New eremophilane-type sesquiterpenes from Synotis solidaginea.

Eleven new highly oxygenated eremophilane-type sesquiterpenoids were isolated from the whole plant of Synotis solidaginea, including two pairs of C-8 S/R epimers. The structures of the new compounds were elucidated on the basis of detailed spectroscopic analysis and the absolute configuration of 1 and 9 was confirmed by single-crystal X-ray crystallography using Cu Kα radiation. All the isolates were tested for the inhibition of LPS-stimulated NO production in macrophage-like mouse monocytic leukemia RAW264.7 cells. Compound 1 exhibited weak inhibitory effects with an IC50 of 71.2 µM.

Pulsed Direct Current Arc-Induced Nanoelectrospray Ionization Mass Spectrometry.

This study explores the innovative field of pulsed direct current arc-induced nanoelectrospray ionization mass spectrometry (DCAI-nano-ESI-MS), which utilizes a low-temperature direct current (DC) arc to induce ESI during MS analyses. By employing a 15 kV output voltage, the DCAI-nano-ESI source effectively identifies various biological molecules, including angiotensin II, bradykinin, cytochrome C, and soybean lecithin, showcasing impressive analyte signals and facilitating multicharge MS in positive- and negative-ion modes. Notably, results show that the oxidation of fatty acids using a DC arc produces [M + O - H]- ions, which aid in identifying the location of C═C bonds in unsaturated fatty acids and distinguishing between isomers based on diagnostic ions observed during collision-induced dissociation tandem MS. This study presents an approach for identifying the sn-1 and sn-2 positions in phosphatidylcholine using phosphatidylcholine and nitrate adduct ions, accurately determining phosphatidylcholine molecular configurations via the Paternò-Büchi reaction. With all the advantages above, DCAI-nano-ESI holds significant promise for future analytical and bioanalytical applications.

Comprehensive analysis of phospholipid in milk and their biological roles as nutrients and biomarkers.

Phospholipids (PL) have garnered significant attention due to their physiological activities. Milk and other dairy products are important dietary sources for humans and have been extensively used to analyze the presence of PL by various analytical techniques. In this paper, the analysis techniques of PL were reviewed with the eight trigrams of phospholipidomics and a comprehensive fingerprint of 1295 PLs covering 8 subclasses in milk and other dairy products, especially. Technology is the primary productive force. Based on phospholipidomics technology, we further review the relationship between the composition of PL and factors that may be involved in processing and experimental operation, and emphasized the significance of the biological role played by PL in dietary supplements and biomarkers (production, processing and clinical research), and providing the future research directions.

Dietary lipoic acid alleviates autism-like behavior induced by acrylamide in adolescent mice: the potential involvement of the gut-brain axis.

Consuming fried foods has been associated with an increased susceptibility to mental health disorders. Nevertheless, the impact of alpha-lipoic acid (α-LA, LA) on fried food-induced autism-like behavior remains unclear. This study aimed to explore how LA affects autism-related behavior and cognitive deficits caused by acrylamide in mice, a representative food hazard found in fried foods. This improvement was accomplished by enhanced synaptic plasticity, increased neurotrophin expression, elevated calcium-binding protein D28k, and restored serotonin. Additionally, LA substantially influenced the abundance of bacteria linked to autism and depression, simultaneously boosted short-chain fatty acid (SCFA) levels in fecal samples, and induced changes in serum amino acid concentrations. In summary, these findings suggested that exposure to acrylamide in adolescent mice could induce the development of social disorders in adulthood. LA showed promise as a nutritional intervention strategy to tackle emotional disorders during adolescence.

Evidence for chromium crosses blood brain barrier from the hypothalamus in chromium mice model.

It has been shown that exposure to hexavalent Chromium, Cr (Ⅵ), via nasal cavity can have neurotoxicological effects and induces behavioral impairment due to the fact that blood brain barrier (BBB) does not cover olfactory bulb. But whether Cr (Ⅵ) can cross the BBB and have a toxicological effects in central nervous system (CNS) remains unclear. Therefore, we investigated the effects of Cr (Ⅵ) on mice treated with different concentrations and exposure time (14 days and 28 days) of Cr (Ⅵ) via intraperitoneal injection. Results revealed that Cr accumulated in hypothalamus (HY) in a timely dependent manner. Much more severer neuropathologies was observed in the group of mice exposed to Cr (Ⅵ) for 28 days than that for 14 days. Gliosis, neuronal morphological abnormalities, synaptic degeneration, BBB disruption and neuronal number loss were observed in HY. In terms of mechanism, the Nrf2 related antioxidant stress signaling dysfunction and activated NF-κB related inflammatory pathway were observed in HY of Cr (Ⅵ) intoxication mice. And these neuropathologies and signaling defects appeared in a timely dependent manner. Taking together, we proved that Cr (Ⅵ) can enter HY due to weaker BBB in HY and HY is the most vulnerable CNS region to Cr (Ⅵ) exposure. The concentration of Cr in HY increased along with time. The accumulated Cr in HY can cause BBB disruption, neuronal morphological abnormalities, synaptic degeneration and gliosis through Nrf2 and NF-κB signaling pathway. This finding improves our understanding of the neurological dysfunctions observed in individuals who have occupational exposure to Cr (Ⅵ), and provided potential therapeutic targets to treat neurotoxicological pathologies induced by Cr (Ⅵ).

Hydralazine represses Fpn ubiquitination to rescue injured neurons via competitive binding to UBA52.

A major impedance to neuronal regeneration after peripheral nerve injury (PNI) is the activation of various programmed cell death mechanisms in the dorsal root ganglion. Ferroptosis is a form of programmed cell death distinguished by imbalance in iron and thiol metabolism, leading to lethal lipid peroxidation. However, the molecular mechanisms of ferroptosis in the context of PNI and nerve regeneration remain unclear. Ferroportin (Fpn), the only known mammalian nonheme iron export protein, plays a pivotal part in inhibiting ferroptosis by maintaining intracellular iron homeostasis. Here, we explored in vitro and in vivo the involvement of Fpn in neuronal ferroptosis. We first delineated that reactive oxygen species at the injury site induces neuronal ferroptosis by increasing intracellular iron via accelerated UBA52-driven ubiquitination and degradation of Fpn, and stimulation of lipid peroxidation. Early administration of the potent arterial vasodilator, hydralazine (HYD), decreases the ubiquitination of Fpn after PNI by binding to UBA52, leading to suppression of neuronal cell death and significant acceleration of axon regeneration and motor function recovery. HYD targeting of ferroptosis is a promising strategy for clinical management of PNI.

Planar Cation Passivation on Colloidal Quantum Dots Enables High-Performance 0.35-1.8 µm Broadband TFT Imager.

Solution-processed colloidal quantum dots (CQDs) are promising candidates for broadband photodetectors from visible light to shortwave infrared (SWIR). However, large-size PbS CQDs sensitive to longer SWIR are mainly exposed with nonpolar (100) facets on the surface, which lack robust passivation strategies. Herein, an innovative passivation strategy that employs planar cation, is introduced to enable face-to-face coupling on (100) facets and strengthen halide passivation on (111) facets. The defect density of CQDs film (Eg ≈ 0.74 eV) is reduced from 2.74 × 1015 to 1.04  × 1015 cm-3 , coupled with 0.1 eV reduction in the activation energy of defects. The resultant CQDs photodiodes exhibit a low dark current density of 14 nA cm-2 with a high external quantum efficiency (EQE) of 62%, achieving a linear dynamic range of 98 dB, a -3dB bandwidth of 103 kHz and a detectivity of 4.7 × 1011 Jones. The comprehensive performance of the CQDs photodiodes outperforms previously reported CQDs photodiodes operating at >1.6 µm. By monolithically integrated with thin-film transistor (TFT) readout circuit, the broadband CQDs imager covering 0.35-1.8 µm realizes the functions including silicon wafer perspectivity and material discrimination, showing its potential for wide range of applications.

Predicting radiation pneumonitis in lung cancer: a EUD-based machine learning approach for volumetric modulated arc therapy patients.

Purpose: This study aims to develop an optimal machine learning model that uses lung equivalent uniform dose (lung EUD to predict radiation pneumonitis (RP) occurrence in lung cancer patients treated with volumetric modulated arc therapy (VMAT). Methods: We analyzed a cohort of 77 patients diagnosed with locally advanced squamous cell lung cancer (LASCLC) receiving concurrent chemoradiotherapy with VMAT. Patients were categorized based on the onset of grade II or higher radiation pneumonitis (RP 2+). Dose volume histogram data, extracted from the treatment planning system, were used to compute the lung EUD values for both groups using a specialized numerical analysis code. We identified the parameter α, representing the most significant relative difference in lung EUD between the two groups. The predictive potential of variables for RP2+, including physical dose metrics, lung EUD, normal tissue complication probability (NTCP) from the Lyman-Kutcher-Burman (LKB) model, and lung EUD-calibrated NTCP for affected and whole lung, underwent both univariate and multivariate analyses. Relevant variables were then employed as inputs for machine learning models: multiple logistic regression (MLR), support vector machine (SVM), decision tree (DT), and K-nearest neighbor (KNN). Each model's performance was gauged using the area under the curve (AUC), determining the best-performing model. Results: The optimal α-value for lung EUD was 0.3, maximizing the relative lung EUD difference between the RP 2+ and non-RP 2+ groups. A strong correlation coefficient of 0.929 (P< 0.01) was observed between lung EUD (α = 0.3) and physical dose metrics. When examining predictive capabilities, lung EUD-based NTCP for the affected lung (AUC: 0.862) and whole lung (AUC: 0.815) surpassed LKB-based NTCP for the respective lungs. The decision tree (DT) model using lung EUD-based predictors emerged as the superior model, achieving an AUC of 0.98 in both training and validation datasets. Discussions: The likelihood of developing RP 2+ has shown a significant correlation with the advancements in RT technology. From traditional 3-D conformal RT, lung cancer treatment methodologies have transitioned to sophisticated techniques like static IMRT. Accurately deriving such a dose-effect relationship through NTCP modeling of RP incidence is statistically challenging due to the increased number of degrees-of-freedom. To the best of our knowledge, many studies have not clarified the rationale behind setting the α-value to 0.99 or 1, despite the closely aligned calculated lung EUD and lung mean dose MLD. Perfect independence among variables is rarely achievable in real-world scenarios. Four prominent machine learning algorithms were used to devise our prediction models. The inclusion of lung EUD-based factors substantially enhanced their predictive performance for RP 2+. Our results advocate for the decision tree model with lung EUD-based predictors as the optimal prediction tool for VMAT-treated lung cancer patients. Which could replace conventional dosimetric parameters, potentially simplifying complex neural network structures in prediction models.

IRF3 activates RB to authorize cGAS-STING-induced senescence and mitigate liver fibrosis.

Cytosolic double-stranded DNA surveillance by cyclic GMP-AMP synthase (cGAS)-Stimulator of Interferon Genes (STING) signaling triggers cellular senescence, autophagy, biased mRNA translation, and interferon-mediated immune responses. However, detailed mechanisms and physiological relevance of STING-induced senescence are not fully understood. Here, we unexpectedly found that interferon regulatory factor 3 (IRF3), activated during innate DNA sensing, forms substantial endogenous complexes in the nucleus with retinoblastoma (RB), a key cell cycle regulator. The IRF3-RB interaction attenuates cyclin-dependent kinase 4/6 (CDK4/6)-mediated RB hyperphosphorylation that mobilizes RB to deactivate E2 family (E2F) transcription factors, thereby driving cells into senescence. STING-IRF3-RB signaling plays a notable role in hepatic stellate cells (HSCs) within various murine models, pushing activated HSCs toward senescence. Accordingly, IRF3 global knockout or conditional deletion in HSCs aggravated liver fibrosis, a process mitigated by the CDK4/6 inhibitor. These findings underscore a straightforward yet vital mechanism of cGAS-STING signaling in inducing cellular senescence and unveil its unexpected biology in limiting liver fibrosis.

Association of GAL-8 promoter methylation levels with coronary plaque inflammation.

BACKGROUND AND AIMS: Coronary heart disease (CHD) is a condition that carries a high risk of mortality and is associated with aging. CHD is characterized by the chronic inflammatory response of the coronary intima. Recent studies have shown that the methylation level of blood mononuclear cell DNA is closely associated with adverse events in CHD, but the roles and mechanisms of DNA methylation in CHD remain elusive. METHODS AND RESULTS: In this study, the DNA methylation status within the epigenome of human coronary tissue in the sudden coronary death (SCD) group and control (CON) group of coronary heart disease was analyzed using the Illumina® Infinium Methylation EPIC BeadChip (850 K chip), resulting in the identification of a total of 2553 differentially methylated genes (DMGs). The differentially methylated genes were then subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and significant differential DNA methylation was found. Among the differentially hypomethylated genes were GAL-8, LTF, and RFPL3, while the highly methylated genes were TMEM9B, ANK3, and C6orF48. These genes were mainly enriched in 10 significantly enriched pathways, such as cell adhesion junctions, among which the differentially methylated gene GAL-8 was involved in inflammatory pathway signaling. For functional analysis of GAL-8, we first examined the differences in GAL-8 promoter methylation levels among different subgroups of human coronary tissue in the CON, CHD, and SCD groups using pyrophosphate sequencing. The results revealed reduced GAL-8 promoter methylation levels in the SCD group, while the difference between the CHD and CON groups was not statistically significant (P > 0.05). The reduced GAL-8 promoter methylation level was associated with upregulated GAL-8 expression, which led to increased expression of the inflammatory markers TNF-α, IL-1ß, MCP-1, MIP-2, MMP-2, and MMP-9. This enhanced inflammatory response contributed to the accumulation of foam cells, thickening of the intima of human coronary arteries, and increased luminal stenosis, which promoted the occurrence of sudden coronary death. Next, we found that GAL-8 promoter methylation levels in PBMC were consistent with human coronary tissue. The unstable angina group (UAP) had significantly lower GAL-8 promoter methylation levels than stable angina (SAP) and healthy controls (CON) (P < 0.05), and there was a significant correlation between reduced GAL-8 promoter methylation levels and risk factors for coronary heart disease. These findings highlight the association between decreased GAL-8 promoter methylation and the presence of coronary heart disease risk factors. ROC curve analysis suggests that methylation of the GAL 8 promoter region is an independent risk factor for CHD. In conclusion, our study confirmed differential expression of GAL-8, LTF, MUC4D, TMEM9B, MYOM2, and ANK3 genes due to DNA methylation in the SCD group. We also established the consistency of GAL-8 promoter methylation alterations between human coronary tissue and patient peripheral blood monocytes. The decreased methylation level of the GAL-8 promoter may be related to the increased expression of GAL-8 and the coronary risk factors. CONCLUSIONS: Accordingly, we hypothesized that reduced levels of GAL-8 promoter methylation may be an independent risk factor for adverse events in coronary heart disease.

Innate immune sensing of lysosomal dysfunction drives multiple lysosomal storage disorders.

Lysosomal storage disorders (LSDs), which are characterized by genetic and metabolic lysosomal dysfunctions, constitute over 60 degenerative diseases with considerable health and economic burdens. However, the mechanisms driving the progressive death of functional cells due to lysosomal defects remain incompletely understood, and broad-spectrum therapeutics against LSDs are lacking. Here, we found that various gene abnormalities that cause LSDs, including Hexb, Gla, Npc1, Ctsd and Gba, all shared mutual properties to robustly autoactivate neuron-intrinsic cGAS-STING signalling, driving neuronal death and disease progression. This signalling was triggered by excessive cytoplasmic congregation of the dsDNA and DNA sensor cGAS in neurons. Genetic ablation of cGAS or STING, digestion of neuronal cytosolic dsDNA by DNase, and repair of neuronal lysosomal dysfunction alleviated symptoms of Sandhoff disease, Fabry disease and Niemann-Pick disease, with substantially reduced neuronal loss. We therefore identify a ubiquitous mechanism mediating the pathogenesis of a variety of LSDs, unveil an inherent connection between lysosomal defects and innate immunity, and suggest a uniform strategy for curing LSDs.

Multifunctional nanozymes for disease diagnosis and therapy.

The development of nanotechnology has brought about groundbreaking advancements in diseases' diagnostics and therapeutics. Among them, multifunctional nanomaterials with enzyme-like activities (i.e., nanozymes) featured with high stability, large surface area for bioconjugation, and easy storage, offer unprecedented opportunities for disease diagnostics and treatment. Recent years have witnessed the great progress of nanozyme-based theranostics. To highlight these achievements, this review first introduces the recent advancements on nanozymes in biosensing and diagnostics. Then, it summarizes the applications of nanozymes in therapeutics including anti-tumor and antibacterial treatment, anti-inflammatory treatment, and other diseases treatment. In addition, several targeted strategies to improve the therapeutic efficacy of nanozyme are discussed. Finally, the opportunities and challenges in the field of diagnosis and therapy are summarized.

Development and Application of a Comprehensive Nontargeted Screening Strategy for Aristolochic Acid Analogues.

Aristolochic acid analogs (AAAs) are naturally occurring carcinogenic and toxic compounds that pose a safety threat to pharmaceuticals and the environment. It is challenging to screen AAAs due to their lack of characteristic mass spectral fragmentation and their presence of structural diversity. A comprehensive nontargeted screening strategy was proposed by taking into account diverse factors and incorporating various self-developed techniques, and a Python3-based toolkit called AAAs_finder was developed for its implementation. The main procedures consist of virtual structure and ultraviolet and visible (UV) spectra database creation, exact mass and UV spectra-based suspect data extraction, tandem mass spectra (MS/MS) anthropomorphic interpretation, and multicondition retention time (RT) prediction-based candidate structures ranking. To initially assess screening feasibility, eight hypothetical unknown samples were subjected to nontargeted screening using the AAAs_finder toolkit and two other advanced tools. The results showed that the former successfully identified all, while the latter two only managed to identify two and three, respectively, indicating that our strategy was more feasible. After that, the strategy was carefully evaluated for false positives and false negatives, instrument dependence, reproducibility, and sensitivity. After the evaluation, the strategy was successfully applied to the screening of AAAs in real samples, such as herbal medicine, spiked soil, and water. Overall, this study proposed a nontargeted screening strategy and toolkit independent of characteristic mass spectral fragmentation and able to overcome challenges posed by structural diversity for the AAAs screening, which is also valuable for other classes of compounds.

Manganese@Albumin Nanocomplex and Its Assembled Nanowire Activate TLR4-Dependent Signaling Cascades of Macrophages.

The immunomodulatory effect of divalent manganese cations (Mn2+ ), such as activation of the cGAS-STING pathway or NLRP3 inflammasomes, positions them as adjuvants for cancer immunotherapy. In this study, it is found that trace Mn2+ ions, bound to bovine serum albumin (BSA) to form Mn@BSA nanocomplexes, stimulate pro-inflammatory responses in human- or murine-derived macrophages through TLR4-mediated signaling cascades. Building on this, the assembly of Mn@BSA nanocomplexes to obtain nanowire structures enables stronger and longer-lasting immunostimulation of macrophages by regulating phagocytosis. Furthermore, Mn@BSA nanocomplexes and their nanowires efficiently activate peritoneal macrophages, reprogramme tumor-associated macrophages, and inhibit the growth of melanoma tumors in vivo. They also show better biosafety for potential clinical applications compared to typical TLR4 agonists such as lipopolysaccharides. Accordingly, the findings provide insights into the mechanism of metalloalbumin complexes as potential TLR agonists that activate macrophage polarization and highlight the importance of their nanostructures in regulating macrophage-mediated innate immunity.

Association between physical activity and diet quality of obese and non-obese MAFLD.

BACKGROUND AND AIM: Clinical data on the prevalence of metabolic-associated fatty liver disease (MAFLD) in obese and non-obese individuals within a diverse US population is scarce. Furthermore, the influence of physical activity (PA) and dietary quality (DQ) on MAFLD risk remains unclear. This study aims to assess the prevalence and clinical features of MAFLD and examine the relationship between PA and DQ with the risk of developing MAFLD. METHODS AND RESULTS: A cross-sectional analysis of data from the 2017-2018 National Health and Nutrition Examination Survey (NHANES) was conducted. The overall MAFLD prevalence was 41.9%, with 28.6% of participants being obese and 13.4% non-obese. Among those with MAFLD, 67.1% (95% confidence interval (CI): 59.1%-75.1%) were obese, and 32.9% (95% CI: 29.1%-36.7%) were non-obese. Non-obese MAFLD was more frequent in Asians (27.2%), while obese MAFLD was more prevalent in Blacks (66.3%). Metabolic comorbidities were more common in individuals with obese MAFLD, who also exhibited more advanced fibrosis. A high-quality diet (HQD) and increased PA were linked to reduced odds of both obese and non-obese MAFLD (odds ratio (OR) and 95% CI: 0.67 [0.51-0.88] and 0.57 [0.47-0.69]; 0.62 [0.43-0.90] and 0.63 [0.46-0.87], respectively). PA and HQD significantly decreased the risk of obese and non-obese MAFLD (OR and 95% CI: 0.46 [0.33-0.64] and 0.42 [0.31-0.57]). CONCLUSION: A substantial proportion of the US population is affected by both obese and non-obese MAFLD. A strong association exists between a lower risk of both types of MAFLD and adherence to an HQD and engagement in PA.

A Novel Superparamagnetic Multifunctional Nerve Scaffold: A Remote Actuation Strategy to Boost In Situ Extracellular Vesicles Production for Enhanced Peripheral Nerve Repair.

Extracellular vesicles (EVs) have inherent advantages over cell-based therapies in regenerative medicine because of their cargos of abundant bioactive cues. Several strategies are proposed to tune EVs production in vitro. However, it remains a challenge for manipulation of EVs production in vivo, which poses significant difficulties for EVs-based therapies that aim to promote tissue regeneration, particularly for long-term treatment of diseases like peripheral neuropathy. Herein, a superparamagnetic nanocomposite scaffold capable of controlling EVs production on-demand is constructed by incorporating polyethyleneglycol/polyethyleneimine modified superparamagnetic nanoparticles into a polyacrylamide/hyaluronic acid double-network hydrogel (Mag-gel). The Mag-gel is highly sensitive to a rotating magnetic field (RMF), and can act as mechano-stimulative platform to exert micro/nanoscale forces on encapsulated Schwann cells (SCs), an essential glial cell in supporting nerve regeneration. By switching the ON/OFF state of the RMF, the Mag-gel can scale up local production of SCs-derived EVs (SCs-EVs) both in vitro and in vivo. Further transcriptome sequencing indicates an enrichment of transcripts favorable in axon growth, angiogenesis, and inflammatory regulation of SCs-EVs in the Mag-gel with RMF, which ultimately results in optimized nerve repair in vivo. Overall, this research provides a noninvasive and remotely time-scheduled method for fine-tuning EVs-based therapies to accelerate tissue regeneration, including that of peripheral nerves.

Stevioside Ameliorates Prenatal Obesity Induced Postpartum Depression: The Potential Role of Gut Barrier Homeostasis.

SCOPE: Postpartum depression and cognitive impairment are the common complications of prenatal obesity. Stevioside is a non-nutritive natural sweetener with antioxidant and anti-inflammatory. However, its effects on depression behaviors and cognitive impairment induced by a high-fat diet (HFD) remain unclear. METHODS AND RESULTS: An 8-week HFD is used to establish a prenatal obesity model in female C57BL/6J mice to explore the improvement effects of stevioside (0.5 mg mL-1 in drinking water) on maternal depression and cognitive dysfunction after weaning. The results demonstrated that stevioside improves behavioral performance of obese maternal mice, and inhibits neuronal damage and 5-hydroxytryptamine (5-HT) abnormality induced by HFD. In addition, stevioside inhibits oxidative stress by reducing malondialdehyde (MDA) and increasing superoxide dismutase (SOD) and glutathione (GSH) activities in the brains of obese maternal mice. Additionally, stevioside improves gut barrier integrity and prevented lipopolysaccharide (LPS) extravasation, and alleviates neuroinflammation. Correlation analysis shows that gut barrier and serum LPS are closely related to behavioral performance and brain biochemical indicators. CONCLUSION: Stevioside is capable to prevent prenatal obesity-induced cognitive and mood disorders by restoring intestinal barrier damage and inhibiting inflammation.

Quantitative Biofabrication Platform for Collagen-Based Peripheral Nerve Grafts with Structural and Chemical Guidance.

Owing to its crucial role in the human body, collagen has immense potential as a material for the biofabrication of tissues and organs. However, highly refined fabrication using collagen remains difficult, primarily because of its notably soft properties. A quantitative biofabrication platform to construct collagen-based peripheral nerve grafts, incorporating bionic structural and chemical guidance cues, is introduced. A viscoelastic model for collagen, which facilitates simulating material relaxation and fabricating collagen-based neural grafts, achieving a maximum channel density similar to that of the native nerve structure of longitudinal microchannel arrays, is established. For axonal regeneration over considerable distances, a gradient printing control model and quantitative method are developed to realize the high-precision gradient distribution of nerve growth factor required to obtain nerve grafts through one-step bioprinting. Experiments verify that the bioprinted graft effectively guides linear axonal growth in vitro and in vivo. This study should advance biofabrication methods for a variety of human tissue-engineering applications requiring tailored cues.

Distinct functions of EHMT1 and EHMT2 in cancer chemotherapy and immunotherapy.

EHTM1 (GLP) and EHMT2 (G9a) are closely related protein lysine methyltransferases often thought to function together as a heterodimer to methylate histone H3 and non-histone substrates in diverse cellular processes including transcriptional regulation, genome methylation, and DNA repair. Here we show that EHMT1/2 inhibitors cause ATM-mediated slowdown of replication fork progression, accumulation of single-stranded replication gaps, emergence of cytosolic DNA, and increased expression of STING. EHMT1/2 inhibition strongly potentiates the efficacy of alkylating chemotherapy and anti-PD-1 immunotherapy in mouse models of tripe negative breast cancer. The effects on DNA replication and alkylating agent sensitivity are largely caused by the loss of EHMT1-mediated methylation of LIG1, whereas the elevated STING expression and remarkable response to immunotherapy appear mainly elicited by the loss of EHMT2 activity. Depletion of UHRF1, a protein known to be associated with EHMT1/2 and LIG1, also induces STING expression, and depletion of either EHMT2 or UHRF1 leads to demethylation of specific CpG sites in the STING1 promoter, suggestive of a distinct EHMT2-UHRF1 axis that regulates DNA methylation and gene transcription. These results highlight distinct functions of the two EHMT paralogs and provide enlightening paradigms and corresponding molecular basis for combination therapies involving alkylating agents and immune checkpoint inhibitors.

Effects of digital transformation and environmental resource integration capability on medical equipment suppliers' green innovation performance.

In today's digital age, the effort of medical enterprises towards green innovation has gained traction in academic and business circles. However, the current research system for medical equipment suppliers lacks a systematic study on how digital transformation can enhance the outcomes of green innovation. This research aims to develop a theoretical framework for digital transformation, environmental resource integration capability, managerial environmental concern and green innovation performance with respect to the resource-based view and conducting empirical analysis using survey data from medical equipment supply enterprises. Our findings reveal that digital transformation has a significant effect on the promotion of green innovation performance through environmental resource integration capability. Moreover, the managerial environmental concern moderates above mediation effect. These findings not only provide compelling insights into the impact of digital transformation on green innovation performance but also have important implications for sustainable development and cleaner production relevant academic research and policy-making.