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Abstract Background Recent advances in ultrasound technology have led to widespread adoption of ultrasonic energy devices in liver resections. While various studies have assessed the comparative advantages of ultrasonic devices and traditional clamp-crushing, their findings vary. Moreover, a specific systematic review on this topic has not yet been conducted. Objectives This study aims to present a comprehensive, up-to-date analysis comparing outcomes between ultrasonic devices and conventional clamp-crushing methods in liver resection, based on currently available literature. Patients and methods We conducted a systematic literature search in databases such as PubMed, Embase, Web of Science, and CNKI up to November 2023. Studies that compared the efficacy or safety of ultrasonic devices against traditional clamp-crushing methods in hepatectomy were included. The analysis covered intraoperative outcomes like operating time, blood loss, and transfusion rate, as well as postoperative outcomes such as complication rate, mortality, postoperative bleeding, and bile leakage. Review Manager version 5.3 (Cochrane Collaboration, Oxford, UK) and Stata 17.0 (Stata Corp, College Station, TX, USA) were used for data analysis. Results Thirteen studies, involving a total of 1,417 patients (630 using ultrasonic devices and 787 using clamp-crushing methods), were included. The clamp-crush method resulted in a shorter operation time. Contrarily, the ultrasonic device group experienced reduced blood loss and lower transfusion rates. Postoperatively, there was no significant difference in mortality or postoperative bleeding between the groups. However, the ultrasonic group had a lower overall complication rate, particularly a reduced incidence of bile leakage. Overall, the ultrasonic devices were associated with improved perioperative outcomes. Conclusions The findings suggest that ultrasonic devices provide better outcomes in hepatectomy compared to traditional clamp-crushing techniques. Nonetheless, large-scale randomized controlled trials are needed to confirm these results due to potential heterogeneity and biases. The choice of using ultrasonic devices should consider the surgeon’s experience and individual patient circumstances.

Objective: Heterotopic ossification (HO) refers to the abnormal development of bone in soft tissue rather than within bone itself. Previous research has shown that sensory nerve prostaglandin E2 receptor 4 (EP4) signaling not only governs pain perception but also influences bone formation. However, the relationship between sensory nerve EP4 and the pathogenesis of HO in the Achilles tendon remains unclear. This study aims to investigate this relationship and the underlying mechanisms. Methods: We generated sensory nerve EP4-specific knockout mice, with the genotype of Avil-CreEP4fl/fl, was propagated. Transcriptome sequencing and bioinformatics analysis techniques were used to identify the potential molecular pathways involving with sensory nerve EP4. Additionally, a neurectomy mouse model was created by transecting the sciatic nerve transection, to examine the effects and mechanisms of peripheral innervation on HO in vivo. Micro-CT, immunofluorescence (IF), Hematoxylin and Eosin (H&E) Staining, Safranin O-Fast Green staining and western blotting were used to analyze changes in cellular and tissue components. Results: We here observed an increase in sensory nerve EP4 and H-type vessels during the pathogenesis of HO in both human subjects and mice. Proximal neurectomy through sciatic nerve transection or the targeted knockout of EP4 in sensory nerves hindered angiogenesis-dependent bone formation and the development of HO at the traumatic site of the Achilles tendon. Furthermore, we identified the Efnb2 (Ephrin-B2)/Dll4 (Delta-like ligand 4) axis as a potential downstream element influenced by sensory nerve EP4 in the regulation of HO. Notably, administration of an EP4 inhibitor demonstrated the ability to alleviate HO. Based on these findings, sensory nerve EP4 emerges as an innovative and promising approach for managing HO. Conclusion: Our findings demonstrate that the sensory nerve EP4 promotes ectopic bone formation by modulating angiogenesis-associated osteogenesis during HO. The translational potential of this article: Our results provide a mechanistic rationale for targeting sensory nerve EP4 as a promising candidate for HO therapy.

Objective: Osteoclast (OC) over-activation is an important cause of bone loss that is strongly correlated with inflammation. Although the CD163/TWEAK/Fn14 axis has been implicated in several inflammatory pathologies, its contributions to inflammatory bone loss remain poorly understood. This study aimed to evaluate the interaction of the CD163/TWEAK/Fn14 axis with OC in inflammatory bone loss. Methods: To assess the role of CD163 in bone homeostasis, we characterized the bone phenotypes of CD163-deficient mice and their wild-type littermates. CD163 and TWEAK levels were evaluated in the bone marrow of mice with LPS-induced bone loss and individuals with rheumatoid arthritis (RA). Bone mass changes were assessed using uCT and histology following supplementation with recombinant mouse CD163 protein (rCD163) or blockade of TWEAK/Fn14 signaling in CD163-deficient mice and mice with LPS-induced bone loss. The impact of CD163/TWEAK on OC differentiation and bone resorption capacity was analyzed in vitro. Results: CD163 deficiency caused decreased bone mass and increased OC abundance. Lower CD163 expression and higher TWEAK expression were observed in the bone marrow of mice with LPS-induced bone loss and individuals with RA. TWEAK, mainly derived from CD68+ macrophages, was responsible for bone loss, and supplementing rCD163 or blocking TWEAK/Fn14 signaling contributed to rescue bone loss. TWEAK/Fn14 synergistically promoted RANKL-dependent OC differentiation and bone resorption capability through downstream mitogen-activated protein kinases (MAPK) signaling, while the pro-osteoclastic effect of TWEAK was suppressed by CD163. Conclusion: Our findings suggest that the CD163/TWEAK/Fn14 axis is a potential therapeutic target for inflammatory bone loss by regulating osteoclastogenesis.

OBJECTIVES Ascending to altitudes >2500 m may lead to acute mountain sickness (AMS). METHODS The demographics, height, weight, body mass index (BMI), smoking, and alcohol consumption of 104 healthy controls were collected in Chengdu (500 m). Heart rate (HR), saturation of pulse oxygen (SpO2), and AMS-related symptoms were collected in Hoh Xil (4200 m). A headache with Lake Louise score ≥3 was defined as AMS. RESULTS The incidence of AMS was 60.58%. AMS group had a lower SpO2 and higher HR than non-AMS group. Alcohol consumption seemed a risk factor for AMS. There was no difference in the BMI, age, height, weight, and smoking between AMS and non-AMS groups. The most common AMS symptom was headache, followed by dyspnea, insomnia, dizziness, lassitude, and anorexia. Women were prone to suffer from dizziness. The value of SpO2 and HR was improved both in AMS and non-AMS groups after hypoxia acclimatization, and the value showed greater improvement in AMS group. Oxygen therapy decreased the AMS-induced tachycardia, which had no any effect on SpO2 and symptom alleviating time. CONCLUSION Lower SpO2 and higher HR following exposure to high altitude were associated with AMS susceptibility. The anthropometric data changes were larger in AMS group than non-AMS group before and after hypoxia acclimatization.

Abstract In response to the safety and stability issues of current electric vehicle charging connection devices, this study proposes a charging system planning for electric vehicles with different capacity charging piles based on the user behavior characteristics of electric vehicles and Monte Carlo methods. It is found that the predicted results under the set management strategy are most consistent with the trend of actual load changes. Moreover, in the prediction of weekly load, the research strategy has better performance than traditional unmanaged strategies. Under the research scheme, the average charging speed of charging piles with capacity of A and B in the peak period was 41.4 min/ and 18.8 min/, respectively, which increased by 29.3% and 11.7% respectively compared with 58.6 min/ and 21.3 min/ in the normal period. The total economic cost of the research plan was 4.871 million yuan, which was 67.0 million yuan and 3.833 million yuan lower than the control methods 1 and 2, respectively. The total number of charging stations of types a and b that need to be purchased for the research method decreased by 18.47% and 63.24% compared to the comparative method 3. The results indicate that the research method significantly improves the utilization rate of charging stations in the electric vehicle charging system. This study has important application value in the intelligent management of electric vehicle charging systems.

Abstract Background Autophagy dysfunction in glial cells is implicated in the pathogenesis of Parkinson’s disease (PD). The previous study reported that α-synuclein (α-Syn) disrupted autophagy in cultured microglia. However, the mechanism of microglial autophagy dysregulation is poorly understood. Methods Two α-Syn-based PD models were generated via AAV-mediated α-Syn delivery into the mouse substantia nigra and striatal α-Syn preformed fibril (PFF) injection. The levels of microglial UNC-51-like kinase 1 (Ulk1) and other autophagy-related genes in vitro and in PD mice, as well as in the peripheral blood mononuclear cells of PD patients and healthy controls, were determined via quantitative PCR, western blotting and immunostaining. The regulatory effect of signal transducer and activator of transcription 1 (STAT1) on Ulk1 transcription was determined via a luciferase reporter assay and other biochemical studies and was verified through Stat1 knockdown or overexpression. The effect of α-Syn on glial STAT1 activation was assessed by immunohistochemistry and western blotting. Changes in microglial status, proinflammatory molecule expression and dopaminergic neuron loss in the nigrostriatum of PD and control mice following microglial Stat1 conditional knockout (cKO) or treatment with the ULK1 activator BL-918 were evaluated by immunostaining and western blotting. Motor behaviors were determined via open field tests, rotarod tests and balance beam crossing. Results The transcription of microglial ULK1, a kinase that controls autophagy initiation, decreased in both in vitro and in vivo PD mouse models. STAT1 plays a critical role in suppressing Ulk1 transcription. Specifically, Stat1 overexpression downregulated Ulk1 transcription, while Stat1 knockdown increased ULK1 expression, along with an increase in LC3II and a decrease in the SQSTM1/p62 protein. α-Syn PFF caused toll-like receptor 4-dependent activation of STAT1 in microglia. Ablation of Stat1 alleviated the decrease in microglial ULK1 expression and disruption of autophagy caused by α-Syn PFF. Importantly, the ULK1 activator BL-918 and microglial Stat1 cKO attenuated neuroinflammation, dopaminergic neuronal damage and motor defects in PD models. Conclusions These findings reveal a novel mechanism by which α-Syn impairs microglial autophagy and indicate that targeting STAT1 or ULK1 may be a therapeutic strategy for PD.

Abstract The expression and biological function of junctional adhesion molecule-like protein (JAML) in colorectal cancer (CRC) remain unclear. Paraffin tissue samples from 50 cases of CRC were collected to determine the expression of JAML. JAML was overexpressed or knock-down in CRC cells to evaluated the proliferation, migration and invasion in vitro and in vivo. Western-blot and others were applied to explore the mechanisms. The study showed that JAML was highly expressed within cancer tissues in 50% (25/50) of patients with CRC, and was correlated with higher TNM stage (p

Abstract Cognitive offloading refers to using an external medium such as paper to remember information rather than relying solely on memory. Previous research has suggested that individuals’ perceived memory performance may influence their decision to employ cognitive offloading as a learning strategy. However, ubiquitous distortions in metacognitive judgments limit the learning gains. Motivated by this, the current study incorporated second-order metacognitive judgments (SOJs) with distorted first-order metacognitive judgments (FOJs) within a learning context that allowed cognitive offloading. We investigated how individuals decide to employ cognitive offloading based on two levels of self-assessments. Eighty participants from the U.S. were recruited remotely to complete online paired-associate tasks. They learned 48 paired associates on an item-by-item basis, providing a FOJ, an SOJ, and a strategy (offload or not) on each trial. Our findings showed a significant effect of interaction between FOJs and SOJs on the selection of cognitive offloading. Additionally, there were significant variabilities in employing cognitive offloading across individual participants and word pairs. We concluded that SOJs influence the association between FOJs and strategy choices. Furthermore, we attributed the observed interaction to the assessment and regulation of SOJ about FOJ.

Abstract Excessive glucocorticoid (GC) action is linked to various metabolic disorders. Recent findings suggest that disrupting skeletal GC signaling prevents bone loss and alleviates metabolic disorders in high-fat diet (HFD)-fed obese mice, underpinning the neglected contribution of skeletal GC action to obesity and related bone loss. Here, we show that the elevated expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), the enzyme driving local GC activation, and GC signaling in osteoblasts, are associated with bone loss and obesity in HFD-fed male mice. Osteoblast-specific 11β-HSD1 knockout male mice exhibit resistance to HFD-induced bone loss and metabolic disorders. Mechanistically, elevated 11β-HSD1 restrains glucose uptake and osteogenic activity in osteoblast. Pharmacologically inhibiting osteoblastic 11β-HSD1 by using bone-targeted 11β-HSD1 inhibitor markedly promotes bone formation, ameliorates glucose handling and mitigated obesity in HFD-fed male mice. Taken together, our study demonstrates that osteoblastic 11β-HSD1 directly contributes to HFD-induced bone loss, glucose handling impairment and obesity.

Abstract Chronic hypobaric hypoxia at high altitudes can impair cognitive functions, especially causing deficits in learning and memory, which require therapeutic intervention. Here, we showed that mice subjected to hypobaric hypoxia (simulating an altitude of 5000 m) for one month experienced significant cognitive impairment, accompanied by increased biomarker levels of oxidative stress in the brain and blood. Oral administration of a novel formulation of edaravone, a free radical scavenger approved for the treatment of ischaemic stroke and amyotrophic lateral sclerosis, significantly alleviated oxidative stress and cognitive impairments caused by chronic hypobaric hypoxia. Furthermore, oral edaravone treatment also mitigated neuroinflammation and restored hippocampal neural stem cell exhaustion. Additionally, periostin (Postn) is vital in the cognitive deficits caused by chronic hypobaric hypoxia and may be a molecular target of edaravone. In conclusion, our results suggest that oxidative stress plays a crucial role in the cognitive deficits caused by chronic hypobaric hypoxia and that oral edaravone is a potential medicine for protecting against cognitive deficits caused by chronic hypobaric hypoxia in high-altitude areas.

Abstract Background The Domain of unknown function 679 membrane protein (DMP) family, which is unique to plants, plays a crucial role in reproductive development, stress response and aging. A comprehensive study was conducted to identify the DMP gene members of oat (Avena sativa) and to investigate their structural features and tissue-specific expression profiles. Utilizing whole genome and transcriptome data, we analyzed the physicochemical properties, gene structure, cis-acting elements, phylogenetic relationships, conserved structural (CS) domains, CS motifs and expression patterns of the AsDMP family in A. sativa. Results The DMP family genes of A. sativa were distributed across 17 chromosomal scaffolds, encompassing a total of 33 members. Based on phylogenetic relationships, the AsDMP genes were classified into five distinct subfamilies. The gene structure also suggests that A. sativa may have undergone an intron loss event during its evolution. Covariance analysis indicates that genome-wide duplication and segmental duplication may be the major contributor to the expansion of the AsDMP gene family. Ka/Ks selective pressure analysis of the AsDMP gene family suggests that DMP gene pairs are generally conserved over evolutionary time. The upstream promoters of these genes contain several cis-acting elements, suggesting a potential role in abiotic stress responses and hormone induction. Transcriptome data revealed that the expression patterns of the DMP genes are involved in tissue and organ development. In this study, the AsDMP genes (AsDMP1, AsDMP19, and AsDMP22) were identified as potential regulators of seed senescence in A. sativa. These genes could serve as candidates for breeding studies focused on seed longevity and anti-aging germplasm in A. sativa. The study provides valuable insights into the regulatory mechanisms of the AsDMP gene family in the aging process of A. sativa germplasm and offers theoretical support for further function investigation into the functions of AsDMP genes and the molecular mechanisms underlying seed anti-aging. Conclusions This study identified the AsDMP genes as being involved in the aging process of A. sativa seeds, marking the first report on the potential role of DMP genes in seed aging for A. sativa.

Abstract Controversies persist about the protective effects of vaccines against acute cardiovascular events. Using electronic medical records from hospitals and influenza vaccine administration data in Beijing, China, we studied individuals vaccinated between January 1, 2016, and December 31, 2018, who experienced at least one acute cardiovascular event within two years. A self-controlled case series design calculated the relative incidence (RI) and 95% confidence interval (CI) of acute cardiovascular events within one year after vaccination. Among 1647 participants (median age: 65 years, 38.43% female), the risk of events 29–365 days post-vaccination was 0.76 times the baseline level (RI: 0.76; 95% CI: 0.68–0.84). The protective effect was more pronounced in younger participants (P = 0.043) and those without cardiovascular history (P

Introduction: Ischemia-reperfusion injury (IRI) is detrimental to kidney transplants and may contribute to poor long-term outcomes of transplantation. Programmed cell death (PCD), a regulated cell death form triggered by IRI, is often indicative of an unfavorable prognosis following transplantation. However, given the intricate pathophysiology of IRI and the considerable variability in clinical conditions during kidney transplantation, the specific patterns of cell death within renal tissues remain ambiguous. Consequently, accurately predicting the outcomes for transplanted kidneys continues to be a formidable challenge. Methods: Eight Gene Expression Omnibus datasets of biopsied transplanted kidney samples post-IRI and 1,548 PCD-related genes derived from 18 PCD patterns were collected in our study. Consensus clustering was performed to identify distinct IRI subtypes based on PCD features (IRI PCD subtypes). Differential enrichment analysis of cell death, metabolic signatures, and immune infiltration across these subtypes was evaluated. Three machine learning algorithms were used to identify PCD patterns related to prognosis. Genes associated with graft loss were screened for each PCD type. A predictive model for graft loss was constructed using 101 combinations of 10 machine learning algorithms. Results: Four IRI subtypes were identified: PCD-A, PCD-B, PCD-C, and PCD-D. PCD-A, characterized by high enrichment of multiple cell death patterns, significant metabolic paralysis, and immune infiltration, showed the poorest prognosis among the four subtypes. While PCD-D involved the least kind of cell death patterns with the features of extensive activation of metabolic pathways and the lowest immune infiltration, correlating with the best prognosis in the four subtypes. Using various machine learning algorithms, 10 cell death patterns and 42 PCD-related genes were identified as positively correlated with graft loss. The predictive model demonstrated high sensitivity and specificity, with area under the curve values for 0.5-, 1-, 2-, 3-, and 4-year graft survival at 0.888, 0.91, 0.926, 0.923, and 0.923, respectively. Conclusion: Our study explored the comprehensive features of PCD patterns in transplanted kidney samples post-IRI. The prediction model shows great promise in forecasting graft loss and could aid in risk stratification in patients following kidney transplantation.

It remains controversial as to whether a face-centered cubic (FCC) phase exists in pure titanium (Ti) upon deformation, since the FCC structures in deformed Ti may well be TiHx resulting from the sample preparation process. Here, by using in situ transmission electron microscopy (TEM), we uncover direct evidences on the nucleation and growth of FCC-Ti right in front of the crack tip in the α-Ti matrix. Atomic resolution images further reveal that the transformation can be mediated by either partial dislocations on basal planes or shear and atomic shuffle on the FCC1 1 0|HCP1 0 -1 0 interfaces.

Background Familial hypercholesterolemia (FH) is an autosomal dominant inherited disorder characterized by severe hypercholesterolemia and significantly elevated levels of serum low-density lipoprotein cholesterol (LDL-C). Patients with FH are at an increased risk of premature atherosclerotic cardiovascular disease, and early detection and treatment can improve their survival rates. Objective This study aims to explore the clinical value and significance of screening for FH among patients with hypercholesterolemia in community populations. Methods During the period from July to December 2023, a total of 164 patients diagnosed with hyperlipidemia and exhibiting LDL-C levels ≥4.90 mmol/L underwent gene sequencing at Department of Cardiology, the Affiliated Suzhou Hospital of Nanjing Medical University and its 5 community health centers within the medical alliance. Based on quartile intervals of LDL-C levels, the patients were stratified into four groups: Q1 group (LDL-C ≤5.10 mmol/L, n=43), Q2 group (5.10 mmol/L≤LDL-C≤5.32 mmol/L, n=40), Q3 group (5.32 mmol/L≤LDL-C≤5.67 mmol/L, n=41), and Q4 group (LDL-C≥5.67 mmol/L, n=40). Baseline data and laboratory test results of the patients were collected. Results A total of 164 patients with hypercholesterolemia were included, with a prevalence of awareness of dyslipidemia at 39.02% (64/164), and 21.95% (36/164) of the patients had previously taken lipid-lowering medications. The comparison of total cholesterol (TC) and LDL-C among Q1 to Q4 groups showed statistically significant differences (P0.05) . Conclusion In community populations with hypercholesterolemia and LDL-C ≥ 4.9 mmol/L, the rate of FH gene mutations is relatively high, and the rate of other primary (genetic) lipid metabolism gene mutations is also high. Screening for FH among patients with hypercholesterolemia in community populations has significant clinical importance and value.

Abstract This study presents a global database of pitted cones on Mars. This database was created using an active deep-learning approach based on a global mosaic of Mars Context Camera (CTX) images, followed by extensive manual verification. The global database contains 250,547 pitted cones along with their central coordinates and diameters. 94.2% of the pitted cones have diameters ranging from 100 m to 1 km. Most of them are in the northern lowlands, while some are scattered in the southern highlands. Systematic evaluation of the extracted pitted cones is performed in Isidis Planitia, Acidalia Planitia, and Cerberus Palus on Mars. The results reveal that the precision ranges from 79.2% to 85.6%, and the recall rate ranges from 62.4% to 87.7%, indicating a varying among regions but satisfactory performance. Manual digitizing evaluation indicates that over 94.1% of manual labels by different annotators have a differentiation rate of 10%, showing promising precision and consistency. This global database can facilitate further research on the origin and evolution of pitted cones on Mars.

Abstract Background Accumulating studies have highlighted the significant role of circulating metabolomics in the etiology of reproductive system disorders. However, the causal effects between genetically determined metabolites (GDMs) and reproductive diseases, including primary ovarian insufficiency (POI), polycystic ovary syndrome (PCOS), and abnormal spermatozoa (AS), still await thorough clarification. Methods With the currently most comprehensive genome-wide association studies (GWAS) data of metabolomics, systematic two-sample Mendelian randomization (MR) analyses were conducted to disclose causal associations between 1,091 blood metabolites and 309 metabolite ratios with reproductive disorders. The inverse-variance weighted (IVW) method served as the primary analysis approach, and multiple effective MR methods were employed as complementary analyses including MR-Egger, weighted median, constrained maximum likelihood (cML-MA), contamination mixture method, robust adjusted profile score (MR-RAPS), and debiased inverse-variance weighted method. Heterogeneity and pleiotropy were assessed via MR-Egger intercept and Cochran’s Q statistical analysis. Outliers were detected by Radial MR and MR-PRESSO methods. External replication and metabolic pathway analysis were also conducted. Results Potential causal associations of 63 GDMs with POI were unearthed, and five metabolites with strong causal links to POI were emphasized. Two metabolic pathways related to the pathogenesis of POI were pinpointed. Suggestive causal effects of 70 GDMs on PCOS were detected, among which 7 metabolites stood out for strong causality with elevated PCOS risk. Four metabolic pathways associated with PCOS mechanisms were recognized. For AS, 64 GDMs as potential predictive biomarkers were identified, particularly highlighting two metabolites for their strong causal connections with AS. Three pathways underneath the AS mechanism were identified. Multiple assessments were conducted to further confirm the reliability and robustness of our causal inferences. Conclusion By extensively assessing the causal implications of circulating GDMs on reproductive system disorders, our study underscores the intricate and pivotal role of metabolomics in reproductive ill-health, laying a theoretical foundation for clinical strategies from metabolic insights.

Abstract Swin Transformer is an important work among all the attempts to reduce the computational complexity of Transformers while maintaining its excellent performance in computer vision. Window-based patch self-attention can use the local connectivity of the image features, and the shifted window-based patch self-attention enables the communication of information between different patches in the entire image scope. Through in-depth research on the effects of different sizes of shifted windows on the patch information communication efficiency, this article proposes a Dual-Scale Transformer with double-sized shifted window attention method. The proposed method surpasses CNN-based methods such as U-Net, AttenU-Net, ResU-Net, CE-Net by a considerable margin (Approximately 3% $$\sim$$ ∼ 6% increase), and outperforms the Transformer based models single-scale Swin Transformer(SwinT)(Approximately 1% increase), on the datasets of the Kvasir-SEG, ISIC2017, MICCAI EndoVisSub-Instrument and CadVesSet. The experimental results verify that the proposed dual scale shifted window attention benefits the communication of patch information and can enhance the segmentation results to state of the art. We also implement an ablation study on the effect of the shifted window size on the information flow efficiency and verify that the dual-scale shifted window attention is the optimized network design. Our study highlights the significant impact of network structure design on visual performance, providing valuable insights for the design of networks based on Transformer architectures.

Abstract Background Triple-negative breast cancer (TNBC) is a recurrent, heterogeneous, and invasive form of breast cancer. The treatment of TNBC patients with paclitaxel and fluorouracil in a sequential manner has shown promising outcomes. However, it is challenging to deliver these chemotherapeutic agents sequentially to TNBC tumors. We aim to explore a precision therapy strategy for TNBC through the sequential delivery of paclitaxel and fluorouracil. Methods We developed a dual chemo-loaded aptamer with redox-sensitive caged paclitaxel for rapid release and non-cleavable caged fluorouracil for slow release. The binding affinity to the target protein was validated using Enzyme-linked oligonucleotide assays and Surface plasmon resonance assays. The targeting and internalization abilities into tumors were confirmed using Flow cytometry assays and Confocal microscopy assays. The inhibitory effects on TNBC progression were evaluated by pharmacological studies in vitro and in vivo. Results Various redox-responsive aptamer-paclitaxel conjugates were synthesized. Among them, AS1411-paclitaxel conjugate with a thioether linker (ASP) exhibited high anti-proliferation ability against TNBC cells, and its targeting ability was further improved through fluorouracil modification. The fluorouracil modified AS1411-paclitaxel conjugate with a thioether linker (FASP) exhibited effective targeting of TNBC cells and significantly improved the inhibitory effects on TNBC progression in vitro and in vivo. Conclusions This study successfully developed fluorouracil-modified AS1411-paclitaxel conjugates with a thioether linker for targeted combination chemotherapy in TNBC. These conjugates demonstrated efficient recognition of TNBC cells, enabling targeted delivery and controlled release of paclitaxel and fluorouracil. This approach resulted in synergistic antitumor effects and reduced toxicity in vivo. However, challenges related to stability, immunogenicity, and scalability need to be further investigated for future translational applications.

Sclerostin emerges as a novel target for bone anabolic therapy in bone diseases. Osteogenesis imperfecta (OI) and X-linked hypophosphatemia (XLH) are rare bone diseases in which therapeutic potential of sclerostin inhibition cannot be ignored. In OI, genetic/pharmacologic sclerostin inhibition promoted bone formation of mice, but responses varied by genotype and age. Serum sclerostin levels were higher in young OI-I patients, while lower in adult OI-I/III/IV. It's worth investigating whether therapeutic response of OI to sclerostin inhibition could be clinically predicted by genotype and age. In XLH, preclinical/clinical data suggested factors other than identified FGF23 contributing to XLH. Higher levels of circulating sclerostin were detected in XLH. Sclerostin inhibition promoted bone formation in Hyp mice, while restored phosphate homeostasis in age-/gender-dependent manner. The role of sclerostin in regulating phosphate metabolism deserves investigation. Sclerostin/FGF23 levels of XLH patients with/without response to FGF23-antibody warrants study to develop precise sclerostin/FGF23 inhibition strategy or synergistic/additive strategy. Notably, OI patients were associated with cardiovascular abnormalities, so were XLH patients receiving conventional therapy. Targeting sclerostin loop3 promoted bone formation without cardiovascular risks. Further, blockade of sclerostin loop3-LRP4 interaction while preserving sclerostin loop2-ApoER2 interaction could be a potential precise sclerostin inhibition strategy for OI and XLH with cardiovascular safety.The Translational Potential of this Article.Preclinical data on the molecular understanding of sclerostin inhibition in OI and therapeutic efficacy in mouse models of different genotypes, as well as clinical data on serum sclerostin levels in patients with different phenotypes of OI, were reviewed and discussed. Translationally, it would facilitate to develop clinical prediction strategies (e.g. based on genotype and age, not just phenotype) for OI patients responsive to sclerostin inhibition. Both preclinical and clinical data suggested sclerostin as another factor contributing to XLH, in addition to the identified FGF23. The molecular understanding and therapeutic effects of sclerostin inhibition on both promoting bone anabolism and improving phosphate homostasis in Hyp mice were reviewed and discussed. Translationaly, it would facilitate the development of precise sclerostin/FGF23 inhibition strategy or synergistic/additive strategy for the treatment of XLH. Cardiovascular risk could not be ruled out during sclerostin inhibition treatment, especially for OI and XLH patients with cardiovascular diseases history and cardiovascular abnormalities. Studies on the role of sclerostin in inhiting bone formation and protecting cardiovascular system were reviewed and discussed. Translationaly, blockade of sclerostin loop3-LRP4 interaction while preserving sclerostin loop2-ApoER2 interaction could be a potential precise sclerostin inhibition strategy for OI and XLH with cardiovascular safety.

Abstract Optoelectronic neural interfaces can leverage the photovoltaic effect to convert light into electrical current, inducing charge redistribution and enabling nerve stimulation. This method offers a non-genetic and remote approach for neuromodulation. Developing biodegradable and efficient optoelectronic neural interfaces is important for achieving transdermal stimulation while minimizing infection risks associated with device retrieval, thereby maximizing therapeutic outcomes. We propose a biodegradable, flexible, and miniaturized silicon-based neural interface capable of transdermal optoelectronic stimulation for neural modulation and nerve regeneration. Enhancing the device interface with thin-film molybdenum significantly improves the efficacy of neural stimulation. Our study demonstrates successful activation of the sciatic nerve in rodents and the facial nerve in rabbits. Moreover, transdermal optoelectronic stimulation accelerates the functional recovery of injured facial nerves.

BackgroundWhile observational research has highlighted a possible link between ankylosing spondylitis (AS) and type 2 diabetes (T2DM), the quality of evidence remains limited, and the causal relationship is yet to be established. This study aims to explore the causal link between AS and T2DM, as well as its impact on traits related to glucose metabolism.MethodTo infer a causal relationship between AS and various diabetes-related traits, including type 1 diabetes (T1DM), T2DM, blood glucose levels, fasting glucose, glycated hemoglobin, and fasting insulin, we employed Mendelian randomization (MR) analysis. We sourced GWAS summary data for both exposure and outcome variables from the IEU OpenGWAS database, GWAS Catalog, and FinnGen database. To synthesize the results of the MR analyses, we applied meta-analysis techniques using either a fixed or random effects model. For identifying and excluding instrumental variants (IVs) that exhibit horizontal pleiotropy with the outcomes, we utilized the MR-PRESSO method. Sensitivity analyses were conducted using the MR-Egger method, along with Q and I^2 tests, to ensure the robustness of our findings.ResultsOur analysis revealed a significant association between AS and an increased risk of T1DM with an odds ratio (OR) of 1.5754 (95% CI: 1.2935 to 1.9187) and T2DM with an OR of 1.0519 (95% CI: 1.0059 to 1.1001). Additionally, AS was associated with elevated levels of fasting glucose (beta coefficient = 0.0165, 95% CI: 0.0029 to 0.0301) and blood glucose (beta coefficient = 0.0280, 95% CI: 0.0086 to 0.0474), alongside a decrease in fasting insulin levels (beta coefficient = -0.0190, 95% CI: -0.0330 to -0.0050).ConclusionOur findings collectively underscore the detrimental impact of AS on the development of diabetes, highlighting the critical influence of autoimmune disorders in diabetes onset. This provides profound insights into the pathogenesis of diabetes from an immunological standpoint.

The in vitro research found that Auricularia auricula-judae (A. auricula) crude polysaccharides showed hypoglycemic and antioxidant properties, whereas purified polysaccharides were more effective. A. auricula polysaccharide was identified as a typical heteropolysaccharide, with a pyran-type sugar ring coupled via α- and β-type glycosidic linkage. The monosaccharide composition includes Man, Xyl, Ara, Glc, Rha, and galactose (Gal), at a molar ratio of 61.36:37.92:36.27:25.79:24.30:20.38, while also containing a small amount of galacturonic and glucuronic acid. A. auricula polysaccharide showed smooth, flaky structures, with a small portion exhibiting a filamentous and spherical morphology. A. auricula polysaccharides activate glycogen synthetase kinase 3β (GSK3β) phosphorylation, leading to increased hepatic glycogen production, and they reduce glucose synthesis and lower blood sugar levels by decreasing phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) enzyme activity, and enhancing FOXO1 phosphorylation. The findings suggested that A. auricula polysaccharides could be used as natural hypoglycemic agents.

The immune responses play a profound role in the progression of lung lesions in both infectious and non-infectious diseases. Dendritic cells, as the “frontline” immune cells responsible for antigen presentation, set up a bridge between innate and adaptive immunity in the course of these diseases. Among the receptors equipped in dendritic cells, Toll-like receptors are a group of specialized receptors as one type of pattern recognition receptors, capable of sensing environmental signals including invading pathogens and self-antigens. Toll-like receptor 4, a pivotal member of the Toll-like receptor family, was formerly recognized as a receptor sensitive to the outer membrane component lipopolysaccharide derived from Gram-negative bacteria, triggering the subsequent response. Moreover, its other essential roles in immune responses have drawn significant attention in the past decade. A better understanding of the implication of Toll-like receptor 4 in dendritic cells could contribute to the management of pulmonary diseases including pneumonia, pulmonary tuberculosis, asthma, acute lung injury, and lung cancer.

ABSTRACT About 35% of grassland in Sanjiangyuan area of China has degenerated into black‐soil mountain. Artificial grassland is considered to be an effective measure to alleviate the severely degraded grassland in the alpine region of the three rivers and has been widely used. However, the pattern, potential function, and changes of carbon and nitrogen contents of soil microorganisms in degraded grassland in Heimushan by planting artificial grassland are still unclear. In this study, mixed‐sown artificial alpine grassland (AG) was the focus of our study, whereas degraded black‐soil mountain grassland (BG) and natural alpine grassland (NG) served as controls. Illumina 16S and ITS gene sequence analyses were used to analyze the community structure of the soil bacteria and fungi. The functional groups of NG, AG, and BG were predicted using the FAPROTAX and FUNGuild databases. In addition, the levels of soil carbon, nitrogen, and soil enzyme activities were evaluated. The results indicated a significant increase in the aboveground biomass of BG due to the planting artificial grassland. Moreover, the contents of total carbon (TC), total nitrogen (TN), ammonium nitrogen (NH4+−N), microbial biomass carbon (MBC), microbial biomass nitrogen (MBN), and leucine aminopeptidase (LAP) increased in the soil. Planting artificial grasslands changed the composition of bacterial and fungal communities. Among these, the bacterial community was more sensitive to planting artificial grasslands. The relative abundance of bacterial functional groups involved in carbon and nitrogen cycling changed significantly, suggesting that bacteria may play a role in regulating nutrient cycling during artificial grassland planting. Soil TC, TN, LAP, and NH4+−N affected the microbial community structure related to carbon and nitrogen. NH4+−N and β‐1,4‐glucosidase were carbon and nitrogen factors, respectively, that affected functional changes in fungi. These results indicate that planting artificial grasslands can effectively enhance the productivity of degraded black‐soil mountain and regulate soil microbial communities and soil physical and chemical properties.

Objectives Pancreatic cancer presents a formidable challenge with its aggressive nature and dismal prognosis, often hampered by elusive early symptoms. The tumor microenvironment (TME) emerges as a pivotal player in pancreatic cancer progression and treatment responses, characterized notably by hypoxia and immunosuppression. In this study, we aimed to identify hypoxia-related genes and develop a prognostic model for pancreatic cancer leveraging these genes. Methods Through analysis of gene expression data from The Cancer Genome Atlas (TCGA) and subsequent GO/KEGG enrichment analysis, hypoxia-related pathways were identified. We constructed a prognostic model using lasso regression and validated it using an independent dataset. Results Our results showed that expression levels of PLAU, SLC2A1, and CA9 exhibited significant associations with prognosis in pancreatic cancer. The prognostic model, built upon these genes, displayed robust predictive accuracy and was validated in an independent dataset. Furthermore, we found a correlation between the risk score of the prognostic model and clinical parameters of pancreatic cancer patients. At the same time, we also explored the relationship between the established hypoxia-related prognostic model and the immune microenvironment at the single-cell level. RT-qPCR results showed notable differences in the expression of hypoxia pathway-related genes between normal PANC-1 and hypoxic-treated PANC-1 cells. Conclusion Our study provides insights into the role of the hypoxic microenvironment in pancreatic cancer and offers a promising prognostic tool for clinical application.

ObjectiveChronic subdural hematoma (CSDH) is a common neurologic disorder with increasing incidence, which can be preceded by head trauma or occur in the absence of trauma. In order to deeply understand the clinical characteristics of this disease, we conducted this retrospective study to explore the clinical differences between traumatic and not otherwise specified (NOS) CSDH.MethodsAccording to the inclusion and exclusion criteria, 168 traumatic CSDH patients and 133 NOS CSDH patients were recruited from January 2015 to October 2023 in our cohort. The collected data and compared parameters including baseline clinical features and radiological outcomes of hematoma within 24 h of hospital admission, as well as the treatment method and clinical outcome of traumatic and NOS CSDH patients.ResultsCompared to NOS CSDH patients, the average age was younger, epilepsy was more frequent, asymptomatic cases were more common, and the taking of anticoagulants and antiplatelet drugs were rarer in traumatic CSDH patients (all P < 0.05). However, no differences were found in the radiological presentations of hematoma at admission, the treatment methods and clinical outcomes of traumatic and NOS CSDH patients (all P > 0.05).ConclusionTraumatic CSDH patients were more likely to be asymptomatic or have seizures, while NOS CSDH were more common in elder people and in individuals with the history of taking anticoagulants and antiplatelet drugs. The treatment methods and clinical outcomes were similar in traumatic and NOS CSDH patients.

ObjectiveAntiviral medications for influenza could be ineffective due to the emergence of resistant influenza virus strains. Ruhao Dashi (RHDS) granules possess anti-inflammatory and antibacterial effects. The present study aimed to determine the efficacy of RHDS granules in treating influenza-infected mice and the mechanism underlying this treatment as well as its effect on the intestinal flora composition of the infected mice.MethodsThe HPLC-UV method was used to identify the active components of RHDS granules. ICR mice were infected with influenza A virus (IAV) H1N1 subtype through a nasal drip. After the influenza mice model was successfully established, the pathological changes in the lungs were observed for 5 days after gavage treatment with 0.9% sterile saline and low, medium, and high doses (0.07, 0.14, and 0.28 g/mL, respectively) of RHDS granules. The serum levels of the cytokines IL-6 and TNF-α and sIgA were detected by ELISA. Real-time fluorescence quantitative PCR and western blotting assay were performed to determine the expression levels of the tight junction (TJ) proteins claudin-1, occludin, and zonula occludens-1 (ZO-1) in colon tissues. Furthermore, 16S rRNA gene sequencing of feces samples was conducted to assess the effect of RHDS granules on the gut microbiota.ResultsRHDS granules exerted a protective effect on the lung tissues of IAV-infected mice; moreover, the granules reduced the synthesis of proinflammatory cytokines and increased the relative expression levels of claudin-1, occludin, and ZO-1 in colon tissues. Furthermore, RHDS granule treatment increased the relative abundance of Lactobacillus, Akkermansia, and Faecalibaculum and decreased the relative abundance of Muribaculaceae; thus, RHDS granules could stabilize the intestinal microbiota to some extent.ConclusionRHDS granules exert a therapeutic effect on IAV-infected mice probably by modifying the structural composition of their intestinal microbiota.

One pulse one wire mode was proposed for butt welding ultrafine 304 stainless steel wire mesh by pulsed microplasma arc welding. The weld morphologies and the resultant microstructure and mechanical properties were investigated. The results show that with an increase in duty ratio, the weld tends to vary from quasi-spherical to elliptical-spherical welds. However, the change tendency of welds is opposite when peak current rises. The microstructures in weld zone are γ austenite and δ ferrite, and grow and increase with a rising in duty ratio at peak current 2.2 or 2.4 A though refine in the δ ferrite at peak current 2.6 A. The weld with peak current 2.2 A and duty ratio 30% performs the better mechanical properties.

Abstract The demand for high‐performance X‐ray detectors leads to material innovation for efficient photoelectric conversion and carrier transfer. However, current X‐ray detectors are often susceptible to chemical and irradiation instability, complex fabrication processes, hazardous components, and difficult compatibility. Here, we investigate a two‐dimensional (2D) material with a relatively low atomic number, Ti3C2Tx MXenes, and single crystal silicon for X‐ray detection and single‐pixel imaging (SPI). We fabricate a Ti3C2Tx MXene/Si X‐ray detector demonstrating remarkable optoelectronic performance. This detector exhibits a sensitivity of 1.2 × 107 μC Gyair−1 cm−2, a fast response speed with a rise time of 31 μs, and an incredibly low detection limit of 2.85 nGyair s−1. These superior performances are attributed to the unique charge coupling behavior under X‐ray irradiation via intrinsic polaron formation. The device remains stable even after 50 continuous hours of high‐dose X‐ray irradiation. Our device fabrication process is compatible with silicon‐based semiconductor technology. Our work suggests new directions for eco‐friendly X‐ray detectors and low‐radiation imaging system.

The structure containing explosives may encounter different fire scenarios in application. The influence factors of flame radiant heat flow are numerous and the control mechanism is complex due to the complexity and diversity of fire scenes. It is necessary to identify key physical quantities, analyze the controlling mechanism, and establish boundary heat flow load model. Several factors were considered to comprehend and assess the thermal response characteristics of ammunition in a real fire environment, including the boundary heat flow load, the combined heat transfer effect of the air inter-layer, and the thermal decomposition of energetic explosive. Numerical model and calculation method were developed, and the thermal response characteristics of ammunition exposed to fire were investigated. The results demonstrate that the ammunition's temperature rise increases non-linearly as the thickness of flame engulfment increases. Conversely, the temperature rise decreases non-linearly as distance from the fire source increases. In terms of initiation delay time, it decreases non-linearly as the thickness of flame engulfment increases. However, initiation delay time increases non-linearly as distance from the fire source increases. A comprehensive model that considers real fire environment is crucial for prompt and accurate interventions, when assessing the thermal safety of ammunition in complex fire scenarios.

Abstract Background Colorectal cancer (CRC) is a complex malignancy characterized by diverse molecular profiles, clinical outcomes, and limited precision in prognostic markers. Addressing these challenges, this study utilized multi-omics data to define consensus molecular subtypes in CRC and elucidate their association with clinical outcomes and underlying biological processes. Methods Consensus molecular subtypes were obtained by applying ten integrated multi-omics clustering algorithms to analyze TCGA-CRC multi-omics data, including mRNA, lncRNA, miRNA, DNA methylation CpG sites, and somatic mutation data. The association of subtypes with prognoses, enrichment functions, immune status, and genomic alterations were further analyzed. Next, we conducted univariate Cox and Lasso regression analyses to investigate the potential prognostic application of biomarkers associated with multi-omics subtypes derived from weighted gene co-expression network analysis (WGCNA). The function of one of the biomarkers MID2 was validated in CRC cell lines. Results Two CRC subtypes linked to distinct clinical outcomes were identified in TCGA-CRC cohort and validated with three external datasets. The CS1 subtype exhibited a poor prognosis and was characterized by higher tumor-related Hallmark pathway activity and lower metabolism pathway activity. In addition, the CS1 was predicted to have less immunotherapy responder and exhibited more genomic alteration compared to CS2. Then a prognostic model comprising five genes was established, with patients in the high-risk group showing substantial concordance with the CS1 subtype, and those in the low-risk group with the CS2 subtype. The gene MID2, included in the prognostic model, was found to be correlated with epithelial–mesenchymal transition (EMT) pathway and distinct DNA methylation patterns. Knockdown of MID2 in CRC cells resulted in reduced colony formation, migration, and invasion capacities. Conclusion The integrative multi-omics subtypes proposed potential biomarkers for CRC and provided valuable knowledge for precision oncology.

Abstract Doxorubicin has been used extensively as a potent anticancer agent, but its clinical use is limited by its cardiotoxicity. However, the underlying mechanisms remain to be fully elucidated. In this study, we tested whether NADPH oxidase 2 (Nox2) mediates cardiac sympathetic nerve terminal abnormalities and myocyte autophagy, resulting in cardiac atrophy and dysfunction in doxorubicin-induced heart failure. Nox2 knockout (KO) and wild-type (WT) mice were randomly assigned to receive a single injection of doxorubicin (15 mg/kg, i.p.) or saline. WT doxorubicin mice exhibited the decreases in survival rate, left ventricular (LV) wall thickness and LV fractional shortening and the increase in the lung wet-to-dry weight ratio 1 week after the injections. These alterations were attenuated in Nox2 KO doxorubicin mice. In WT doxorubicin mice, myocardial oxidative stress was increased, myocardial noradrenergic nerve fibers were reduced, myocardial expression of PGP9.5, GAP43, tyrosine hydroxylase and norepinephrine transporter was decreased, and these changes were prevented in Nox2 KO doxorubicin mice. Myocyte autophagy was increased and myocyte size was decreased in WT doxorubicin mice, but not in Nox2 KO doxorubicin mice. Nox2 mediates cardiac sympathetic nerve terminal abnormalities and myocyte autophagy—both of which contribute to cardiac atrophy and failure after doxorubicin treatment.

Abstract Background This study aimed to develop a novel nomogram that can accurately estimate platinum resistance to enhance precision medicine in epithelial ovarian cancer(EOC). Methods EOC patients who received primary therapy at the General Hospital of Ningxia Medical University between January 31, 2019, and June 30, 2021 were included. The LASSO analysis was utilized to screen the variables which contained clinical features and platinum-resistance gene immunohistochemistry scores. A nomogram was created after the logistic regression analysis to develop the prediction model. The consistency index (C-index), calibration curve, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA) were used to assess the nomogram’s performance. Results The logistic regression analysis created a prediction model based on 11 factors filtered down by LASSO regression. As predictors, the immunohistochemical scores of CXLC1, CXCL2, IL6, ABCC1, LRP, BCL2, vascular tumor thrombus, ascites cancer cells, maximum tumor diameter, neoadjuvant chemotherapy, and HE4 were employed. The C-index of the nomogram was found to be 0.975. The nomogram’s specificity is 95.35% and its sensitivity, with a cut-off value of 165.6, is 92.59%, as seen by the ROC curve. After the nomogram was externally validated in the test cohort, the coincidence rate was determined to be 84%, and the ROC curve indicated that the nomogram’s AUC was 0.949. Conclusion A nomogram containing clinical characteristics and platinum gene IHC scores was developed and validated to predict the risk of EOC platinum resistance.