A natural agent, 5-deoxycajanin, mitigates estrogen-deficiency bone loss via modulating osteoclast-osteoblast homeostasis.

Hyperactive osteoclasts and hypoactive osteoblasts usually result in osteolytic conditions such as estrogen-deficiency bone loss. Few natural compounds that both attenuating bone resorption and enhancing bone formation could exert effects on this imbalance. 5-Deoxycajanin (5-D), an isoflavonoid extracted from Cajan leaf with estrogen-like properties, were found to have beneficial pharmacological effects on rebalancing the activities of osteoclasts and osteoblasts. This study revealed that 5-D at the same concentration could inhibit osteoclastogenesis of BMMs and promoted osteoblast differentiation of BMSCs. 5-D not only attenuated the fluorescent formation of RANKL-induced F-actin belts and NFATc1, but also activated ALP and RUNX2 expressions. As to downstream factor expressions, 5-D could block osteoclast-specific genes and proteins including NFATc1 and CTSK, while increased osteogenic genes and proteins including OPG and OCN, as confirmed by Real-time PCR and Western Blotting. Additionally, the network pharmacology and molecular docking identified the involvement of 5-D in the MIF and MAPK signaling pathways and the stable binding between 5-D and MAPK2K1. Further Western blot studies showed that 5-D decreased the phosphorylation of p38 and ERK in osteoclasts, but promoted these phosphorylations in osteoblasts. In a female C57BL/6J mouse model of estrogen deficiency-induced bone loss, 5-D demonstrated efficacy in enhancing BMD through attenuating osteoclast activities and promoting osteogenesis. These results underscore the potential application of 5-D on treating osteolysis resulting from hyperactive osteoclasts and hypoactive osteoblasts, shedding light on modulating osteoclast-osteoblast homeostasis.

Retinal Arterial Macroaneurysm Combined with Branch Retinal Artery Occlusion: Literature Review.

PURPOSE: Summarizing the causes of retinal arterial microaneurysm (RAM) combined with branch retinal artery occlusion (BRAO). METHODS: The case reports of RAM combined with BRAO were searched in PubMed, Web of Science, and CNKI databases before May 1, 2024. A total of 9 participants from 9 case reports were included to analyze factors leading to complications. RESULTS: The reasons for this complication are as follows: complications during photocoagulation therapy. Intraretinal hemorrhage and exudation result in compression of adjacent or distal arteries, resulting in BRAO. Embolus dislodgement or intra-arterial embolus formation can block the artery, damage the wall, and provide conditions for the development of RAM. In addition, it is necessary to be alert to the optic-disc macroaneurysm, if hemorrhage or embolus formation in the macroaneurysm will affect the blood supply of the downstream artery, affecting a large range of the retina. CONCLUSIONS: Based on the review of case reports, we found that RAM and BRAO can cause each other. Acute vision loss can result when a complication occurs. In addition, retinal vascular diseases can reflect the whole body, suggesting that ophthalmologists need to pay attention not only to the patient's fundus but also to the patient's systemic diseases.

The Multi-Functional Third Acceptor Realizes the Synergistic Improvement in Photovoltaic Parameters and the High-Ratio Tolerance of Ternary Organic Photovoltaics.

The ternary strategy proves effective for breakthroughs in organic photovoltaics (OPVs). Elevating three photovoltaic parameters synergistically, especially the proportion-insensitive third component, is crucial for efficient ternary devices. This work introduces a molecular design strategy by comprehensively analyzing asymmetric end groups, side-chain engineering, and halogenation to explore the outstanding optoelectronic properties of the proportion-insensitive third component in efficient ternary systems. Three asymmetric non-fullerene acceptors (BTP-SA1, BTP-SA2, and BTP-SA3) are synthesized based on the Y6 framework and incorporated as the third component into the D18:Y6 binary system. BTP-SA3, featuring asymmetric terminal (difluoro-indone and dichloride-cyanoindone terminal), with branched alkyl side chains, exhibited high open-circuit voltage (VOC), balanced crystallinity and compatibility, achieving synergistic enhancements in VOC (0.862 V), short circuit-current density (JSC, 27.52 mA cm-2), fill fact (FF, 81.01%), and power convert efficiency (PCE, 19.19%). Device based on D18/Y6:BTP-SA3 (layer-by-layer processed) reached a high efficiency of 19.36%, demonstrating a high tolerance for BTP-SA3 (10-50%). This work provides novel insights into optimizing OPVs performances in multi-component systems and designing components with enhanced tolerance.

Low-dose ionizing radiation-induced RET/PTC1 rearrangement via the non-homologous end joining pathway to drive thyroid cancer.

Thyroid cancer incidence increases worldwide annually, primarily due to factors such as ionizing radiation (IR), iodine intake, and genetics. Papillary carcinoma of the thyroid (PTC) accounts for about 80% of thyroid cancer cases. RET/PTC1 (coiled-coil domain containing 6 [CCDC6]-rearranged during transfection) rearrangement is a distinctive feature in over 70% of thyroid cancers who exposed to low doses of IR in Chernobyl and Hiroshima‒Nagasaki atomic bombings. This study aims to elucidate mechanism between RET/PTC1 rearrangement and IR in PTC. N-thy-ori-3-1 cells were subjected to varying doses of IR (2/1/0.5/0.2/0.1/0.05 Gy) of IR at different days, and result showed low-dose IR-induced RET/PTC1 rearrangement in a dose-dependent manner. RET/PTC1 has been observed to promote PTC both in vivo and in vitro. To delineate the role of different DNA repair pathways, SCR7, RI-1, and Olaparib were employed to inhibit non-homologous end joining (NHEJ), homologous recombination (HR), and microhomology-mediated end joining (MMEJ), respectively. Notably, inhibiting NHEJ enhanced HR repair efficiency and reduced IR-induced RET/PTC1 rearrangement. Conversely, inhibiting HR increased NHEJ repair efficiency and subsequent RET/PTC1 rearrangement. The MMEJ did not show a markable role in this progress. Additionally, inhibiting DNA-dependent protein kinase catalytic subunit (DNA-PKcs) decreased the efficiency of NHEJ and thus reduced IR-induced RET/PTC1 rearrangement. To conclude, the data suggest that NHEJ, rather than HR or MMEJ, is the critical cause of IR-induced RET/PTC1 rearrangement. Targeting DNA-PKcs to inhibit the NHEJ has emerged as a promising therapeutic strategy for addressing IR-induced RET/PTC1 rearrangement in PTC.

Growth, fusion and degradation of lipid droplets: advances in lipid droplet regulatory protein.

Context: An adequate supply of energy is essential for the proper functioning of all life activities in living organisms. As organelles that store neutral lipids, lipid droplets (LDs) are involved in the synthesis and metabolism of lipids in cells and are also an important source of energy supply.Methods and mechanisms: A comprehensive summary of the literature was first carried out to screen for relevant proteins affecting the morphological size of LDs.The size of milk fat globules (MFGs) is directly influenced by the morphological size of LDs, which also controls the energy storage capacity of LDs. In this review, we detail the progress of research into the role of some protein in regulating the morphological size of LDs.Conclusion: It has been discovered that the number of protein are involved in the control of LD growth and degradation, such as Rab18-mediated local synthesis of triacylglycerol (TAG), cell death-inducing DFF45-like effector family proteins (CIDEs)-mediated atypical fusion between LDs, Stomatin protein-mediated LD fusion and autophagy-related proteins (ATGs)-mediated autophagic degradation of LDs. However, more studies are needed in the future to enrich the network of mechanisms that regulate the morphological size of LDs.

TNKS1BP1 mediates AECII senescence and radiation induced lung injury through suppressing EEF2 degradation.

BACKGROUND: Although recent studies provide mechanistic understanding to the pathogenesis of radiation induced lung injury (RILI), rare therapeutics show definitive promise for treating this disease. Type II alveolar epithelial cells (AECII) injury in various manner results in an inflammation response to initiate RILI. RESULTS: Here, we reported that radiation (IR) up-regulated the TNKS1BP1, causing progressive accumulation of the cellular senescence by up-regulating EEF2 in AECII and lung tissue of RILI mice. Senescent AECII induced Senescence-Associated Secretory Phenotype (SASP), consequently activating fibroblasts and macrophages to promote RILI development. In response to IR, elevated TNKS1BP1 interacted with and decreased CNOT4 to suppress EEF2 degradation. Ectopic expression of EEF2 accelerated AECII senescence. Using a model system of TNKS1BP1 knockout (KO) mice, we demonstrated that TNKS1BP1 KO prevents IR-induced lung tissue senescence and RILI. CONCLUSIONS: Notably, this study suggested that a regulatory mechanism of the TNKS1BP1/CNOT4/EEF2 axis in AECII senescence may be a potential strategy for RILI.

Multi-grained contrastive representation learning for label-efficient lesion segmentation and onset time classification of acute ischemic stroke.

Ischemic lesion segmentation and the time since stroke (TSS) onset classification from paired multi-modal MRI imaging of unwitnessed acute ischemic stroke (AIS) patients is crucial, which supports tissue plasminogen activator (tPA) thrombolysis decision-making. Deep learning methods demonstrate superiority in TSS classification. However, they often overfit task-irrelevant features due to insufficient paired labeled data, resulting in poor generalization. We observed that unpaired data are readily available and inherently carry task-relevant cues, but are less often considered and explored. Based on this, in this paper, we propose to fully excavate the potential of unpaired unlabeled data and use them to facilitate the downstream AIS analysis task. We first analyze the utility of features at the varied grain and propose a multi-grained contrastive learning (MGCL) framework to learn task-related prior representations from both coarse-grained and fine-grained levels. The former can learn global prior representations to enhance the location ability for the ischemic lesions and perceive the healthy surroundings, while the latter can learn local prior representations to enhance the perception ability for semantic relation between the ischemic lesion and other health regions. To better transfer and utilize the learned task-related representation, we designed a novel multi-task framework to simultaneously achieve ischemic lesion segmentation and TSS classification with limited labeled data. In addition, a multi-modal region-related feature fusion module is proposed to enable the feature correlation and synergy between multi-modal deep image features for more accurate TSS decision-making. Extensive experiments on the large-scale multi-center MRI dataset demonstrate the superiority of the proposed framework. Therefore, it is promising that it helps better stroke evaluation and treatment decision-making.

Sulfonic Acid-Functionalized Tetraphenylethylene-Amplified Electrochemiluminescence by Regulating π-π Interaction.

The electrochemiluminescence (ECL) effectiveness of the tris(bipyridine) ruthenium(II) (Ru(bpy)32+) system is hampered by aggregation-caused quenching (ACQ) in optoelectronic systems as a result of π-π accumulation of the aromatic ring structure. In this work, a negatively charged tetraphenylvinyl molecule (TPE-2SO3Na, TPE-4SO3Na) was synthesized to modify the electrode interface, and the π-π accumulation between Ru(bpy)32+ molecules was transformed into the π-π interaction between Ru(bpy)32+ and TPE molecules. Interestingly, the ECL signal intensity of the Ru(bpy)32+-tripropylamine (TPA) system in the presence of TPE-2SO3Na was increased by about 15 times due to the π-π action and electrostatic action. In comparison with traditional physical packaging with porous zeolites, metal-organic frameworks (MOFs), and covalent organic frameworks (COFs), the fabricated electrode interface modification strategy was simple and efficient to avoid π-π accumulation in aqueous solutions. Our success will inspire other researchers to investigate the supramolecular interaction (π-π interaction, electrostatic interaction, hydrophilic interaction, and host-guest interaction) at the electrode interface to amplify the ECL intensities of Ru(bpy)32+.

Analysis revealed the molecular mechanism of oxidative stress-autophagy-induced liver injury caused by high alkalinity: integrated whole hepatic transcriptome and metabolome.

Introduction: High-alkalinity water is a serious health hazard for fish and can cause oxidative stress and metabolic dysregulation in fish livers. However, the molecular mechanism of liver damage caused by high alkalinity in fish is unclear. Methods: In this study, 180 carp were randomly divided into a control (C) group and a high-alkalinity (A25) group and were cultured for 56 days. High-alkalinity-induced liver injury was analysed using histopathological, whole-transcriptome, and metabolomic analyses. Results: Many autophagic bodies and abundant mitochondrial membrane damage were observed in the A25 group. High alkalinity decreased superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activity and the total antioxidant capacity (T-AOC) and increased the malondialdehyde (MDA) content in liver tissues, causing oxidative stress in the liver. Transcriptome analysis revealed 61 differentially expressed microRNAs (miRNAs) and 4008 differentially expressed mRNAs. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that mammalian target of rapamycin (mTOR), forkhead box O (FoxO), mitogen-activated protein kinase (MAPK), and the autophagy signalling pathway were the molecular mechanisms involved. High alkalinity causes oxidative stress and autophagy and results in autophagic damage in the liver. Bioinformatic predictions indicated that Unc-51 Like Kinase 2 (ULK2) was a potential target gene for miR-140-5p, demonstrating that high alkalinity triggered autophagy through the miR-140-5p-ULK2 axis. Metabolomic analysis revealed that the concentrations of cortisol 21-sulfate and beta-aminopropionitrile were significantly increased, while those of creatine and uracil were significantly decreased. Discussion: The effects of high alkalinity on oxidative stress and autophagy injury in the liver were analysed using whole-transcriptome miRNA-mRNA networks and metabolomics approaches. Our study provides new insights into liver injury caused by highly alkaline water.

Solar-driven water evaporation using a collaborative photothermal conversion material system based on carbonized waste polyphenylene sulfide and copper sulfide.

Recently, water resources have become scarce due to the growing global population and human impact on the environment, coupled with the effects of climate change. For solving the problem of global freshwater shortage and increasing the value of discarded polyphenylene sulfide (PPS) filter bags, in this study, balsa wood was used as the base of a photothermal solar evaporator, chitosan solution was used as the binder, and the main photothermal conversion materials used were polyphenylene sulfide (CP) carbide and copper sulfide. In order to create synergistic photothermal conversion materials, freeze-drying and in situ precipitation were used to deposit the photothermal conversion materials on top of the balsa wood. The prepared CP/CuS-wood evaporator has excellent water evaporation performance and light conversion capability, with a water evaporation rate of 2.68 kg m-2 h-1 and a photothermal conversion efficiency of 93.2% under simulated one solar intensity irradiation. In addition, the evaporator can effectively remove organic dyes such as methylene blue and methyl orange. The evaporator's durability and seawater desalination capability have also been confirmed through seawater desalination experiments and outdoor tests. Studies have shown that solar interface photothermal evaporators are a viable solution for desalination and wastewater treatment. This eco-friendly, economically viable and stable photothermal evaporator mentioned in this paper has pioneering features and will be a new paradigm for desalination and wastewater treatment.

Synergistic effects of oxygen vacancies and mesoporous structures in amorphous C@TiO2 for photocatalytic CO2 reduction.

In this study, the theoretical calculations proves that the combination of oxygen vacancy and amorphous carbon films in TiO2 (VO-CT) can effectively reduce the energy bandgap and work function. The minimum Gibbs free energies required for the CO2RR reaction of VO-CT are 0.20 eV, which is lower than pure TiO2. The amorphous c@TiO2 nanomaterials with oxygen vacancy and mesoporous structures (VO-MCT) are prepared with the P123 surfactant as the template and oxalic acid as an inducer. The electron paramagnetic resonance indicates the presence of abundant oxygen vacancy defects in the samples. UV-vis spectra indicate that the mesoporous structure enhances light absorption capacity. The photocatalytic CO2 reduction tests show that the highest conversion rates for CH4 and CO of VO-MCT are 14 µmol g-1 h-1 and 10.66 µmol g-1 h-1, respectively. The electron consumption rate of VO-MCT is 12.43 times higher than that of commercial TiO2 (P200).

Case report: A case report of co-morbidity of cervical intraepithelial neoplasia III and urethral cancer associated with HPV16.

In this report, we present a case of a woman with concurrent cervical intraepithelial neoplasia grade III (CIN III) and urethral cancer, both associated with HPV16 infection. This unique case was initially brought to attention due to postmenopausal vaginal bleeding, despite the absence of urological symptoms and negative tumor markers. An unexpected discovery of pelvic lymph node metastasis during a hysterectomy intended for CIN III highlighted the rare coexistence of these conditions, with urethral cancer also linked to HPV-16 within the urethral lesion. This case emphasizes the diagnostic challenges faced by HPV-related cervical lesions and the critical need for increased vigilance, even when urological symptoms are not apparent. The findings underline the potential complexity of HPV-associated lesions and advocate for comprehensive screening strategies to ensure the timely detection and management of such intricate cases.

Decrotonylation of cGAS K254 prompts homologous recombination repair by blocking its DNA binding and releasing PARP1.

Cyclic GMP-AMP synthase (cGAS), a cytosolic DNA sensor, also exhibits nuclear genomic localization and is involved in DNA damage signaling. In this study, we investigated the impact of cGAS crotonylation on the regulation of the DNA damage response, particularly homologous recombination repair, following exposure to ionizing radiation (IR). Lysine 254 of cGAS is constitutively crotonylated by the CREB-binding protein; however, IR-induced DNA damage triggers sirtuin 3 (SIRT3)-mediated decrotonylation. Lysine 254 decrotonylation decreased the DNA-binding affinity of cGAS and inhibited its interaction with PARP1, promoting homologous recombination repair. Moreover, SIRT3 suppression led to homologous recombination repair inhibition and markedly sensitized cancer cells to IR and DNA-damaging chemicals, highlighting SIRT3 as a potential target for cancer therapy. Overall, this study revealed the crucial role of cGAS crotonylation in the DNA damage response. Furthermore, we propose that modulating cGAS and SIRT3 activities could be potential strategies for cancer therapy.

Nationwide trends and features of human salmonellosis outbreaks in China.

Salmonellosis is one of the most common causes of diarrhea, affecting 1/10 of the global population. Salmonellosis outbreaks (SO) pose a severe threat to the healthcare systems of developing regions. To elucidate the patterns of SO in China, we conducted a systematic review and meta-analysis encompassing 1,134 reports across 74 years, involving 89,050 patients and 270 deaths. A rising trend of SO reports has been observed since the 1970s, with most outbreaks occurring east of the Hu line, especially in coastal and populated regions. It is estimated to have an overall attack rate of 36.66% (95% CI, 33.88-39.45%), and antimicrobial resistance towards quinolone (49.51%) and beta-lactam (73.76%) remains high. Furthermore, we developed an online website, the Chinese Salmonellosis Outbreak Database (CSOD), for visual presentation and data-sharing purposes. This study indicated that healthcare-associated SO required further attention, and our study served as a foundational step in pursuing outbreak intervention and prediction.

Pathological Asymmetry-Guided Progressive Learning for Acute Ischemic Stroke Infarct Segmentation.

Quantitative infarct estimation is crucial for diagnosis, treatment and prognosis in acute ischemic stroke (AIS) patients. As the early changes of ischemic tissue are subtle and easily confounded by normal brain tissue, it remains a very challenging task. However, existing methods often ignore or confuse the contribution of different types of anatomical asymmetry caused by intrinsic and pathological changes to segmentation. Further, inefficient domain knowledge utilization leads to mis-segmentation for AIS infarcts. Inspired by this idea, we propose a pathological asymmetry-guided progressive learning (PAPL) method for AIS infarct segmentation. PAPL mimics the step-by-step learning patterns observed in humans, including three progressive stages: knowledge preparation stage, formal learning stage, and examination improvement stage. First, knowledge preparation stage accumulates the preparatory domain knowledge of the infarct segmentation task, helping to learn domain-specific knowledge representations to enhance the discriminative ability for pathological asymmetries by constructed contrastive learning task. Then, formal learning stage efficiently performs end-to-end training guided by learned knowledge representations, in which the designed feature compensation module (FCM) can leverage the anatomy similarity between adjacent slices from the volumetric medical image to help aggregate rich anatomical context information. Finally, examination improvement stage encourages improving the infarct prediction from the previous stage, where the proposed perception refinement strategy (RPRS) further exploits the bilateral difference comparison to correct the mis-segmentation infarct regions by adaptively regional shrink and expansion. Extensive experiments on public and in-house NCCT datasets demonstrated the superiority of the proposed PAPL, which is promising to help better stroke evaluation and treatment.

Environmental endocrine disrupting chemical 4-tert-butylphenol induced calcium overload and subsequent autophagy impairment via miRNA-363/CACNA1D Axis in epithelioma papulosum cyprini cells.

Environmental endocrine disrupting chemical 4-tert-butylphenol (4-tBP), a widely-utilized surfactant in various industries, poses potential risks to aquatic organisms. Our previous sequencing results suggested that 4-tBP-induced common carp liver injury might be associated with Ca2+ signaling and autophagy. However, the intricate involvement of these pathways in 4-tBP-induced cytotoxic mechanisms remained unexplored. To bridge these knowledge gaps, this study focused on epithelioma papulosum cyprini (EPC) cells, a significant cell type in fish biology. Initial observations showed that 4-tBP induced a dose-dependent perturbation in Ca2+ levels. Further investigations, with siRNA and L-type Ca2+ channel agonist (BAYK8644), identified L-type calcium channel gene CACNA1D as a critical regulator of 4-tBP-induced Ca2+ overload. Predictive analysis using miRanda platform suggested a potential interaction between miR-363 and CACNA1D, which was subsequently verified through dual-luciferase reporter gene assays. We then established miR-363 mimic/inhibitor models, along with miR-363 and CACNA1D co-suppression models in EPC cells. Through TEM observation, immunofluorescence assay, Ca2+ staining, and qRT-PCR analysis, we evaluated the role of miR-363/CACNA1D axis in modulating the effects of 4-tBP on Ca2+ signaling and autophagy. Results showed that miR-363 inhibitor exacerbated 4-tBP-induced increase in CALM2, CAMKII, Calpain2, and p62 expression and also led to decrease in ATG5, ATG7, and LC3b expression. In contrast, miR-363 mimic notably alleviated these changes. Notably, siRNA CACNA1D effectively modulating miR-363 inhibitor's effect. Our study revealed that 4-tBP induced Ca2+ overload and subsequent autophagy impairment via miR-363/CACNA1D axis. These findings illuminated a profound understanding of molecular mechanisms underlying 4-tBP-induced cytotoxicity and spotlighted a potential therapeutic target.

Stigmasterol Activates the mTOR Signaling Pathway by Inhibiting ORP5 Ubiquitination to Promote Milk Synthesis in Bovine Mammary Epithelial Cells.

Stigmasterol (ST), a phytosterol found in food, has various biological activities. However, the effect of ST on milk synthesis in dairy cows remains unclear. Therefore, bovine primary mammary epithelial cells (BMECs) were isolated, cultured, and treated with ST to determine the effect of ST on milk synthesis. The study revealed that 10 µM ST significantly increased milk synthesis in BMECs by activating the mammalian target of rapamycin (mTOR) signaling pathway. Further investigation revealed that this activation depends on the regulatory role of oxysterol binding protein 5 (ORP5). ST induces the translocation of ORP5 from the cytoplasm to the lysosome, interacts with the mTOR, recruits mTOR to target the lysosomal surface, and promotes the activation of the mTOR signaling pathway. Moreover, ST was found to increase ORP5 protein levels by inhibiting its degradation via the ubiquitin-proteasome pathway. Specifically, the E3 ubiquitin ligase membrane-associated cycle-CH-type finger 4 (MARCH4) promotes the ubiquitination and subsequent degradation of ORP5. ST mitigates the interaction between MARCH4 and ORP5, thereby enhancing the structural stability of ORP5 and reducing its ubiquitination. In summary, ST stabilizes ORP5 by inhibiting the interaction between MARCH4 and ORP5, thereby activating mTOR signaling pathway and enhancing milk synthesis.

DNA-PKcs/AKT1 inhibits epithelial-mesenchymal transition during radiation-induced pulmonary fibrosis by inducing ubiquitination and degradation of Twist1.

INTRODUCTION: Radiation-induced pulmonary fibrosis (RIPF) is a chronic, progressive, irreversible lung interstitial disease that develops after radiotherapy. Although several previous studies have focused on the mechanism of epithelial-mesenchymal transition (EMT) in lung epithelial cells, the essential factors involved in this process remain poorly understood. The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) exhibits strong repair capacity when cells undergo radiation-induced damage; whether DNA-PKcs regulates EMT during RIPF remains unclear. OBJECTIVES: To investigate the role and molecular mechanism of DNA-PKcs in RIPF and provide an important theoretical basis for utilising DNA-PKcs-targeted drugs for preventing RIPF. METHODS: DNA-PKcs knockout (DPK-/-) mice were generated via the Cas9/sgRNA technique and subjected to whole chest ionizing radiation (IR) at a 20 Gy dose. Before whole chest IR, the mice were intragastrically administered the DNA-PKcs-targeted drug VND3207. Lung tissues were collected at 1 and 5 months after IR. RESULTS: The expression of DNA-PKcs is low in pulmonary fibrosis (PF) patients. DNA-PKcs deficiency significantly exacerbated RIPF by promoting EMT in lung epithelial cells. Mechanistically, DNA-PKcs deletion by shRNA or inhibitor NU7441 maintained the protein stability of Twist1. Furthermore, AKT1 mediated the interaction between DNA-PKcs and Twist1. High Twist1 expression and EMT-associated changes caused by DNA-PKcs deletion were blocked by insulin-like growth factor-1 (IGF-1), an AKT1 agonist. The radioprotective drug VND3207 prevented IR-induced EMT and alleviated RIPF in mice by stimulating the kinase activity of DNA-PKcs. CONCLUSION: Our study clarified the critical role and mechanism of DNA-PKcs in RIPF and showed that it could be a potential target for preventing RIPF.

Tetrahedral framework nucleic acid-based small-molecule inhibitor delivery for ecological prevention of biofilm.

Biofilm formation constitutes the primary cause of various chronic infections, such as wound infections, gastrointestinal inflammation and dental caries. While preliminary achievement of biofilm inhibition is possible, the challenge lies in the difficulty of eliminating the bactericidal effects of current drugs that lead to microbiota imbalance. This study, utilizing in vitro and in vivo models of dental caries, aims to efficiently inhibit biofilm formation without inducing bactericidal effects, even against pathogenic bacteria. The tetrahedral framework nucleic acid (tFNA) was employed as a delivery vector for a small-molecule inhibitor (smI) specifically targeting the activity of glucosyltransferases C (GtfC). It was observed that tFNA loaded smI in a small-groove binding manner, efficiently transferring it into Streptococcus mutans, thereby inhibiting GtfC activity and extracellular polymeric substances formation without compromising bacterial survival. Furthermore, smI-loaded tFNA demonstrated a reduction in the severity of dental caries in vivo without adversely affecting oral microbial diversity and exhibited desirable topical and systemic biosafety. This study emphasizes the concept of 'ecological prevention of biofilm', which is anticipated to advance the optimization of biofilm prevention strategies and the clinical application of DNA nanocarrier-based drug formulations.

Paracrinal regulation of neutrophil functions by coronaviral infection in iPSC-derived alveolar type II epithelial cells.

Coronaviruses (CoVs) are enveloped single-stranded RNA viruses that predominantly attack the human respiratory system. In recent decades, several deadly human CoVs, including SARS-CoV, SARS-CoV-2, and MERS-CoV, have brought great impact on public health and economics. However, their high infectivity and the demand for high biosafety level facilities restrict the pathogenesis research of CoV infection. Exacerbated inflammatory cell infiltration is associated with poor prognosis in CoV-associated diseases. In this study, we used human CoV 229E (HCoV-229E), a CoV associated with relatively fewer biohazards, to investigate the pathogenesis of CoV infection and the regulation of neutrophil functions by CoV-infected lung cells. Induced pluripotent stem cell (iPSC)-derived alveolar epithelial type II cells (iAECIIs) exhibiting specific biomarkers and phenotypes were employed as an experimental model for CoV infection. After infection, the detection of dsRNA, S, and N proteins validated the infection of iAECIIs with HCoV-229E. The culture medium conditioned by the infected iAECIIs promoted the migration of neutrophils as well as their adhesion to the infected iAECIIs. Cytokine array revealed the elevated secretion of cytokines associated with chemotaxis and adhesion into the conditioned media from the infected iAECIIs. The importance of IL-8 secretion and ICAM-1 expression for neutrophil migration and adhesion, respectively, was demonstrated by using neutralizing antibodies. Moreover, next-generation sequencing analysis of the transcriptome revealed the upregulation of genes associated with cytokine signaling. To summarize, we established an in vitro model of CoV infection that can be applied for the study of the immune system perturbations during severe coronaviral disease.