Novel coumarin-piperazine-2(5H)-furanone hybrids as potential anti-lung cancer agents: Synthesis, biological evaluation and molecular docking studies.

Novel coumarin-piperazine-2(5H)-furanone hybrids 5a-l were efficiently synthesized by introducing a furanone scaffold into coumarin using piperazine as a linker. The cytotoxicity of all hybrids 5a-l were evaluated by MTT assay on human lung cancer A549 cells and normal human lung fibroblast WI-38 cells with cytarabine (CAR) as a positive control. Hybrid 5 l (IC50 = 11.28 µM) was the most toxic to A549 cells, 18-fold more toxic than the reference CAR (IC50 = 202.57 µM). Moreover, hybrid 5 l (IC50 = 411.93 µM) was less toxic to WI-38 cells, with a much higher selectivity (5 l, SI ≈ 37, WI-38/A549) than CAR (SI ≈ 2). Structure-activity relationship analysis showed that both the cytotoxicity against A549 cells and selectivity (WI-38/A549) were greatly improved when the bornyl group was incorporated in the hybrids (5c, 5f, 5i and 5 l). Further, hybrid 5 l was more toxic and selective against four types of human lung cancer cells (A549, Calu-1, PC-9 and H460; IC50 = 5.72-45.46 µM; SI ≈ 9-72) than three other types of human cancer cells (SK-BR-3, 786-O and SK-OV-3, IC50 = 39.07-130.82 µM; SI ≈ 0-2), showing remarkable specificity. In particular, hybrid 5 l (IC50 = 5.72 µM) showed the highest cytotoxicity against H460 cells with the highest selectivity of up to 72 (WI-38/H460). Flow cytometric analysis showed that hybrid 5 l induced apoptosis in H460 cells in a concentration-dependent manner. Molecular docking studies revealed a high binding affinity of hybrid 5 l with CDK2 protein. Hybrid 5 l is expected to be a leading candidate for anti-lung cancer agents.

Related Clinical Factors of Platinum-Based Chemotherapy Resistance in Patients with Epithelial Ovarian Cancer.

OBJECTIVE: Ovarian cancer is the second most common malignancy in women, but it is a fatal gynecological tumor. Although it has a standard treatment regimen, resistance to chemotherapy makes patients more prone to early recurrence, leading to poor survival rates. Therefore, this study investigated factors related to platinum resistance through a complete analysis of clinical data. DESIGN: Clinical data of patients with ovarian cancer were collected, and the patients were categorized into platinum-sensitive and platinum-resistant groups. By comparing the differences in clinical data between the groups, the key factors affecting platinum resistance were analyzed. PARTICIPANTS/MATERIALS, SETTING, METHODS: We collected the clinical data of patients with epithelial ovarian cancer (EOC) who were admitted to the Department of Oncology of the General Hospital of Ningxia Medical University between January 1, 2019, and December 31, 2020. We conducted univariate and multivariate analyses and evaluated overall survival and progression-free survival using the Kaplan-Meier method. RESULTS: We enrolled 161 patients with EOC, of whom 124 demonstrated platinum sensitivity and 37 demonstrated platinum resistance after the initial platinum-based chemotherapy. Univariate analyses revealed that the International Federation of Gynecology and Obstetrics (FIGO) stage, neoadjuvant chemotherapy, and Fagotti score were associated with an increased risk of platinum resistance for the first recurrence. In multivariate logistic regression analysis, only Fagotti score and neoadjuvant chemotherapy were associated with an increased risk of platinum resistance (odds ratio: 0.372 and 0.328, 95% confidence interval: 0.160-0.863 and 0.141-0.762, p = 0.021 and 0.010, respectively). LIMITATIONS: The sample size of this study was relatively small because of nonstandard treatment of some patients, the absence of clinical data, and failure of follow-up. CONCLUSIONS: Patients with EOC exhibiting platinum resistance had a very poor prognosis. The Fagotti score and neoadjuvant chemotherapy appeared to increase the risk of platinum resistance at first recurrence.

Identification of a G-protein coupled receptor-related gene signature through bioinformatics analysis to construct a risk model for ovarian cancer prognosis.

BACKGROUND: Ovarian cancer (OV) is a common malignant tumor of the female reproductive system with a 5-year survival rate of ∼30 %. Inefficient early diagnosis and prognosis leads to poor survival in most patients. G protein-coupled receptors (GPCRs, the largest family of human cell surface receptors) are associated with OV. We aimed to identify GPCR-related gene (GPCRRG) signatures and develop a novel model to predict OV prognosis. METHOD: We downloaded data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Prognostic GPCRRGs were screened using least absolute shrinkage and selection operator (LASSO) Cox regression analysis, and a prognostic model was constructed. The predictive ability of the model was evaluated by Kaplan-Meier (K-M) survival analysis. The levels of GPCRRGs were examined in normal and OV cell lines using quantitative reverse-Etranscription polymerase chain reaction. The immunological characteristics of the high- and low-risk groups were analyzed using single-sample gene set enrichment analysis (ssGSEA) and CIBERSORT. RESULTS: Based on the risks scores, 17 GPCRRGs were associated with OV prognosis. CXCR4, GPR34, LGR6, LPAR3, and RGS2 were significantly expressed in three OV datasets and enabled accurate OV diagnosis. K-M analysis of the prognostic model showed that it could differentiate high- and low-risk patients, which correspond to poorer and better prognoses, respectively. GPCRRG expression was correlated with immune infiltration rates. CONCLUSIONS: Our prognostic model elaborates on the roles of GPCRRGs in OV and provides a new tool for prognosis and immune response prediction in patients with OV.

Conversion therapy of a giant hepatocellular carcinoma with portal vein thrombus and inferior vena cava thrombus: A case report and review of literature.

BACKGROUND: The prognosis of hepatocellular carcinoma (HCC) combined with portal and hepatic vein cancerous thrombosis is poor, for unresectable patients the combination of targeted therapy and immune therapy was the first-line recommended treatment for advanced HCC, with a median survival time of only about 2.7-6 months. In this case report, we present the case of a patient with portal and hepatic vein cancerous thrombosis who achieved pathologic complete response after conversion therapy. CASE SUMMARY: In our center, a patient with giant HCC combined with portal vein tumor thrombus and hepatic vein tumor thrombus was treated with transcatheter arterial chemoembolization (TACE), radiotherapy, targeted therapy and immunotherapy, and was continuously given icaritin soft capsules for oral regulation. After 7 months of conversion therapy, the patient's tumor shrank and the tumor thrombus subsided significantly. The pathology of surgical resection was in complete remission, and there was no progression in the postoperative follow-up for 7 months, which provided a basis for the future strategy of combined conversion therapy. CONCLUSION: In this case, atezolizumab, bevacizumab, icaritin soft capsules combined with radiotherapy and TACE had a good effect. For patients with hepatocellular carcinoma combined with hepatic vein/inferior vena cava tumor thrombus, adopting a high-intensity, multimodal proactive strategy under the guidance of multidisciplinary team (MDT) is an important attempt to break through the current treatment dilemma.

Transcriptome Analysis of Potato Leaves under Oxidative Stress.

Potato (Solanum tuberosum L.) is a major global food crop, and oxidative stress can significantly impact its growth. Previous studies have shown that its resistance to oxidative stress is mainly related to transcription factors, post-translational modifications, and antioxidant enzymes in vivo, but the specific molecular mechanisms remain unclear. In this study, we analyzed the transcriptome data from potato leaves treated with H2O2 and Methyl viologen (MV), and a control group, for 12 h. We enriched 8334 (CK vs. H2O2) and 4445 (CK vs. MV) differentially expressed genes (DEGs), respectively, and randomly selected 15 DEGs to verify the sequencing data by qRT-PCR. Gene ontology (GO) enrichment analysis showed that the DEGs were mainly concentrated in cellular components and related to molecular function, and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated that most of the DEGs were related to metabolic pathways, plant hormone signal transduction, MAPK-signaling pathway, and plant-pathogen interactions. In addition, several candidate transcription factors, mainly including MYB, WRKY, and genes associated with Ca2+-mediated signal transduction, were also found to be differentially expressed. Among them, the plant hormone genes Soltu.DM.03G022780 and Soltu.DM.06G019360, the CNGC gene Soltu.DM.06G006320, the MYB transcription factors Soltu.DM.06G004450 and Soltu.DM.09G002130, and the WRKY transcription factor Soltu.DM.06G020440 were noticeably highly expressed, which indicates that these are likely to be the key genes in the regulation of oxidative stress tolerance. Overall, these findings lay the foundation for further studies on the molecular mechanisms of potato leaves in response to oxidative stress.

Altered nucleocytoplasmic export of adenosine-rich circRNAs by PABPC1 contributes to neuronal function.

Circular RNAs (circRNAs) are upregulated during neurogenesis. Where and how circRNAs are localized and what roles they play during this process have remained elusive. Comparing the nuclear and cytoplasmic circRNAs between H9 cells and H9-derived forebrain (FB) neurons, we identify that a subset of adenosine (A)-rich circRNAs are restricted in H9 nuclei but exported to cytosols upon differentiation. Such a subcellular relocation of circRNAs is modulated by the poly(A)-binding protein PABPC1. In the H9 nucleus, newly produced (A)-rich circRNAs are bound by PABPC1 and trapped by the nuclear basket protein TPR to prevent their export. Modulating (A)-rich motifs in circRNAs alters their subcellular localization, and introducing (A)-rich circRNAs in H9 cytosols results in mRNA translation suppression. Moreover, decreased nuclear PABPC1 upon neuronal differentiation enables the export of (A)-rich circRNAs, including circRTN4(2,3), which is required for neurite outgrowth. These findings uncover subcellular localization features of circRNAs, linking their processing and function during neurogenesis.

TACE combined Lenvatinib plus Camrelizumab versus TACE alone in efficacy and safety for unresectable hepatocellular carcinoma: a propensity score-matching study.

BACKGROUNDS: To compare the efficacy and safety of transcatheter arterial chemoembolization (TACE) combined Lenvatinib plus Camrelizumab (TLC) in unresectable hepatocellular carcinoma (uHCC) with those of TACE alone . METHODS: A retrospective analysis was performed on 222 patients with uHCC who were treated between September 2013 and Jun 2023. One group received TACE + lenvatinib + camrelizumab (TLC) (n = 97) and another group received TACE alone (n = 151). Efficacy and safety were compared after propensity score matching between the TLC and TACE groups. RESULTS: After propensity matching, the TLC group had higher objective response rate (ORR) (88.6% vs. 28.6%, P < 0.001), disease control rate (DCR) (94.3%% vs. 72.9%, P < 0.001), and conversion rates before and after propensity matching were 44.1% and 41.4%, respectively, compared with the TACE group. The median progression free survival (PFS) was longer in the TLC group than in the TACE group (12.7 vs. 6.1 months, P = 0.005). The median overall survival (OS) was longer in the TLC group than in the TACE group (19.4 vs. 13.0 months, P = 0.023). Cox multivariate analysis with different modes of adjustment showed that treatment was an independent influencing factor of PFS and OS. The interaction analysis showed that cirrhosis and Child-Pugh stage an interactive role in the PFS of different treatment. Decreased AFP after treatment portends higher ORR and DCR. CONCLUSION: TACE combined Lenvatinib plus Camrelizumab regimen was safe and superior to TACE alone in improving PFS, OS, and tumor response rates for unresectable recurrent HCC patients.

Joint effect of abnormal systemic immune-inflammation index (SII) levels and diabetes on cognitive function and survival rate: A population-based study from the NHANES 2011-2014.

OBJECTIVE: The purpose of this study was to investigate whether the combination of abnormal systemic immune-inflammation index (SII) levels and hyperglycemia increased the risk of cognitive function decline and reduced survival rate in the United States. METHODS: This cross-sectional study used data from the National Health and Nutrition Examination Survey (NHANES) database from 2011-2014 and enrolled 1,447 participants aged 60 years or older. Restricted cubic splines (RCS), linear regression and kaplan-meier(KM) curve were employed to explore the combined effects of abnormal SII and hyperglycemia on cognitive function and survival rate, and subgroup analysis was also conducted. RESULTS: The RCS analysis revealed an inverted U-shaped relationship between lgSII levels and cognitive function. Linear regression analysis indicated that neither abnormal SII nor diabetes alone significantly contributed to the decline in cognitive function compared to participants with normal SII levels and blood glucose. However, when abnormal SII coexisted with diabetes (but not prediabetes), it resulted to a significant decline in cognitive function. After adjusting for various confounding factors, these results remained significant in Delayed Word Recall (ß:-0.76, P<0.05) and Digit Symbol Substitution tests (ß:-5.02, P<0.05). Nevertheless, these results showed marginal significance in Total Word Recall test as well as Animal Fluency test. Among all subgroup analyses performed, participants with both abnormal SII levels and diabetes exhibited the greatest decline in cognitive function compared to those with only diabetes. Furthermore, KM curve demonstrated that the combination of abnormal SII levels and diabetes decreased survival rate among participants. CONCLUSION: The findings suggest that the impact of diabetes on cognitive function/survival rate is correlated with SII levels, indicating that their combination enhances predictive power.

Enhancing surgical instrument segmentation: integrating vision transformer insights with adapter.

PURPOSE: In surgical image segmentation, a major challenge is the extensive time and resources required to gather large-scale annotated datasets. Given the scarcity of annotated data in this field, our work aims to develop a model that achieves competitive performance with training on limited datasets, while also enhancing model robustness in various surgical scenarios. METHODS: We propose a method that harnesses the strengths of pre-trained Vision Transformers (ViTs) and data efficiency of convolutional neural networks (CNNs). Specifically, we demonstrate how a CNN segmentation model can be used as a lightweight adapter for a frozen ViT feature encoder. Our novel feature adapter uses cross-attention modules that merge the multiscale features derived from the CNN encoder with feature embeddings from ViT, ensuring integration of the global insights from ViT along with local information from CNN. RESULTS: Extensive experiments demonstrate our method outperforms current models in surgical instrument segmentation. Specifically, it achieves superior performance in binary segmentation on the Robust-MIS 2019 dataset, as well as in multiclass segmentation tasks on the EndoVis 2017 and EndoVis 2018 datasets. It also showcases remarkable robustness through cross-dataset validation across these 3 datasets, along with the CholecSeg8k and AutoLaparo datasets. Ablation studies based on the datasets prove the efficacy of our novel adapter module. CONCLUSION: In this study, we presented a novel approach integrating ViT and CNN. Our unique feature adapter successfully combines the global insights of ViT with the local, multi-scale spatial capabilities of CNN. This integration effectively overcomes data limitations in surgical instrument segmentation. The source code is available at: https://github.com/weimengmeng1999/AdapterSIS.git .

Identification of shared molecular mechanisms and diagnostic biomarkers between heart failure and idiopathic pulmonary fibrosis.

Background: Heart failure (HF) and idiopathic pulmonary fibrosis (IPF) are global public health concerns. The relationship between HF and IPF is widely acknowledged. However, the interaction mechanisms between these two diseases remain unclear, and early diagnosis is particularly difficult. Through the integration of bioinformatics and machine learning, our work aims to investigate common gene features, putative molecular causes, and prospective diagnostic indicators of IPF and HF. Methods: The Gene Expression Omnibus (GEO) database provided the RNA-seq datasets for HF and IPF. Utilizing a weighted gene co-expression network analysis (WGCNA), possible genes linked to HF and IPF were found. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) were then employed to analyze the genes that were shared by HF and IPF. Using the cytoHubba and iRegulon algorithms, a competitive endogenous RNA (ceRNA) network was built based on seven basic diagnostic indicators. Additionally, hub genes were identified using machine learning approaches. External datasets were used to validate the findings. Lastly, the association between the number of immune cells in tissues and the discovered genes was estimated using the CIBERSORT method. Results: In total, 63 shared genes were identified between HF- and IPF-related modules using WGCNA. Extracellular matrix (ECM)/structure organization, ECM-receptor interactions, focal, and protein digestion and absorption, were shown to be the most enrichment categories in GO and KEGG enrichment analysis of common genes. Furthermore, a total of seven fundamental genes, including COL1A1, COL3A1, THBS2, CCND1, ASPN, FAP, and S100A12, were recognized as pivotal genes implicated in the shared pathophysiological pathways of HF and IPF, and TCF12 may be the most important regulatory transcription factor. Two characteristic molecules, CCND1 and NAP1L3, were selected as potential diagnostic markers for HF and IPF, respectively, using a support vector machine-recursive feature elimination (SVM-RFE) model. Furthermore, the development of diseases and diagnostic markers may be associated with immune cells at varying degrees. Conclusions: This study demonstrated that ECM/structure organisation, ECM-receptor interaction, focal adhesion, and protein digestion and absorption, are common pathogeneses of IPF and HF. Additionally, CCND1 and NAP1L3 were identified as potential diagnostic biomarkers for both HF and IPF. The results of our study contribute to the comprehension of the co-pathogenesis of HF and IPF at the genetic level and offer potential biological indicators for the early detection of both conditions.

Inhibition of Hmbox1 Promotes Cardiomyocyte Survival and Glucose Metabolism Through Gck Activation in Ischemia/Reperfusion Injury.

BACKGROUND: Exercise-induced physiological cardiac growth regulators may protect the heart from ischemia/reperfusion (I/R) injury. Homeobox-containing 1 (Hmbox1), a homeobox family member, has been identified as a putative transcriptional repressor and is downregulated in the exercised heart. However, its roles in exercise-induced physiological cardiac growth and its potential protective effects against cardiac I/R injury remain largely unexplored. METHODS: We studied the function of Hmbox1 in exercise-induced physiological cardiac growth in mice after 4 weeks of swimming exercise. Hmbox1 expression was then evaluated in human heart samples from deceased patients with myocardial infarction and in the animal cardiac I/R injury model. Its role in cardiac I/R injury was examined in mice with adeno-associated virus 9 (AAV9) vector-mediated Hmbox1 knockdown and in those with cardiac myocyte-specific Hmbox1 ablation. We performed RNA sequencing, promoter prediction, and binding assays and identified glucokinase (Gck) as a downstream effector of Hmbox1. The effects of Hmbox1 together with Gck were examined in cardiomyocytes to evaluate their cell size, proliferation, apoptosis, mitochondrial respiration, and glycolysis. The function of upstream regulator of Hmbox1, ETS1, was investigated through ETS1 overexpression in cardiac I/R mice in vivo. RESULTS: We demonstrated that Hmbox1 downregulation was required for exercise-induced physiological cardiac growth. Inhibition of Hmbox1 increased cardiomyocyte size in isolated neonatal rat cardiomyocytes and human embryonic stem cell-derived cardiomyocytes but did not affect cardiomyocyte proliferation. Under pathological conditions, Hmbox1 was upregulated in both human and animal postinfarct cardiac tissues. Furthermore, both cardiac myocyte-specific Hmbox1 knockout and AAV9-mediated Hmbox1 knockdown protected against cardiac I/R injury and heart failure. Therapeutic effects were observed when sh-Hmbox1 AAV9 was administered after I/R injury. Inhibition of Hmbox1 activated the Akt/mTOR/P70S6K pathway and transcriptionally upregulated Gck, leading to reduced apoptosis and improved mitochondrial respiration and glycolysis in cardiomyocytes. ETS1 functioned as an upstream negative regulator of Hmbox1 transcription, and its overexpression was protective against cardiac I/R injury. CONCLUSIONS: Our studies unravel a new role for the transcriptional repressor Hmbox1 in exercise-induced physiological cardiac growth. They also highlight the therapeutic potential of targeting Hmbox1 to improve myocardial survival and glucose metabolism after I/R injury.

An Ultrathin, Fast-Response, Large-Scale Liquid-Crystal-Facilitated Multi-Functional Reconfigurable Metasurface for Comprehensive Wavefront Modulation.

The rapid advancement of prevailing communication/sensing technologies necessitates cost-effective millimeter-wave arrays equipped with a massive number of phase-shifting cells to perform complicated beamforming tasks. Conventional approaches employing semiconductor switch/varactor components or tunable materials encounter obstacles such as quantization loss, high cost, high complexity, and limited adaptability for realizing large-scale arrays. Here, a low-cost, ultrathin, fast-response, and large-scale solution relying on metasurface concepts combined together with liquid crystal (LC) materials requiring a layer thickness of only 5 µm is reported. Rather than immersing resonant structures in LCs, a joint material-circuit-based strategy is devised, via integrating deep-subwavelength-thick LCs into slow-wave structures, to achieve constitutive metacells with continuous phase shifting and stable reflectivity. An LC-facilitated reconfigurable metasurface sub-system containing more than 2300 metacells is realized with its unprecedented comprehensive wavefront manipulation capacity validated through various beamforming functions, including beam focusing/steering, reconfigurable vortex beams, and tunable holograms, demonstrating a milli-second-level function-switching speed. The proposed methodology offers a paradigm shift for modulating electromagnetic waves in a non-resonating broadband fashion with fast-response and low-cost properties by exploiting functionalized LC-enabled metasurfaces. Moreover, this extremely agile metasurface-enabled antenna technology will facilitate a transformative impact on communication/sensing systems and empower new possibilities for wavefront engineering and diffractive wave calculation/inference.

Dissolving microneedles loaded with nimodipine for prevention of sleep disorders at a high altitude.

Sleep disorders are one of the most common acute reactions on the plateau, which can cause serious complications. However, there is no effective and safe treatment currently available. Nimodipine (NMD) is a dihydropyridine calcium channel blocker with neuroprotective and vasodilating activity, mainly used for the treatment of ischemic brain injury. Commercial oral or injectable NMD formulations are not a good option for central neuron diseases due to their poor brain delivery. In this study, nimodipine dissolving microneedles (NDMNs) were prepared for the prevention of sleep disorders caused by hypoxia. NDMNs were composed of NMD and polyvinyl pyrrolidone (PVP) K90 with a conical morphology and high rigidity. After administration of NDMNs on the back neck of mice, the concentration of NMD in the brain was significantly higher than that of oral medication as was confirmed by the fluorescent imaging on mouse models. NDMNs enhanced cognitive function, alleviated oxidative stress, and improved the sleep quality of mice with high-altitude sleep disorders. The blockage of calcium ion overloading may be an important modulation mechanism. NDMNs are a promising and user-friendly formulation for the prevention of high-altitude sleep disorders.

Multihydrogen Bond Modulated Polyzwitterionic Removable Adhesive Hydrogel with Antibacterial and Hemostatic Function for Wound Healing.

Wound management is a major challenge worldwide, placing a huge financial burden on the government of every nation. Wound dressings that can protect wounds, accelerate healing, prevent infection, and avoid secondary damage continue to be a major focus of research in the health care and clinical communities. Herein, a novel zwitterionic polymer (LST) hydrogel incorporated with [2-(methacryloyloxy) ethyl] dimethyl-(3-sulfopropyl) ammonium hydroxide (SBMA), mussel-inspired N-[tris(hydroxymethyl)methyl] acrylamide (THMA), and lithium magnesium salt was prepared for functional wound dressings. The incorporation of the THMA monomer containing three hydroxyl groups gives the hydrogel suitable adhesion properties (∼6.0 KPa). This allows the LST zwitterionic hydrogels to bind well to the skin, which not only protects the wound and ensures its therapeutic efficacy but also allows for painless removal and reduced patient pain. Zwitterionic sulfobetaine units of SBMA provide antimicrobial and mechanical properties. The chemical structure and microscopic morphology of LST zwitterionic hydrogels were systematically studied, along with their swelling ratio, adhesion, and mechanical properties. The results showed that the LST zwitterionic hydrogels had a uniform and compact porous structure with the highest swelling and mechanical strain of 1607% and 1068.74%, respectively. The antibacterial rate of LST zwitterionic hydrogels was as high as 99.49%, and the hemostatic effect was about 1.5 times that of the commercial gelatin hemostatic sponges group. In further studies, a full-thickness mouse skin model was selected to evaluate the wound healing performance. Wounds covered by LST zwitterionic hydrogels had a complete epithelial reformation and new connective tissue, and its vascular regenerative capacity was increased to about 2.4 times that of the commercial group, and the wound could completely heal within 12-13 days. This study provides significant advances in the design and construction of multifunctional zwitterionic hydrogel adhesives and wound dressings.

[Spatial-temporal Variation and Spatial Differentiation Geographic Detection of PM2.5 Concentration in the Shandong Province Based on Spatial Scale Effect].

PM2.5 remote sensing data was applied in this study, and Theil-Sen Median trend analysis and the Mann-Kendall significance test were utilized to analyze the temporal and spatial variation in PM2.5 in the Shandong Province from 2000 to 2021. The influencing power of the influencing factors on the spatial differentiation of PM2.5 concentration in the Shandong Province was detected at the provincial-city-county levels based on Geo-detector data. The results showed that:① on the temporal scale, the mean ρ(PM2.5)in the Shandong Province ranged from 38.15 to 88.63 µg·m-3 from 2000 to 2021, which was slightly higher than the secondary limit of inhalable particulate matter (35 µg·m-3) in the Ambient Air Quality Standards. On the interannual scale, 2013 was the peak year for the variation in ρ(PM2.5) with a value of 83.36 µg·m-3, according to which the trend of PM2.5 concentrations in the Shandong Province was divided into two phases:a continuous increase and a rapid decrease. On the seasonal scale, PM2.5 concentration presented the distribution characteristics of "low in summer and high in winter and moderate in spring and autumn" and the U-shaped change rule of first decreasing and then increasing. ② On the spatial scale, the PM2.5 concentration in the Shandong Province presented a spatial distribution pattern of "high in the west and low in the east." The areas with high PM2.5 concentration were distributed in the western area of the Shandong Province, whereas the areas with low PM2.5 concentration were distributed in the eastern peninsula region. The spatial variation in the changing trend of PM2.5 concentration showed significant spatial heterogeneity, and the extremely significant decrease was mainly distributed in the eastern peninsula region. ③ The results of factor detection showed that climate factor was an important factor affecting the spatial differentiation of PM2.5 concentration in the Shandong Province. Mean temperature had the highest influence on the spatial differentiation of PM2.5 concentration in the Shandong Province, with a q value of 0.512. Provincial-city-county multi-scale detection results showed that the influencing factors affecting the spatial differentiation of PM2.5 concentration and their influencing power differed at different spatial scales. At the provincial scale, mean temperature, sunshine duration, and slope were the main factors affecting the spatial differentiation of PM2.5 concentration. At the city level, precipitation, elevation, and relative humidity were the main factors affecting the spatial differentiation of PM2.5. At the county level, precipitation, mean temperature, and sunshine duration were the main factors affecting the spatial variation in PM2.5 concentration.

Review of biomimetic ordered microstructures in advancing synergistic integration of adhesion and microfluidics.

Many ordered arrangements are observable in the natural world, serving not only as pleasing aesthetics but also as functional improvements. These structured arrangements streamline cohesion while also facilitating the spontaneous drainage of liquids in microfluidics, resulting in effective separation and signal enhancement. Nevertheless, there is a substantial challenge when handling microstructured chips with microfluidic detection and adhesion. The arrangement of the adhesive interface's microstructure affects the liquid flow in the microfluidic chip, impacting the detection's sensitivity and accuracy. Additionally, the liquid in the microfluidic chip corrodes the adhesive material and structure, reducing the adhesion strength due to the hydration layer between the material and the contact interface. Therefore, this review explores the application of ordered structures in the integration of adhesion and microfluidics. We discussed the standard preparation method, appropriate materials, and the application of ordered structures in biomimetic adhesion and microfluidics. Furthermore, the paper discusses the major challenges in this field and provides opinions on its future developments.

Therapeutic application of circular RNA aptamers in a mouse model of psoriasis.

Efforts to advance RNA aptamers as a new therapeutic modality have been limited by their susceptibility to degradation and immunogenicity. In a previous study, we demonstrated synthesized short double-stranded region-containing circular RNAs (ds-cRNAs) with minimal immunogenicity targeted to dsRNA-activated protein kinase R (PKR). Here we test the therapeutic potential of ds-cRNAs in a mouse model of imiquimod-induced psoriasis. We find that genetic supplementation of ds-cRNAs leads to inhibition of PKR, resulting in alleviation of downstream interferon-α and dsRNA signals and attenuation of psoriasis phenotypes. Delivery of ds-cRNAs by lipid nanoparticles to the spleen attenuates PKR activity in examined splenocytes, resulting in reduced epidermal thickness. These findings suggest that ds-cRNAs represent a promising approach to mitigate excessive PKR activation for therapeutic purposes.

Oral Curcumin-Thioketal-Inulin Conjugate Micelles against Radiation-Induced Enteritis.

Radiation-induced enteritis is an unavoidable complication associated with pelvic tumor radiotherapy, significantly influencing the prognosis of cancer patients. The limited availability of commercial gastrointestinal radioprotectors in clinical settings poses a substantial challenge in preventing radiation enteritis. Despite the inherent radioprotective characteristics of Cur in vitro, its poor solubility in water, instability, and low bioavailability lead to inferior therapeutic effects in vivo. Herein, we developed novel ROS-responsive micelles (CTI) from inulin and curcumin, aimed at mitigating radiation enteritis. CTI micelles had excellent solubility and stability. Importantly, CTI improved the cytotoxicity and bioavailability of curcumin, thereby showing enhanced effectiveness in neutralizing ROS induced by radiation, safeguarding against DNA damage, and reducing radiation-induced cellular mortality. Moreover, in a radiation enteritis mice model, CTI not only alleviated severe radiation-induced intestinal injury but also improved redox-related indicators and reduced inflammatory cytokine expression. Furthermore, CTI effectively increased gut microbiota abundance and maintained gut homeostasis. In conclusion, CTI could be a promising candidate for the clinical management of radiation enteritis. Our study provides a new perspective for radioprotection using natural antioxidants.

In Defense of Clip-Based Video Relation Detection.

Video Visual Relation Detection (VidVRD) aims to detect visual relationship triplets in videos using spatial bounding boxes and temporal boundaries. Existing VidVRD methods can be broadly categorized into bottom-up and top-down paradigms, depending on their approach to classifying relations. Bottom-up methods follow a clip-based approach where they classify relations of short clip tubelet pairs and then merge them into long video relations. On the other hand, top-down methods directly classify long video tubelet pairs. While recent video-based methods utilizing video tubelets have shown promising results, we argue that the effective modeling of spatial and temporal context plays a more significant role than the choice between clip tubelets and video tubelets. This motivates us to revisit the clip-based paradigm and explore the key success factors in VidVRD. In this paper, we propose a Hierarchical Context Model (HCM) that enriches the object-based spatial context and relation-based temporal context based on clips. We demonstrate that using clip tubelets can achieve superior performance compared to most video-based methods. Additionally, using clip tubelets offers more flexibility in model designs and helps alleviate the limitations associated with video tubelets, such as the challenging long-term object tracking problem and the loss of temporal information in long-term tubelet feature compression. Extensive experiments conducted on two challenging VidVRD benchmarks validate that our HCM achieves a new state-of-the-art performance, highlighting the effectiveness of incorporating advanced spatial and temporal context modeling within the clip-based paradigm.

A Review of Recent Advances in Microneedle-Based Sensing within the Dermal ISF That Could Transform Medical Testing.

Interstitial fluid (ISF) has attracted extensive attention in an extremely wide range of areas due to its unique advantages, such as portability, high precision, comfortable operation, and superior stability. In recent years, the microneedle (MN) technique has been considered to be an excellent tool for extracting ISF because it is painless and noninvasive. Recent reports have shown that MN has good application prospects in ISF extraction. In this review, we provide comprehensive and in-depth insight into integrated MN devices for ISF detection, covering the basic structure as well as the fabrication of integrated MN devices and various applications in ISF extraction. Challenges and prospects are highlighted, with a discussion on how to transition such MN-integrated devices toward personalized healthcare monitoring systems.