analyses validated that Ber-lipo suppressed the activation of the TLR4/MyD88/NF-κB signaling axis responsible for ALI progression. In conclusion, this study demonstrates for the first time that new inhalable nanomedicine (Ber-lipo) can target inflamed lungs and ameliorates ALI by reprogramming macrophage polarization to an anti-inflammatory state via inactivating the TLR4/MyD88/NF-κB pathway, hence providing a promising strategy for enhanced ALI therapy in the clinic.

Abstract Cancer cells acquire the ability to reprogram their phenotype in response to targeted therapies, yet the transition from dormancy to proliferation in drug-resistant cancers remains poorly understood. In prostate cancer, we utilized high-plasticity mouse models and enzalutamide-resistant (ENZ-R) cellular models to elucidate NR2F1 as a key factor in lineage transition and ENZ resistance. Depletion of NR2F1 drives ENZ-R cells into a relative dormancy state, characterized by reduced proliferation and heightened drug resistance, while NR2F1 overexpression yields contrasting outcomes. Transcriptional sequencing analysis of NR2F1-silenced prostate cancer cells and tissues from the Cancer Genome Atlas-prostate cancer and SU2C cohorts indicated exosomes as the most enriched cell component, with pathways implicated in steroid hormone biosynthesis and drug metabolism. Moreover, NR2F1-AS1 forms a complex with SRSF1 to upregulate NR2F1 expression, facilitating its binding with ESR1 to sustain hormonal receptor expression and enhance proliferation in ENZ-R cells. Furthermore, HnRNPA2B1 interacts with NR2F1 and NR2F1-AS1, assisting their packaging into exosomes, wherein exosomal NR2F1 and NR2F1-AS1 promote the proliferation of dormant ENZ-R cells. Our works offer novel insights into the reawaking of dormant drug-resistant cancer cells governed by NR2F1 upregulation triggered by exosome-derived NR2F1-AS1 and NR2F1, suggesting therapeutic potential for phenotype reversal. Graphical Abstract

Abstract Background Identification of mutations in the SERPINC1 has illuminated the intricate pathways underlying antithrombin (AT) deficiency. Our group identified a variation in the SERPINC1 gene (c.964 A > T, p.Lys322stop) and further investigated the mechanism of this variant causing AT deficiency. Methods Multiple in silico tools were utilized to predict the conservation of mutations and their impact on the AT structure. The coagulation state was evaluated using the thrombin generation assay. Recombinant AT was overexpressed in HEK293T cells. Intracellular kinetics and extracellular secretion of recombinant AT-K322* were scrutinized by RT-qPCR, Western blotting, ELISA, and immunocytofluorescence. Results Analysis of conservation in silico indicated 43 out of the 143 amino acids deleted byAT-K322* in AT were highly conserved across homologous species. In vitro expression experiments showed that there was no significant difference in mRNA levels between the mutant (AT-K322*) and wild-type (AT-WT) forms of the protein. The truncated AT-K322* protein was clearly detected in cell lysates, but not in the culture medium. Conclusion AT-K322* resulted in the generation of a truncated protein, which in turn affected the secretion of AT, ultimately leading to AT deficiency.

With the rapid advancement of the Internet of Things (IoT) era, the demand for wireless sensing and communication is increasingly prominent. Tens of thousands of sensing and communication nodes have presented new challenges to distributed energy. As a green energy harvesting technology, the triboelectric nanogenerator (TENG), with its outstanding characteristics of simple configuration, low cost, and high compatibility, demonstrates significant advantages in self-powered sensing systems and great application potential in the fields of human–machine interaction and wearable devices in the IoT era. More importantly, the electric displacement field and modulated electromagnetic waves that TENG triggers have opened a new paradigm for self-powered wireless communication, making up for the disadvantages of power supply by traditional distributed power sources. This review comprehensively discusses the latest scientific and technological progress in wireless communication technology prompted by TENG and further discusses its potential applications in various promising fields. Finally, a summary and outlook of TENG-based self-powered sensing and wireless communication synergic systems are presented, aiming to stimulate future innovation in the field and accelerating the paradigm shift to a fully self-powered IoT era.

Tumor microenvironment governs various therapeutic tolerability of cancer such as ferroptosis and immunotherapy through rewiring tumor metabolic reprogramming like Warburg metabolism. Highly expressed carbonic anhydrases (CA) in tumor that maintaining the delicate metabolic homeostasis is thus the most potential target to be modulated to resolve the therapeutic tolerability. Hence, in this article, a self-healable and pH-responsive spermidine/ferrous ion hydrogel loaded with CA inhibitor (acetazolamide, ACZ) and glucose oxidase (ACZ/GOx@SPM-HA Gel) was fabricated through the Schiff-base reaction between spermidine-dextran and oxidized hyaluronic acid, along with ferrous coordination. Investigation on cancer cell lines (MOC-1) demonstrated ACZ/GOx@SPM-HA Gel may induce cellular oxidative stress and mitochondrial dysfunction through disrupting the cellular homeostasis. Moreover, with the facilitation of autophagy induced by spermidine, ACZ/GOx@SPM-HA Gel may trigger a positive feedback loop to maximally amplify cellular ferroptosis and promote DAMPs release. The anti-tumor evaluation on xenograft mice models furtherly proved the local injection of such hydrogel formulation could efficiently inhibit the tumor growth and distinctively promote the immunogenicity of tumor bed to provide a more favorable environment for immunotherapy. Overall, ACZ/GOx@SPM-HA Gel, with such feasible physiochemical properties and great biocompatibility, holds great potential in treating solid tumors with acidosis-mediated immunotherapy tolerance.

This paper proposes an innovative Traditional Chinese Medicine Ancient Text Education Intelligent Visual Question Answering System (TCM-VQA IoTNet), which integrates Internet of Things (IoT) technology with multimodal learning to achieve a deep understanding and intelligent question answering of both the images and textual content of traditional Chinese medicine ancient texts. The system utilizes the VisualBERT model for multimodal feature extraction, combined with Gated Recurrent Units (GRU) to process time-series data from IoT sensors, and employs an attention mechanism to optimize feature fusion, dynamically adjusting the question answering strategy. Experimental evaluations on standard datasets such as VQA v2.0, CMRC 2018, and the Chinese Traditional Medicine Dataset demonstrate that TCM-VQA IoTNet achieves accuracy rates of 72.7%, 69.%, and 75.4% respectively, with F1-scores of 70.3%, 67.5%, and 73.9%, significantly outperforming existing mainstream models. Furthermore, TCM-VQA IoTNet has shown excellent performance in practical applications of traditional Chinese medicine education, significantly enhancing the precision and interactivity of intelligent education. Future research will focus on improving the model’s generalization ability and computational efficiency, further expanding its application potential in traditional Chinese medicine diagnosis and education.

Peptide vaccines based on tumor antigens face the challenges of rapid clearance of peptides, low immunogenicity, and immune suppressive tumor microenvironment. However, the traditional solution mainly uses exogenous substances as adjuvants or carriers to enhance innate immune responses, but excessive inflammation can damage adaptive immunity. In the current study, we propose a straightforward novel nanovaccine strategy by employing homologous human ferritin light chain for minimized innate immunity and dendritic cell (DC) targeting, the cationic KALA peptide for enhanced cellular uptake, and suppressor of cytokine signaling 1 (SOCS1) siRNA for modulating DC activity. Upon fusing with the KALA peptide, this nanovaccine presents as a novel 40-mer cage structure, with highly enriched antigen peptides of proper size (25 nm) for targeted delivery to lymph nodes. The loading of SOCS1 siRNA onto the KALA peptide promoted DC maturation in tumor environment, leading to a 3-fold increase in antigen presentation compared to alum adjuvant. Moreover, it demonstrates remarkable efficacy in suppressing tumor progression and metastasis, together with prolonged survival. In addition, the nanovaccine stimulates up to 40 % memory T cells, thereby achieving sustained protection against tumor re-challenge. This unprecedented nanovaccine platform can ignite fresh interdisciplinary discussions on interactive strategies for future peptide vaccine development.

Abstract:: Intervertebral disc degeneration (IVDD) is a prevalent chronic spinal condition characterized by the deterioration of the intervertebral discs (IVD), leading to structural damage and associated pain. This degenerative process is closely linked to oxidative stress injury, which plays a pivotal role in its onset and progression. Oxidative stress in IVDD results from the excessive production of reactive oxygen species (ROS) and impaired ROS clearance mechanisms, disrupting the redox balance within the intervertebral disc. Consequently, oxidative stress contributes to the degradation of the extracellular matrix (ECM), promotes cell apoptosis, and exacerbates disc tissue damage. Current treatment options for IVDD face significant challenges in effectively alleviating the oxidative stress-induced damage and facilitating disc tissue repair. However, recent advancements in biomaterials have opened new avenues of hope for IVDD treatment by addressing oxidative stress. In this review, we first provide an overview of the pathophysiological process of IVDD and explore the mechanisms and pathways associated with oxidative stress injury. Then, we delve into the current research on antioxidant biomaterials employed in the treatment of IVDD, and outline the advantages and limitations of hydrogel, nanomaterials, polyphenol and inorganic materials. Finally, we propose the future research direction of antioxidant biomaterials in IVDD treatment. The main idea of this review is shown in Scheme 1.

The fatigue cracking mechanism of Ti–2Al-2.5Zr alloy was investigated under different stress amplitudes. The evolution of fatigue damage was analyzed using quasi in-situ tests. The dependence of transgranular and intergranular crack nucleation on microstructure features was discussed in detail. The mechanisms of slip-induced and twinning-detwinning (T-D) induced crack nucleation were elucidated, respectively. It was found that, at the stress amplitude of 442 MPa, the slip damage, in the form of intrusions/extrusions, dominated crack nucleation. Transgranular cracks primarily nucleate along the prismatic planes of the variants with highest Schmid Factor of prismatic slip (SFpris.); intergranular cracks are mainly induced at grain boundaries (GBs) by slip impacting/shearing GB behaviors and at GB triple junctions due to strain incompatibility. As the stress amplitude increased to 475 MPa, the dominant crack mode transitioned from slip-dominant cracks to T-D induced cracks and intergranular cracks due to the competition between the T-D and slip behavior. Twin boundaries (TBs), GBs, slip planes adjacent to the activated T-D regions, and the twin pairs/chains in adjacent grains were identified as preferred sites for crack nucleation.

The structure changes and hydrogen permeation behavior of Titanium alloy TA17 in simulated water environment of small modular reactor (SMR) at 320 °C for 8000h was investigated. We found a corrosion layer consist of TiO2 and FeTiO3 with a good hydrogen permeation resistance. The structure and hydrogen permeation resistance change with the increase of corrosion period. At the first corrosion period of 3000h, FeTiO3 grows rapidly with an exponential parameter of 0.663 fitted by parabolic law. As the initial TiO2 layer destroyed, the deuterium permeation flux increases. After the thickness of FeTiO3 reaches a limit at corrosion time of 4000h, there exists a dynamic balance between the growth and the dissolution of FeTiO3, result in a small fluctuant deuterium permeation flux at corrosion periods of 5000–8000h. The deuterium permeation flux of the corrosion layer can be two orders of magnitude lower to that of Titanium alloy TA17 substrate. The formation process of corrosion layer and its effect on hydrogen permeation resistance are discussed in detail.

Abstract Background Sponge-associated microorganisms are promising resources for the production of bioactive compounds with cytotoxic potential. The main goal of our study is to isolate the fungal endophytes from the Red Sea sponge Hyrtios sp. followed by investigating their cytotoxicity against number of cell lines. Results The fungal strain UR3 was isolated from the Red Sea sponge using Sabouraud dextrose agar media. It was identified based on partial 18 S rRNA gene and ITS sequence analyses as Cladosporium sp. UR3. The in vitro cytotoxic potential of the ethyl acetate extract of the fungal isolate was evaluated using MTT assay against three cancer cell lines: CACO2, MCF7, and HEPG2. Metabolomics profiling of the obtained ethyl acetate extract using LC-HR-ESI-MS, along with molecular docking and pharmacological network studies for the dereplicated compounds were performed to explore its chemical profile and the possible cytotoxic mechanism of the sponge-associated fungi. Conclusion These results highlighted the role of sponge-associated fungi as a fruitful resource for the discovery of cytotoxic metabolites.

Abstract Purpose: Estrogen receptor-positive (ER+), progesterone receptor-negative (PR-) and human epidermal growth factor receptor 2-negative (HER2−) breast cancer (BC) often developed resistance to endocrine treatment (ET). We aimed to explore (1) the different clinicopathological features between ER+/PR+/HER2- and ER+/PR-/HER2- BC, and (2) whether ER+/PR-/HER2- early BC patients could benefit from adjuvant ET. Methods: All patients treated for ER+/HER2- early BC who underwent surgery between 2010 and 2021 from a BC database in China were retrospectively examined. The cases followed up for less than six months were excluded. Results: The records of ER+/PR+/HER2- (n = 10843) and ER+/PR-/HER2- BC (n = 1193) cases were reviewed, with median follow-up times of 35.8 and 47.0 months, respectively. Compared with ER+/PR+/HER2- cases, ER+/PR-/HER2- BC occurred more in postmenopausal women (73.1% vs. 52.9%, p = 0.000) and were more likely to be T > 2 cm (40.6% vs. 37.6%, p = 0.048) and Ki67 > 20%+ (48.1% vs. 36.9%, p = 0.000). However, ER+/PR-/HER2- cases had fewer nodal involvement (32.9% vs. 36.9%, p = 0.000). Approximately 82.2% (981/1193) of ER+/PR-/HER2- patients received ET, while approximately 17.8% (212/1193) did not. Compared to patients did not receive adjuvant ET, the ET group had similar disease-free survival (DFS) (HR = 1.33, 95% confidence interval (CI): 0.68–2.59, p = 0.444) and overall survival (OS) (HR = 1.17, 95%CI: 0.37–3.68, p = 0.799). 65.7% of recurrent ER+/PR-/HER2- patients experienced distant relapse (65.7% vs. 48.2% (for ER+/PR + cases), p = 0.011). By comparison, recurrent ER+/PR+/HER2- patients were more likely to experience only local relapse (31.6% vs. 14.9% (for ER+/PR- cases), p = 0.007). Conclusions: ER+/PR-/HER2- BC was a special subtype with aggressive clinicopathological features and more tend to have distant metastasis rather than nodal involvement or local relapse. ER+/PR-/HER2- early BC did not seem to benefit from adjuvant ET.

Abstract The ovary is crucial for female reproduction and health, as it generates oocytes and secretes sex hormones. Transplantation of mesenchymal stem cells (MSCs) has been shown to alleviate pathological ovarian aging. However, it is unclear whether MSCs could benefit the naturally aging ovary. In this study, we first examined the dynamics of ovarian reserve of Chinese women during perimenopause. Using a naturally aging cynomolgus monkey (Macaca fascicularis) model, we found that transplanting human embryonic stem cells-derived MSC-like cells, which we called M cells, into the aging ovaries significantly decreased ovarian fibrosis and DNA damage, enhanced secretion of sex hormones and improved fertility. Encouragingly, a healthy baby monkey was born after M-cell transplantation. Moreover, single-cell RNA sequencing analysis and in vitro functional validation suggested that apoptosis, oxidative damage, inflammation, and fibrosis were mitigated in granulosa cells and stromal cells following M-cell transplantation. Altogether, these findings demonstrate the beneficial effects of M-cell transplantation on aging ovaries and expand our understanding of the molecular mechanisms underlying ovarian aging and stem cell-based alleviation of this process.

Oxidative stress and inflammation are key drivers of osteoarthritis (OA) pathogenesis and disease progression. Herein we report the synthesis of poly(p-coumaric) nanoparticles (PCA NPs) from p-courmaic acid (p-CA), a naturally occurring phytophenolic acid, to be a multifunctional and drug-free therapeutic for temporomandibular joint osteoarthritis (TMJOA). Compared to hyaluronic acid (HA) that is clinically given as viscosupplementation, PCA NPs exhibited long-term efficacy, superior anti-oxidant and anti-inflammatory properties in alleviating TMJOA and repairing the TMJ cartilage and subchondral bone in a rat model of TMJOA. Notably, TMJ repair mediated by PCA NPs could be attributed to their anti-oxidant and anti-inflammatory properties in enhancing cell proliferation and matrix synthesis, while reducing inflammation, oxidative stress, matrix degradation, and chondrocyte ferroptosis. Overall, our study demonstrates a multifunctional nanoparticle, synthesized from natural p-coumaric acid, that is stable and possess potent antioxidant, anti-inflammatory properties and ferroptosis inhibition, beneficial for treatment of TMJOA.

Abstract Background The association between uric acid and pulmonary embolism(PE) remains controversial, and there has been limited investigation into how uric acid influences pulmonary embolism across different age groups. Our study aimed to elucidate the relationship between uric acid levels and pulmonary embolism, considering variations across age groups. Methods A total of 368 patients who underwent computed tomography pulmonary angiography from July 2018 to May 2022 were included in the analysis. Subsequently, the cohort was stratified by age, with separate univariate and multivariate logistic regression analyses conducted for the elderly (aged ≥ 60 years) and non-elderly (aged

Abstract Background Lung injury and pulmonary fibrosis (PF), frequently arising as sequelae of severe and acute lung disease, currently face a dearth of effective therapeutic potions. Mesenchymal stem cells (MSCs) with immunomodulatory and tissue repair functions have immense potential to treat lung injury and PF. However, the optimal route of administration, timing, and frequency of dosing remain elusive. Human embryonic stem cell-derived immunity-and-matrix-regulatory cells (IMRCs) have shown therapeutic potential for lung injury and PF. Methods To ascertain the optimal therapeutic regimen for IMRCs in PF, we conducted an experimental study. Utilizing a mouse model of PF induced by bleomycin (BLM), IMRCs were administered via either a single or double intravenous (IV) or intratracheal (IT) injection on the first and seventh days post-BLM induction. Results Our findings revealed that IV infusion of IMRCs surpassed IT infusion in enhancing survival rates, facilitating body weight recovery, and optimizing Ashcroft and Szapiel scores among the model mice. Notably, IV administration exhibited a more profound ability to mitigate lung inflammation and fibrosis. Moreover, earlier and more frequent administrations of IMRCs were found to be advantageous in enhancing their therapeutic effects. Specifically, early administration with two IV infusions significantly improved body weight, lung organ coefficient, pulmonary ventilation and diffusion functions, and PF. This was accompanied by an increase in alveolar type I and II epithelial cells and a suppression of macrophage infiltration via CD24. Conclusion Collectively, these results suggested that IMRCs infusion ameliorated lung injury by promoting lung regeneration and inhibiting macrophage infiltration in a route, time, and frequency-dependent manner.

Abstract Osteoporosis remains incurable. The most widely used antiresorptive agents, bisphosphonates (BPs), also inhibit bone formation, while the anabolic agent, teriparatide, does not inhibit bone resorption, and thus they have limited efficacy in preventing osteoporotic fractures and cause some side effects. Thus, there is an unmet need to develop dual antiresorptive and anabolic agents to prevent and treat osteoporosis. Hydroxychloroquine (HCQ), which is used to treat rheumatoid arthritis, prevents the lysosomal degradation of TNF receptor-associated factor 3 (TRAF3), an NF-κB adaptor protein that limits bone resorption and maintains bone formation. We attempted to covalently link HCQ to a hydroxyalklyl BP (HABP) with anticipated low antiresorptive activity, to target delivery of HCQ to bone to test if this targeting increases its efficacy to prevent TRAF3 degradation in the bone microenvironment and thus reduce bone resorption and increase bone formation, while reducing its systemic side effects. Unexpectedly, HABP-HCQ was found to exist as a salt in aqueous solution, composed of a protonated HCQ cation and a deprotonated HABP anion. Nevertheless, it inhibited osteoclastogenesis, stimulated osteoblast differentiation, and increased TRAF3 protein levels in vitro. HABP-HCQ significantly inhibited both osteoclast formation and bone marrow fibrosis in mice given multiple daily PTH injections. In contrast, HCQ inhibited marrow fibrosis, but not osteoclast formation, while the HABP alone inhibited osteoclast formation, but not fibrosis, in the mice. HABP-HCQ, but not HCQ, prevented trabecular bone loss following ovariectomy in mice and, importantly, increased bone volume in ovariectomized mice with established bone loss because HABP-HCQ increased bone formation and decreased bone resorption parameters simultaneously. In contrast, HCQ increased bone formation, but did not decrease bone resorption parameters, while HABP also restored the bone lost in ovariectomized mice, but it inhibited parameters of both bone resorption and formation. Our findings suggest that the combination of HABP and HCQ could have dual antiresorptive and anabolic effects to prevent and treat osteoporosis.

This study investigates the hot compression behavior of a molybdenum- Rhenium (Mo–Re) alloy, focusing on deformation mechanisms and instability. Utilizing electron backscattered diffraction (EBSD) and transmission electron microscope (TEM), we characterized the microstructure, grain orientation, and deformation behavior across temperatures (650, 750, 850, and 950 °C) and strain rates (0.01, 0.1, 1, and 10s-1). The study reveals that Mo–Re alloys exhibit high hot deformation resistance, necessitating optimal processing conditions for effective plastic deformation. Key findings by EBSD and TEM include the formation of dislocation networks and substructures enhancing grain plasticity. We established a constitutive equation and processing maps, providing valuable insights for industrial applications and future alloy development.

Three new species of the genus Fignya Solovyev & Witt, 2009, F. qiana sp. nov., F. trigonum sp. nov., and F. samkosa sp. nov., are described from China and Cambodia. Additionally, a new combination, F. brachygnatha (Wu & Fang, 2008), comb. nov., is proposed. The new species are illustrated with images of the adults and male genitalia, and compared with similar species. A key to all known species in the genus, along with their geographical distributions, is provided.

Objective To clarify the oil and gas accumulation patterns and main controlling factors of the thin weathered crust volcanic rock reservoir at the top of Member 2 of the Fengcheng Formation in the southern Mahu Sag(Manan Sag). Methods This paper provides a comprehensively analyses of the volcanic rock characteristics, reservoir properties, and oil and gas geological features. Furthmore, an oil and gas accumulation model for volcanic rocks in the slope area is established. Results Research has shown that Member 2 of the Fengcheng Formation in the southern Mahu Sag is mainly composed of basalt and tuff. The basalt with the volcanic overflow phase developed high-permeability reservoirs abundant in oil and gas. Overall, the crude oil is medium-high viscosity and light-medium waxy. Its distribution pattern of C20, C21, and C23 tricyclic terpanes resembles a mountain peak, showing a significantly higher relative content of tricyclic terpanes. In contrast to crude oil, the distribution of tricyclic terpanes in in-situ source rocks demonstrates an upward pattern, with maturity parameters of biomarkers also displaying lower maturity characteristics. Based on the consistent research results of the carbon isotope characteristics of crude oil in the study area and in the Fengcheng Formation source rocks, it is infered that the oil reservoir in the study area has undergone multistage oil and gas charging. Conclusion The volcanic rocks in the study area exhibit strong vertical and horizontal heterogeneities, with crude oil density decreasing with depth. It is believed that oil and gas mainly migrate from low to high parts along permeable strata below volcanic rocks and enter volcanic rock reservoirs under buoyancy. They accumulate reservoirs in structures or lithological traps with relatively good reservoir properties and preservation conditions. This is a typical slope area-structure lithology-multistage volcanic rock oil and gas reservoir formation model.

BackgroundGlutathione (GSH) metabolism supports tumor redox balance and drug resistance, while long non-coding RNAs (lncRNAs) influence lung adenocarcinoma (LUAD) progression. This study developed a prognostic model using GSH-related lncRNAs to predict LUAD outcomes and assess tumor immunity.MethodsThis study analyzed survival data from The Cancer Genome Atlas (TCGA) and identified GSH metabolism-related lncRNAs using Pearson correlation. A prognostic model was built with Cox and Least Absolute Shrinkage and Selection Operator (LASSO) methods and validated by Kaplan-Meier analysis, Receiver Operating Characteristic (ROC) curves, and Principal Component Analysis (PCA). Functional analysis revealed immune infiltration and drug sensitivity differences. Quantitative PCR and experimental studies confirmed the role of lnc-AL162632.3 in LUAD.ResultsOur model included a total of nine lncRNAs, namely AL162632.3, AL360270.1, LINC00707, DEPDC1-AS1, GSEC, LINC01711, AL078590.2, AC026355.2, and AL096701.4. The model effectively forecasted patient survival, and the nomogram, incorporating additional clinical risk factors, satisfied clinical needs adequately. Patient stratification based on model scores revealed significant disparities in immune cell composition, functionality, and mutations between groups. Additionally, variations were noted in the IC50 values for key lung cancer medications such as Cisplatin, Docetaxel, and Paclitaxel. In vitro cell experiment results showed that AL162632.3 was markedly upregulated, while AC026355.2 tended to be downregulated across these cell lines. Ultimately, suppressing lnc-AL162632.3 markedly reduced the growth, mobility, and invasiveness of lung cancer cells.ConclusionThis study identified GSH metabolism-related lncRNAs as key prognostic factors in LUAD and developed a model for risk stratification. High-risk patients showed increased tumor mutation burden (TMB) and stemness, emphasizing the potential of personalized immunotherapy to improve survival outcomes.

Despite treatment with immunosuppressive or clone-targeted chemotherapy, patients with proliferative glomerulonephritis with monoclonal immunoglobulin deposit (PGNMID) frequently progress into end-stage kidney failure, and early recurrence of PGNMID after kidney transplantation is common. The standard management of PGNMID has been unclear, currently based on data from small cohorts, which requires a need for additional therapeutic regimens in this disease. A human IgG monoclonal antibody that targets CD38 (daratumumab) was recently identified as a potential therapeutic option for treating PGNMID. To date, rare data on the application of daratumumab in patients with PGNMID after kidney transplantation have been reported. Herein, we first described a unique patient with recurrent PGNMID in kidney allograft who was treated with daratumumab after not responding to bortezomib-based regimens. Daratumumab was shown to successfully reduce proteinuria with stabilizing kidney function and was well-tolerated in this patient, which supports that daratumumab appears to be a viable option for treatment-resistant PGNMID.

Study regions: This study focuses on the Upper Ting River Watershed (UTRW) in the Ting River Basin, China. Study focus: The study investigates the adverse impacts of urbanization and land-use change on hydrology, proposing the implementation of grey-green-blue infrastructure (GGBI) practices to mitigate these effects. An integrated modeling framework is developed to optimize the placement of GGBI, demonstrated through a case application in the UTRW. New hydrological insights for the region: （1）The proposed modeling framework is highly effective in identifying key nodes and corridors for stormwater processes and flood inundation at both the watershed and city levels. It guides the reconstruction of GGBI spatial patterns at the watershed level and optimizes GGBI placement at the city level.（2）In the central city, flooding covers an area of 8.44 km², or 18.53 % of the total area, with average flood depths of 0.99 m and maximum depths reaching 1.69 m. Areas most suitable for GGBI construction are located along the Ting River, showing clear continuity and concentration in the central city and Xinqiao Town.（3）The optimized placement of GGBI, based on the SWMM model and non-dominated sorting genetic algorithm (NSGA-III), effectively reduces flood damage. Multi-objective optimization solutions outperform alternatives in terms of runoff reduction, pipeline overload duration, and construction costs.

Aflatoxins harm the reproductive system and gamete development in animals. Primordial germ cells (PGCs) in chickens, as ancestral cells of gametes, are essential for genetic transmission, yet the impact and mechanisms of aflatoxins on them remain elusive. This study systematically investigated the effects of aflatoxin B1 (AFB1) on chicken PGCs and their potential mechanisms using an in vitro culture model. We observed a significant reduction in PGC numbers and an increase in apoptosis levels with AFB1 treatment. Further analysis revealed that AFB1 induced mitochondrial structural and functional abnormalities. Additionally, AFB1 treatment led to increased oxidative stress, lipid peroxidation, ferroptosis, and autophagy in chicken PGCs, ultimately affecting their biological characteristics. Interestingly, we found that the NRF2-mediated antioxidant pathway was activated in AFB1-treated PGCs. Inhibiting NRF2 exacerbated oxidative stress and cell death in PGCs, suggesting NRF2 upregulation plays a protective role under AFB1 regulation. This study illuminates AFB1's toxic effects on chicken PGCs and provides insights into potential mechanisms, establishing a basis for strategies to prevent and treat AFB1's adverse effects on poultry genetic transmission.

BackgroundRecent studies have shown that migraine significantly increases the incidence of anxiety and is positively correlated with the severity and frequency of migraine. The relationship between migraine and anxiety has attracted extensive attention. This study focused on the association between migraine and anxiety, aiming to predict potential future research trends.MethodsA bibliometric analysis was conducted using publications from the Core Collection of Web of Science. We utilized CiteSpace.5.8.R3 and VOSviewer 1.6.17 to evaluate the value of articles over the past 10 years.ResultsThe number of publications has increased significantly over the past 10 years. The cooperative network analysis shows that the United States is the most collaborative country. Additionally, Harvard University is the institution and Richard B. Lipton the individual with the highest number of studies on migraine. The analysis of keyword outbreaks indicates that the strong citation burst words are closely related to sex differences, activation, allodynia, and preventive treatment, which represent emerging new research areas and potential hotspots for future research.ConclusionAn overall upward trend in the research of migraine and anxiety was observed. Sex differences, functional magnetic resonance imaging (fMRI), activation, allodynia, and preventive treatment are predicted to be hotspots in the future.

Excessive photovoltaic power in a distributed photovoltaic system may cause problems such as overvoltage and reverse power flow in the distribution network, and the safe and stable operation of distribution networks faces potential challenges or risks. To ensure stable operation,this article proposes an innovative multi-mode coordinated control strategy for DC near-field photovoltaic systems that integrates adaptive mutation particle swarm optimization technology to achieve more efficient control performance. The operation of distributed photovoltaic system is divided into five modes: single-machine reactive power regulation, multi-machine reactive power coordination, active power reduction mode in multi machine systems, Existing power recovery models and reactive power recovery mode; So the mathematical model of the inverter main controller is constructed, using adaptive mutation particle swarm optimization algorithm to solve the model, in order to improve solving efficiency and accuracy Committed to overcoming the limitations of slow convergence speed and susceptibility to local optima in particle swarm optimization algorithms, in order to optimize algorithm performance, when optimizing the particle swarm optimization algorithm, synchronously tuning the learning factor and inertia weight parameters is aimed at accelerating the convergence process and improving the accuracy of the algorithm. By introducing a mutation mechanism, the search domain of the particles is expanded, thereby enhancing the global optimization efficiency of the algorithm. The experimental data shows that the optimized control parameters of the algorithm significantly enhance the dynamic response characteristics of the system, and its convergence speed is faster and its steady-state accuracy is higher. After 60 iterations, the control accuracy reached 98.15%, and the feature value near the virtual axis of the system was optimized from −1328 to −1.647. The fluctuation of each electric quantity of the system was smaller than that of the original parameter, the stability could be reached faster after troubleshooting, and the coordinated control effect is better.

Background & Aims: Dysregulation of one-carbon metabolism is considered an early hallmark of mitochondrial dysfunction and cancer metabolism. ALDH1L2 belongs to the aldehyde dehydrogenase family and plays an important role in tumor progression. However, little is known about the precise role and underlying mechanisms of ALDH1L2 in hepatocellular carcinoma (HCC). Methods: Immunohistochemistry, western blotting, and immunofluorescence staining were used to evaluate ALDH1L2 expression in HCC samples (n = 90) and cell lines (n = 9). A series of in vitro and in vivo assays were performed to explore the role and molecular mechanism of ALDH1L2 in HCC progression. Results: ALDH1L2 upregulation is associated with poor prognosis in HCC (hazard ratio 1.923; 95% confidence interval 1.03–3.59; p = 0.04). ALDH1L2 promotes tumor cell proliferation and metastasis by activating NRF2/IL-6/STAT3 signaling. ALDH1L2 promotes mitochondrial respiration, increases ATP production and protects HCC cells from reactive oxygen species-induced cellular damage via NRF2 stabilization. NRF2 also directly binds to the ALDH1L2 promoter and increases ALDH1L2 transcription, thereby establishing a positive feedback loop to maintain the function of ALDH1L2. The interaction between tumor-associated macrophages and ALDH1L2-overexpressing HCC cells further promotes HCC progression. In addition, ALDH1L2 knockdown enhances the anti-HCC activity of the tyrosine kinase inhibitor sorafenib. Conclusions: These findings provide the first evidence indicating that ALDH1L2 is directly involved in tumor progression by interacting with tumor-associated macrophages through the Jak2/STAT3 signaling pathway and that ALDH1L2 may be a target molecule for HCC therapy. Impact and implications:: This research highlights that ALDH1L2 could serve as a predictive and prognostic marker in HCC. We found that a positive feedback loop between ALDH1L2 and NRF2 promotes HCC progression by activating the IL-6/Jak2/STAT3 signaling axis and tumor-associated macrophage polarization. In addition, we found that ALDH1L2 knockdown enhances the anti-HCC effect of sorafenib.

The mechanism of wave propagation in fluid-saturated porous media is influenced by pressure and frequency. Pressure dependence is mainly dominated by the opening and closing of compliant and stiff pores in rocks, as well as nonlinear deformation respect to high-order elastic constants. Frequency dependence is mainly reflected in the dispersion and attenuation caused by wave-induced fluid flow (WIFF). Therefore, the propagation characteristics of seismic waves in subsurface rocks when pressure and frequency are coupled have broad practical significance, such as geofluid discrimination and in situ stress detection. A new equivalent elastic modulus applicable to fluid-saturated porous media has been established, which simultaneously considers the effects of pressure and WIFF. First, the dual-porosity model is incorporated to account for the changes in rock porosity under pressure and corresponding linear and nonlinear deformations. Then, based on the heterogeneity of rock at the mesocale and microscale, a unified pressure- and frequency-dependent elastic modulus over a wide frequency band is established using the Zener model. The wave equation of fluid-saturated porous media is constructed using the new model, and the pressure- and frequency-dependent phase velocities are derived. Rock physics and digital simulation experiments are applied to analyze the variation of elastic parameters and velocity with pressure and frequency. Comparison with experimental measurement data shows that the new model has higher accuracy than traditional models, especially in the low effective pressure region and the frequency band respect to seismic exploration.

Ductal carcinoma in situ (DCIS), a noninvasive breast cancer, rarely metastasises to distant locations. When the initial lesion is stable, bone marrow metastasis (BMM) and bone marrow necrosis (BMN) are even less common. Here, we report the case of a 47-year-old female patient who underwent localized surgery and radiotherapy for right-sided DCIS. The patient also had a mutation in the breast cancer susceptibility gene 1 (BRCA1, OMIM: 113705) and tested positive for the progesterone and estrogen receptors. After 11 years of disease-free survival, the patient developed severe thrombocytopenia, anemia, fever, malaise, generalized multifocal pain, and irregular vaginal bleeding. A nodule was later found in the right axilla, and a postoperative biopsy revealed tumor cells from the breast. After three bone marrow biopsies, Positron Emission Tomography, 18F-fluorodeoxyglucose, positron emission tomography, computed tomography (18F-FDG PET/CT) scans, and other examinations, she was finally diagnosed with breast cancer BMM and BMN (stable primary lesion without bone metastasis). Despite symptomatic supportive treatment, the patient ultimately died rapidly as her condition deteriorated. In this case, we explored the possible mechanisms of BMM in this patient with DCIS by reviewing the literature related to this case and discussing the heterogeneous clinical presentation and pathologic phenotype. The diagnostic and therapeutic course of this case was extremely challenging. This suggests to clinicians that regular checkups and monitoring are necessary, even if the rate of distant metastasis from DCIS is low.

Abstract Bioprinting technology plays a crucial role for constructing tissue substitutes. However, the mismatched scaffold shapes and the poor treatment timeliness limit its clinical translational application. In situ printing technology that prints bioregenerants directly inside patient's body can meet the needs of specific tissue repair. This study develops a smartphone controlled handheld bioprinter for in situ skin wounds dressing. The mini bioprinter can be handheld and placed on any printing surface to create strips, complex patterns, and 3D structures, and can be equipped with microchannel needles to expand functionality. The size of the strips as well as the printing path can be programmed and controlled by the smartphone to ensure the precision of the printed product quality. Furthermore, the device not only allows for smooth switching between different bioinks for printing heterogeneous structure, but also allows for fast and uniform coverage of large wound surfaces. When dealing with complex wounds in vitro & vivo, the printer can effectively fill and precisely close wounds, promoting wound healing. The programmable handheld bioprinter can balance mobility and customizability in the management of skin wounds and is expected to realize its potential for emergency medical treatment in condition‐constrained scenarios, such as battlefields or disaster areas.

Fibrosis is the outcome of any abnormal tissue repair process that results in normal tissue replacement with scar tissue, leading to persistent tissue damage and cellular injury. During the process of fibrosis, many cytokines and chemokines are involved, and their activities are controlled by post-translational modifications, especially SUMOylation and NEDDylation. Both these modifications entail a three-step process of activation, conjugation, and ligation that involves three kinds of enzymes, namely, E1 activating, E2 conjugating, and E3 ligase enzymes. SUMOylation participates in organ fibrosis by modulating FXR, PML, TGF-β receptor I, Sirt3, HIF-1α, and Sirt1, while NEDDylation influences organ fibrosis by regulating cullin3, NIK, SRSF3, and UBE2M. Further investigations exhibit the therapeutic potentials of SUMOylation/NEDDylation activators and inhibitors against organ fibrosis, especially ginkgolic acid in SUMOylation and MLN4924 in NEDDylation. These results demonstrate the therapeutic effects of SUMOylation and NEDDylation against organ fibrosis and highlight their activators as well as inhibitors as potential candidates. In the future, deeper investigations of SUMOylation and NEDDylation are needed to identify novel substrates against organ fibrosis; moreover, clinical investigations are needed to determine the therapeutic effects of their activators and inhibitors that can benefit patients. This review highlights that SUMOylation and NEDDylation function as potential therapeutic targets for organ fibrosis.

Summary: Here, we present a protocol for neonatal intracerebroventricular (ICV) delivery of adeno-associated viral vectors (AAVs), achieving gene therapy for a Rett syndrome mouse model. We describe steps for preparing mouse lines, replacing foster mothers, sex typing, and genotyping. We then detail procedures for ICV delivery and validation through immunofluorescent and immunoblot techniques. This protocol is also applicable to preclinical gene therapy research that targets the neonatal mouse brain for other neurodevelopmental disorders.For complete details on the use and execution of this protocol, please refer to Yang et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

ABSTRACTWe evaluated the vaccine effectiveness (VE) of two doses of recombinant zoster vaccine (RZV) against herpes zoster (HZ) and postherpetic neuralgia (PHN) in Chinese adults at Kaiser Permanente Southern California (KPSC). Chinese KPSC members were identified based on self-reported ethnicity or self-reported preferred spoken/written language. Those aged ≥50 years who received two doses of RZV 4 weeks to ≤ 6 months apart were matched 1:4 to RZV unvaccinated Chinese members and followed through June 2022; second doses were accrued 6/1/2018–12/31/2020. We estimated incidence and adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) comparing outcomes (HZ and PHN). Adjusted VE (%) was calculated as (1−aHR)×100. 3978 RZV vaccinated Chinese members were matched to 15,912 RZV unvaccinated Chinese members. The incidence per 1000 person-years (95% CI) of HZ in the vaccinated group was 1.5 (0.9–2.5) and 10.9 (9.8–12.1) in the unvaccinated group; aHR (95% CI) was 0.12 (0.07–0.21). Adjusted VE (95% CI) was 87.6% (78.9–92.7) against HZ. We identified 0 PHN cases in the vaccinated group and 19 in the unvaccinated group. Among Chinese adults aged ≥50 years, two doses of RZV provided substantial protection against HZ and PHN supporting the real-world effectiveness of the vaccine in this population.

Myocardial ischemia/reperfusion (I/R) injury is exacerbated in diabetic individuals and animal models. We tested whether autophagy is an important cellular determinant of cell death. First, we utilized a cellular model of hypoxia reoxygenation (H/R) in H9c2 cells cultured in low or high glucose (HG) and tested cell death using flow cytometry to detect Annexin-V and propidium iodide, imaging cell viability ReadyProbe and lactate dehydrogenase release. We observed that cell death induced by H/R was enhanced by HG. Kinetic analysis of caspase-3 activity using a fluorescence reporter probe, stable expression of the VC3AI biosensor and western blotting indicated that H/R induced activation of caspase-3 was enhanced by HG. Temporal autophagy flux analysis using DapRed and DalGreen probes indicated an initial increase in response to H/R that was reduced upon prolonged (24h) R. HG suppressed this induction of autophagy. This was verified using LC3 HiBiT reporter assay, tandem-fluorescent LC3, and western blotting. Lysosomal cathepsin activity was also elevated at 6h and suppressed at 24h R. Autophagy-deficient cells were generated via CRISPR-mediated knockout of atg7 and the effect of combined HG and H/R treatment on caspase activation and cell death was elevated in comparison with wild type cells. We then performed coronary artery ligation surgery to induce ischemia, followed by reperfusion, in wild-type or streptozotocin (STZ)-induced hyperglycemic mice. Non-invasive 3-dimensional imaging using fluorescence molecular tomography combined with computerized tomography was employed to monitor spatio-temporal activation of cardiac autophagy and apoptosis. Upon systemic injection of a near infra-red cathepsin activatable probe we found that hyperglycemic mice had lower activity in the infarct region after I/R versus wild type. In parallel, we observed a higher extent of I/R-induced apoptosis, detected with an annexin-V probe, in hyperglycemic mice. Collectively, these results revealed that impaired autophagic flux in the presence of high glucose levels exacerbates I/R injury.Abbreviation: satg7, autophagy-related 7; FMT, fluorescence molecular tomography; HG, high glucose; H/R, hypoxia/reoxygenation; I/R, ischemia/reperfusion; LC3, MAP1LC3; N, normoxia; NG, normal glucose; NIR, near-infrared; p62, SQSTM1; STZ, streptozotocin.

Diabetic nephropathy (DN) is one of the most serious and frequent complications among diabetes patients and presently constitutes vast the cases of end-stage renal disease worldwide. Tubulointerstitial fibrosis is a crucial factor related to the occurrence and progression of DN. Oridonin (Ori) is a diterpenoid derived from rubescens that has diverse pharmacological properties. Our previous study showed that Ori can protect against DN by decreasing the inflammatory response. However, whether Ori can alleviate renal fibrosis in DN remains unknown. Here, we investigated the mechanism through which Ori affects the Wnt/β-catenin signaling pathway in diabetic rats and human proximal tubular epithelial cells (HK-2) exposed to high glucose (HG) levels. Our results revealed that Ori treatment markedly decreased urinary protein excretion levels, improved renal function and alleviated renal fibrosis in diabetic rats. In vitro, HG treatment increased the migration of HK-2 cells while reducing their viability and proliferation rate, and treatment with Ori reversed these changes. Additionally, the knockdown of β-catenin arrested cell migration and reduced the expression levels of Wnt/β-catenin signaling-related molecules (Wnt4, p-GSK3β and β-catenin) and fibrosis-related molecules (α-smooth muscle actin, collagen I and fibronectin), and Ori treatment exerted an effect similar to that observed after the knockdown of β-catenin. Furthermore, the combination of Ori treatment and β-catenin downregulation exerted more pronounced biological effects than treatment alone. These findings may provide the first line of evidence showing that Ori alleviates fibrosis in DN by inhibiting the Wnt/β-catenin signaling pathway and thereby reveal a novel therapeutic avenue for treating tubulointerstitial fibrosis.

The mechanical properties of soil located at cold areas may be deteriorated under freeze-thaw cycle condition. One-part geopolymer (OPG) is a kind of alkaline-activated material by using industrial by-products and solid alkali. Obviously, OPG can replace ordinary portland cement (OPC) as a soil stabilizer in ground improvement, which presents environmental and low-carbon benefits. The assessment of unconfined compressive strength (UCS) is vital for evaluating OPG-stabilized soil durability under freeze-thaw conditions, typically demanding extensive resources. Leveraging artificial intelligence, a predictive model can be developed for this purpose. This study collected a small sample size of 216 data points of the OPG-stabilized soil's freeze-thaw behaviour. Three deep learning (DL) models, Backpropagation Neural Network [BPNN], Convolutional Neural Network [CNN], Gated Recurrent Unit [GRU], were trained on the small dataset to predict freeze-thaw performance efficiently, offering a promising approach to streamline assessment processes. In the DL models, the ratio of fly ash (FA) and ground granulated blast furnace slag (GGBFS), freezing temperature and freeze-thaw cycle were taken as the input variables, and the target output was the UCS of the OPG-stabilized soil. Among all the models, the CNN achieved the highest prediction accuracy with R2 of 0.9966, and followed by the BPNN (R2=0.9893) and the GRU (R2=0.9872). After that, the interpretable machine learning methods (i.e., Shapley Additive Explanation [SHAP] and Partial Dependence Plot [PDP]) were utilized for the developed CNN model to further understand the impact of input variables on the outcome predictions. In addition, the morphological analysis was used to verify the freeze-thaw mechanism of the OPG-stabilized soil derived from the interpretable CNN model. It is revealed that the inclusion of FA in the OPG crucially enhanced the freeze-thaw resistance of the OPG-stabilized soil. However, beyond a certain threshold, the addition of FA negatively impacted the freeze-thaw resistance of OPG-stabilized soil. Freezing temperature was pinpointed as the key factor affecting the properties of the stabilized soil.

With the development of green, low-carbon, and sustainable economic systems, the issues of high pollution and energy consumption in construction materials have become increasingly prominent. This study focuses on adopting one-part geopolymer (OPG) in soil stabilization for underground engineering, which exhibits environmental and low-carbon advantages. The unconfined compressive strength (UCS) serves as a crucial parameter for assessing stabilized soil’s performance. However, it is necessary to conduct a large number of experiments, inducing high costs and time consumption. In this study, one multiple linear regression model, one Decision Tree (DT) model, five ensemble machine learning (ML) models (i.e. Random Forest [RF], Extra Tree [ET], Gradient Boosting [GB], Gradient Boosting Decision Tree [GBDT], and Extreme Gradient Boosting [XGBoost]), and hybrid models of those single ensemble models with Particle Swarm Optimization (PSO) (i.e. PSO-RF, PSO-ET, PSO-GB, PSO-GBDT, and PSO-XGBoost) were adopted and compared to achieve better prediction on the UCS of the OPG-stabilized soil. Furthermore, the interpretable method including SHAP and PDP (1D and 2D), was employed to investigate the precise mechanisms by which input parameters influenced the output label. The results revealed that the multiple linear regression model delivered the lowest accuracy, and PSO-XGBoost and PSO-ET exhibited the best performance on the prediction of the UCS with R2 value of 0.9964 and 0.9928, respectively. In addition, Curing time exerted the most significant impact on the UCS, followed by FA/GGBFS, Molarity, Water/Binder, and NaOH/Precursor. Compared to the SHAP method, the PDP offered a more intuitive approach to reveal the relationship between the inputs and output. The outcome of the study shed new light on the application of ML models in the prediction of the OPG-stabilized soil’s performance in underground engineering.