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Abstract Aim of the study To investigate the potential of DNA nanoparticles (DNPs) as carriers and adjuvants for mRNA vaccines. Materials and methods Customized oligonucleotides were assembled into DNA tetrahedra (DNA-TH), which were subsequently complexed with streptavidin and mRNA encoding green fluorescent protein (GFP). Various assays were conducted to evaluat the stability of the DNPs, their cellular uptake, immune activation potential, and GFP mRNA transcription efficiency. P53-mutant HSC-3 cells were used to establish a subcutaneous xenograft tumor model to explore the effects of DNPs as carriers and adjuvants in a disease model. Results The DNPs were remained stable extracellularly and rapidly taken up by antigen-presenting cells. Compared to naked GFP mRNA, DNPs statistically significantly activated immune responses and facilitated GFP mRNA transcription and protein expression both in vitro and in vivo. Immunization with DNP-GFP mRNA complexes induced higher antibody titers compared to naked mRNA. The DNPs demonstrated good biocompatibility. DNP-p53 inhibited the growth of subcutaneous xenograft tumors in mice with p53-mutant HSC-3 cells, outperforming both the naked p53 mRNA and blank control groups, with a statistically significant difference (P

Abstract Background Pseudomyxoma peritonei (PMP) is a rare malignant peritoneal tumor that readily recurs and metastasizes. Studies have shown that cancer stem cells (CSCs) play an important role in tumor recurrence, metastasis, and prognosis. Objective In this study, our aim was to isolate CSCs from various tissues of PMP patients and compare their proliferation, migration, and anti-inflammatory abilities. Methods We identified CSCs subsets with markers CD133+, CD166+, and CD133+/CD166+ at the gene level using single-cell mRNA sequencing (scRNA-seq). Appendiceal CSCs (AC), peritoneal CSCs (PC), and mucous CSCs (MC) were obtained using MACSQuant Tyto sorting technology and FlowSight imaging flow cytometry. The cells were cultured and markers were identified. Finally, the functional phenotypes of the three cell types were compared. Results CSCs content was highest in the appendiceal tumor tissue and lowest in the mucous tissue. The cell viability rate of the sorted CSCs was above 98%, and the positive rate of CD133+ and CD166+ was 70–80%, and CD133+/CD166+ was about 30%. Among the three types of CSCs, MC had the highest proliferation ability, and TNF-α has the greatest inhibitory effect on AC migration. Conclusion AC in patients was more inert and anti-inflammatory, whereas abdominal cavity MC and PC were more active. This study revealed the biological characteristics of CSCs in different tumor tissues of patients with PMP, providing a reference for future targeted CSCs therapy.

In the strip coal mining under buildings, railways and water-bodies and other retaining coal pillar mining methods, the long-term stability of coal pillar group is of paramount importance to the safe and efficient green mining. Based on the interaction relationship between coal pillar and surrounding rock, the plane strain model of retaining coal pillar in inclined coal seam is established, and the analytical expressions of coal pillar stress field and displacement field are deduced by using Rits method. On this basis, combined with the actual strip mining in a certain village, the FLAC3D finite difference numerical simulation method is used to establish a numerical calculation model for the long-term stability of coal pillars in inclined coal seams. Based on Burgers combined creep viscoelastic-plastic constitutive model and numerical simulation results, the effect of time and coal pillar width on long-term stability of coal pillar group is studied. Theoretical and numerical research results show that, affected by the inclination angle of the coal seam, the horizontal displacement of a single coal pillar is more than twice of its vertical displacement. Under the long-term action of the gravity of the overlying strata, the two sides of each coal pillar enters the plastic yielding state after 1 day of creep, and presents a shear failure form. The greater the buried depth of coal pillar, the higher the plastic zone range, stress and displacement peak value of coal pillar at any time, and the time required for coal pillar to reach the stable creep stage gradually increases from 75 days to more than 120 days.

Abstract Background Fetal growth monitoring is important for twin pregnancies. However, there has been no clinically validated tool for monitoring fetal growth of twin pregnancies in China. This study aims to develop and validate a chorionicity-specific growth chart of ultrasound estimated fetal weight (EFW) for Chinese twin pregnancies. Methods This retrospective cohort study included all twin pregnancies who delivered two live fetuses with gestational age ≥ 34 weeks without severe obstetric complications at a tertiary hospital from January 2007 to March 2021. The participants were divided into a development set (delivered in or before December 2017) and a validation set (delivered in or after January 2018). Chorionicity-specific growth charts were created using the generalized additive models for location, scale, and shape (GAMLSS) based on the development set. The fetuses from the validation set were classified into three groups based on the last EFW: small-for-gestational-age (SGA) indicated by both the newly established twin charts and the Hadlock singleton chart currently used for twin pregnancies in China, suspected SGA indicated by only the singleton chart, and no SGA indicated by either chart. The incidence of neonatal outcomes among the three groups was then compared accordingly, including intensive care unit (NICU) stay length, respiratory diseases, and neurological disorders. Results The development set included 883 twin pregnancies and a total of 6374 EFW measurements between 16 and 38 weeks of gestation, and the validation set included 801 twin pregnancies and 7630 EFW measurements. In the development set, monochorionic diamniotic (MCDA) twins had a significantly lower EFW compared to dichorionic diamniotic (DCDA) twins beginning at 26 weeks, with the difference gradually increasing thereafter, supporting the establishment of chorionicity-specific growth charts. Of the 1,602 twin neonates in the validation set, 103 (6.4%) were classified into the SGA group, 164 (10.2%) into the suspected SGA group, and 1335 (83.3%) into the no SGA group. The incidence of respiratory diseases and neurological disorders was comparable between the suspected SGA group and the no SGA group, but apparently higher in the SGA group. Meanwhile, NICU stay lengths were consistently longer for twins in the SGA group compared to the no SGA group (difference: 0.57, 95% CI: 0.31–0.83), with no significant differences observed between the suspected SGA and no SGA groups. Conclusions The fetal growth trajectories differed by chorionicity, with a lower EFW for MCDA twins beginning at 26 weeks. The establishment of chorionicity-specific growth chart could reduce overdiagnosis of SGA and improve fetal growth monitoring of twin pregnancies.

Abstract Climate mitigation policies have broad environmental and socioeconomic impacts and thus underpin progress towards the United Nations Sustainable Development Goals (SDGs). Through national-scale integrated modeling, we explore the spillover effects of China’s long-term climate mitigation pathways (CMPs) on achieving all 17 SDGs, and then identify a cost-effective CMP for China with co-benefits for sustainability. Our analysis indicates that the 9 original CMPs and 180 bundled CMPs can both substantially boost the SDGs, resulting in an increase of 6.33–8.86 and 5.90–9.33 points in overall SDG score (0=no progress, 100=full achievement) by 2060, compared to the Reference pathway of 70.75 points, respectively. The identified cost-effective CMP deals with the trade-offs among sustainability, CO2 emissions and mitigation cost, and maximizes the synergies between them. This CMP can inform future directions for China’s policy-makers to maximize the potential synergies between carbon neutrality and long-term sustainable development.

Abstract Cardiovascular diseases have been the leading cause of global mortality and disability. In addition to traditional drug and surgical treatment, more and more studies investigate tissue engineering therapeutic strategies in cardiovascular medicine. Collagen interweaves in the form of trimeric chains to form the physiological network framework of the extracellular matrix of cardiac and vascular cells, possessing excellent biological properties (such as low immunogenicity and good biocompatibility) and adjustable mechanical properties, which renders it a vital tissue engineering biomaterial for the treatment of cardiovascular diseases. In recent years, promising advances have been made in the application of collagen materials in blood vessel prostheses, injectable cardiac hydrogels, cardiac patches, and hemostatic materials, although their clinical translation still faces some obstacles. Thus, we reviewed these findings and systematically summarizes the application progress as well as problems of clinical translation of collagen biomaterials in the cardiovascular field. The present review contributes to a comprehensive understanding of the application of collagen biomaterials in cardiovascular medicine. Graphical abstract

The effects of five strains of Lactobacillus paracasei from Tibet on constipation and gut microbiota of mice were studied. One hundred and sixty male Kunming mice were randomly divided into two groups: A and B. Each group was randomly divided into a blank subgroup, a model subgroup, five experimental strain (including T1-5, T1-7, T1-9, T1-d, and 5B-1) subgroup and a control strain 6108 subgroup for the laxative function test, with 10 mice in each subgroup. Among them, 80 mice in group A were used to measure the small intestine propulsion rate of mice, and 80 mice in group B were used to measure defecation status. Strains T1-5, T1-9, and 5B-1 with good performance in laxative function test were then selected to detect the regulation of intestinal microbiota and total 24 male BALB/c mice were selected for this experiment, and were divided into a blank subgroup, a T1-5 subgroup, T1-9 subgroup, and 5B-1 subgroup, with 6 mice in each subgroup. The experimental results of the laxative function test showed that: Compared with the model group, the small intestine propulsion rate of mice in T1-9 and 5B-1 groups was significantly higher than that of the model group (P

Rice false smut, caused by Ustilaginoidea virens, is a devastating disease that greatly reduces rice yield and quality. However, controlling rice false smut disease is challenging due to the unique infection mode of U. virens. Therefore, there is a need for early diagnosis and monitoring techniques to prevent the spread of this disease. Lateral flow strip-based recombinase polymerase amplification (LF-RPA) overcomes the limitations of current U. virens detection technologies, which are time-consuming, require delicate equipment, and have a high false-positive rate. In this study, we used a comparative genomics approach to identify Uv_3611, a specific gene of U. virens, as the target for the LF-RPA assay. The designed primers and probe efffectively detected the genomic DNA (gDNA) of U. virens and demonstrated no cross-reactivity with related pathogens. Under optimal conditions, the LF-RPA assay demonstrated a sensitivity of 10 pg of U. virens gDNA. Additionally, by incorporating a simplified PEG-NaOH method for plant DNA extraction, the LF-RPA assay enabled the detection of U. virens in rice spikelets within 30 min, without the need for specialized equipment. Furthermore, the LF-RPA assay successfully detected U. virens in naturally infected rice and seed samples in the field. Therefore, the LF-RPA assay is sensitive, efficient, and convenient, and could be developed as a kit for monitoring rice false smut disease in the field.

Metaheuristic algorithms have become increasingly significant in solving complex optimization problems. To address the limitations of the original Aquila Optimizer (AO), such as insufficient local exploitation ability, low optimization precision, and slow convergence rate, an enhanced Aquila Optimizer (PSAO) for global optimization has been proposed. PSAO uses a better ergodic good point set to initialize the Aquila population and modifies the search method by employing the golden sine operator and the mechanism of self-learning and social learning based on particle swarm, followed by designing a nonlinear balance factor γ as the switching condition of the algorithm. The simulation experiments on benchmark functions and CEC2017 functions have verified that the PSAO has better global optimization ability and stronger robustness compared with other intelligent algorithms. Meanwhile, the contribution of each component that belongs to PSAO has been validated by ablation experiments for the CEC2022 test functions. To further illustrate the practical application potential of PSAO, PSAO is successfully applied to four typical engineering design problems, three of which reach the best fitness values. In addition, utilizing PSAO to solve the UAV trajectory planning problem by considering the objectives of trajectory length, altitude and corner of the flight process, the total flight cost is reduced by 60.22 %, 27.94 %, and 22.41 % compared with AO, PSO and Gold-SA, respectively, which proves its applicability and superiority in solving the real optimization problems.

Abstract The outbreaks of severe acute respiratory syndrome coronavirus (SARS-CoV-1), Middle East respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV-2 highlight the need for countermeasures to prevent future coronavirus pandemics. Given the unpredictable nature of spillover events, preparing antibodies with broad coronavirus-neutralizing activity is an ideal proactive strategy. Here, we investigated whether SARS-CoV-2 infection and vaccination could provide cross-neutralizing antibodies (nAbs) against zoonotic sarbecoviruses. We evaluated the cross-neutralizing profiles of plasma and monoclonal antibodies constructed from B cells from coronavirus disease 2019 (COVID-19) convalescents and vaccine recipients; against sarbecoviruses originating from bats, civets, and pangolins; and against SARS-CoV-1 and SARS-CoV-2. We found that the majority of individuals with natural infection and vaccination elicited broad nAb responses to most tested sarbecoviruses, particularly to clade 1b viruses, but exhibited very low cross-neutralization to SARS-CoV-1 in both natural infection and vaccination, and vaccination boosters significantly augmented the magnitude and breadth of nAbs to sarbecoviruses. Of the nAbs, several exhibited neutralization activity against multiple sarbecoviruses by targeting the spike receptor-binding domain (RBD) and competing with angiotensin-converting enzyme 2 (ACE2) binding. SCM12-61 demonstrated exceptional potency, with half-maximal inhibitory concentration (IC50) values of 0.001–0.091 μg/mL against tested sarbecoviruses; while VSM9-12 exhibited remarkable cross-neutralizing breadth against sarbecoviruses and SARS-CoV-2 Omicron subvariants, highlighting the potential of these two nAbs in combating sarbecoviruses and SARS-CoV-2 Omicron subvariants. Collectively, our findings suggest that vaccination with an ancestral SARS-CoV-2 vaccine, in combination with broad nAbs against sarbecoviruses, may provide a countermeasure for preventing further sarbecovirus outbreaks in humans.

Abstract Cervical cancer is the fourth most common malignant tumor among women globally, posing a significant threat to women’s health. In 2022, approximately 600,000 new cases were reported, and 340,000 deaths occurred due to cervical cancer. Magnetic resonance imaging (MRI) is the preferred imaging method for diagnosing, staging, and evaluating cervical cancer. However, manual segmentation of MRI images is time-consuming and subjective. Therefore, there is an urgent need for automatic segmentation models to identify cervical cancer lesions in MRI scans accurately. All MRIs in our research are from cervical cancer patients diagnosed by pathology at Tongren City People’s Hospital. Strict data selection criteria and clearly defined inclusion and exclusion conditions were established to ensure data consistency and accuracy of research results. The dataset contains imaging data from 122 cervical cancer patients, with each patient having 100 pelvic dynamic contrast-enhanced MRI scans. Annotations were jointly completed by medical professionals from Universiti Putra Malaysia and the Radiology Department of Tongren City People’s Hospital to ensure data accuracy and reliability. Additionally, a novel computer-aided diagnosis model named SwinUNeCCt is proposed. This model incorporates (i) A bidirectional hash-based agent multi-head self-attention mechanism, which optimizes the interaction between local and global features in MRI, aiding in more accurate lesion identification. (ii) Reduced computational complexity of the self-attention mechanism. The effectiveness of the SwinUNeCCt model has been validated through comparisons with state-of-the-art 3D medical models, including nnUnet, TransBTS, nnFormer, UnetR, UnesT, SwinUNetR, and SwinUNeLCsT. In semantic segmentation tasks without a classification module, the SwinUNeCCt model demonstrates excellent performance across multiple key metrics: achieving a 95HD of 6.25, an IoU of 0.669, and a DSC of 0.802, all of which are the best results among the compared models. Simultaneously, SwinUNeCCt strikes a good balance between computational efficiency and model complexity, requiring only 442.7 GFLOPs of computational power and 71.2 M parameters. Furthermore, in semantic segmentation tasks that include a classification module, the SwinUNeCCt model also exhibits powerful recognition capabilities. Although this slightly increases computational overhead and model complexity, its performance surpasses other comparative models. The SwinUNeCCt model demonstrates excellent performance in semantic segmentation tasks, achieving the best results among state-of-the-art 3D medical models across multiple key metrics. It balances computational efficiency and model complexity well, maintaining high performance even with the inclusion of a classification module.

Abstract Background Systemic Lupus Erythematosus (SLE) is a complex autoimmune disorder, and transposable elements (TEs) have been hypothesized to play a significant role in its development. However, limited research has explored this connection. Our study aimed to examine the relationship between TE expression and SLE pathogenesis. Methods We analyzed whole blood RNA-seq datasets from 198 SLE patients and 84 healthy controls. The REdiscoverTE pipeline was employed to quantify TE and other gene expressions, identifying differentially expressed TEs. A TE score was calculated to measure overall TE expression for each sample. Gene ontology and gene set enrichment analyses were conducted to explore the functional implications of TE upregulation. Independent datasets were utilized to replicate the results and investigate cell type-specific TE expression. Results Our analysis identified two distinct patient groups: one with high TE expression and another with TE expression comparable to controls. Patients with high TE expression exhibited upregulation of pathways involving nucleic acid sensors, and TE expression was strongly correlated with interferon (IFN) signatures. Furthermore, these patients displayed deregulated cell composition, including increased neutrophils and decreased regulatory T cells. Neutrophils were suggested as the primary source of TE expression, contributing to IFN production. Conclusions Our findings suggest that TE expression may serve as a crucial mediator in maintaining the activation of interferon pathways, acting as an endogenous source of nucleic acid stimulators in SLE patients.

Abstract Background During the aging process, the number and functional activity of endothelial progenitor cells (EPCs) are impaired, leading to the unsatisfactory efficacy of transplantation. Previous studies demonstrated that Yiqihuoxue decoction (Ginseng-Sanqi-Chuanxiong, GSC) exerts anti-vascular aging effects. The purpose of this study is to evaluated the effects of GSC on D-galactose (D-gal)induced senescence and the underlying mechanisms. Methods The levels of cellular senescence-related markers P16, P21, P53, AMPK and p-AMPK were detected by Western blot analysis (WB). SA-β-gal staining was used to evaluate cell senescence. EPCs function was measured by CCK-8, Transwell cell migration and cell adhesion assay. The morphological changes of mitochondria were detected by confocal microscopy. The protein and mRNA expression of mitochondrial fusion fission Drp1, Mff, Fis1, Mfn1, Mfn2 and Opa1 in mitochondria were detect using WB and RT–qPCR. Mitochondrial membrane potential, mtROS and ATP of EPCs were measured using IF. H&E staining was used to observe the pathological changes and IMT of the aorta. The expressions of AGEs, MMP-2 and VEGF in aorta were measured using Immunohistochemical (IHC). The levels of SOD, MDA, NO and ET-1 in serum were detected by SOD, MDA and NO kits. Results In vitro, GSC ameliorated the senescence of EPCs induced by D-gal and reduced the expression of P16, P21 and P53. The mitochondrial morphology of EPCs was restored, the expression of mitochondrial Drp1, Mff and Fis1 protein was decreased, the levels of mtROS and ATP were decreased, and mitochondrial function was improved. Meanwhile, the expression of AMPK and p-AMPK increased. The improvement effects of GSC on aging and mitochondrial morphology and function were were hindered after adding AMPK inhibitor. In vivo, GSC improved EPCs efficiency, ameliorated aortic structural disorder and decreased IMT in aging mice. The serum SOD level increased and MDA level decreased, indicating the improvement of antioxidant capacity. Increased NO content and ET-1 content suggested improvement of vascular endothelial function. The changes observed in SOD and MMP-2 suggested a reduction in vascular stiffness and the degree of vascular damage. The decreased expression of P21 and P53 indicates the delay of vascular senescence.

Abstract Mountainous ethnic tourism lands are important social-ecological system types. With tourism as the main disturbance factor, the theory of social-ecological system resilience provides a new way to realize the sustainable development of ethno-tourism in mountainous areas. This study divides the social-ecological system into social, economic, and ecological subsystems. It constructs an evaluation index system to assess the resilience of ethnic tourism destinations in mountainous areas, considering vulnerability and adaptability. We investigate 64 counties in the Wuling Mountain area and use set-pair analysis to assess the resilience index of the social-ecological system from 2000 to 2020 and reveal the temporal and spatial characteristics. Obstacle degree models and a genetic algorithm-back propagation neural network are utilized to determine the influencing factors and predict future development trends. The following results were obtained: (1) Temporally, the resilience index shows a steady upward trend, reaching a moderate level. The resilience of the social subsystem fluctuates and rises; the economic subsystem exhibits slow, fast, and slow growth rates with occasional abrupt changes; and the ecological subsystem demonstrates a stable, slightly increasing trend. (2) Spatially, the resilience index is high at the edges and low in the central area, exhibiting a concave distribution. Most counties have moderate or higher resilience. The social and ecological subsystems have low resilience in the south and high resilience in the north. The resilience of the economic subsystem is high at the edges and low in the central area. (3) On the distribution of major obstacle factors, the first two are similar at the county level, and the last three are significantly different. The similarity of the barrier factors is related to the degree of regional proximity of the county, and overall, the similarity is decreasing from north to south and from west to east in the distribution pattern within the area. and to a certain extent, it is affected by terrain and geomorphology. (4) The spatial distribution of the resilience index is similar in 2025 and 2030. The index decreases slightly and then increases annually, with a lower growth rate in the south than in the north. Lower values occur in the northern and southwestern parts, whereas higher values are observed around high-value areas. The region as a whole will develop in a coordinated and integrated manner in the future.

Abstract As an abundant agricultural and forestry biomass resource, hemicelluloses are hard to be effectively degraded and utilized by microorganisms due to the constraints of membrane and metabolic regulations. Herein, we report a synthetic extracellular metabolic pathway with hemicellulose-degrading-enzymes controllably displayed on Escherichia coli surface as engineered bacterial consortia members for efficient utilization of xylan, the most abundant component in hemicellulose. Further, we develop a hemicellulose/O2 microbial fuel cell (MFC) configuring of enzyme-engineered bacterial consortia based bioanode and bacterial-displayed laccase based biocathode. The optimized MFC exhibited an open-circuit voltage of 0.71 V and a maximum power density (P max) of 174.33 ± 4.56 µW cm−2. Meanwhile, 46.6% (w/w) α-ketoglutarate was produced in this hemicellulose fed-MFC. Besides, the MFC retained over 95% of the P max during 6 days’ operation. Therefore, this work establishes an effective and sustainable one-pot process for catalyzing renewable biomass into high-value products and electricity in an environmentally-friendly way.

Abstract Background Recurrent spontaneous abortion (RSA) is defined as two or more consecutive spontaneous abortions before 20 weeks with the same spouse [1]. However, approximately 50% of RSA cases of unknown cause are classified as unexplained recurrent spontaneous abortion (URSA). Potential factors include decreased trophoblast cell migration and invasion, leading to impaired placental implantation and maintenance of the normal maternal-fetal interface. However, the mechanism of this pathogenesis remains unknown. In this study, we investigated the potential role and mechanism of KLF4 in regulating URSA by influencing the invasion and migration ability of trophoblast cells. Methods We firstly identified 817 differentially expressed genes by performing a difference analysis of the dataset GSE121950 [2] related to recurrent abortion, and intersected the top 10 genes obtained respectively by the three algorithms: DMNC, MNC, and EPC using Venn Diagram.To detect the expression levels of core genes, villi samples were obtained from normal pregnant women and patients with URSA. RT-qPCR analysis revealed a significant difference in KLF4 mRNA expression and KLF4 was then analyzed. Trophoblast cell lines HTR8 and JEG3 were used to investigate the effect of KLF4 on trophoblastic function. Wound healing and transwell assays was performed to detect the invasion and migration of trophoblast cells. The expression of epithelial-mesenchymal transition(EMT) molecules were detected by RT-qPCR and western blot. Promoter detection and epigenetic modification were detected by chromatin immunoprecipitation (ChIP) assay. Molecular nuclear localization was detected by immunofluorescence and subcellular fractionation. Miscarried mice model was used to study the effects of KLF4 on URSA induced by reduced trophoblast invasion and migration. Results KLF4 is highly expressed in the villi of patients with URSA. KLF4 inhibits the expression level of H3R2ME2a in trophoblast cells by regulating the transcriptional level and nuclear translocation of PRMT6, thereby inhibiting the possible regulatory mechanism of trophoblastic invasion and providing a potential treatment strategy for URSA in vivo. Conclusions The KLF4/PRMT6/H3R2ME2a axis regulates mechanisms associated with unexplained recurrent spontaneous abortion by regulating trophoblast function.

Objective The exact relationship among atypical periprosthetic femoral fractures (APFFs), typical periprosthetic femoral fractures (PFFs), and atypical femur fractures (AFFs) remains unclear. This study aimed to investigate the prevalence of APFFs among PFFs and to identify the clinical characteristics, management, and prognosis that distinguish APFFs from typical PFFs and AFFs to further determine the relationship among these three fracture types. Methods In this retrospective study, we reviewed the clinical data of 117 consecutive patients who had PFFs after hip arthroplasty between January 2012 and December 2022 and further classified them into an APFF group and a typical PFF group according to the revised ASBMR diagnostic criteria for AFF. Moreover, patients who had subtrochanteric or femoral shaft fractures in the same period and met the diagnostic criteria for AFF were recruited and classified into the AFF group. Demographic information, minor features of AFF, comorbidities, history of medication usage, management, and complications were collected and compared among patients with typical PFFs, APFFs, and AFFs. Results Eleven PFFs were identified as APFFs, and the prevalence of APFFs among PFFs was 9.4%. Significant differences were found in generalized increase in cortical thickness (p = 0.019), prodromal symptoms (p

AIM: To investigate the molecular mechanisms underlying the influence of hypoxia and alpha-ketoglutaric acid (α-KG) on scleral collagen expression. METHODS: Meta-analysis and clinical statistics were used to prove the changes in choroidal thickness (ChT) during myopia. The establishment of a hypoxic myopia model (HYP) for rabbit scleral fibroblasts through hypoxic culture and the effects of hypoxia and α-KG on collagen expression were demonstrated by Sirius red staining. Transcriptome analysis was used to verify the genes and pathways that hypoxia and α-KG affect collagen expression. Finally, real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used for reverse verification. RESULTS: Meta-analysis results aligned with clinical statistics, revealing a thinning of ChT, leading to scleral hypoxia. Sirius red staining indicated lower collagen expression in the HYP group and higher collagen expression in the HYP+α-KG group, showed that hypoxia reduced collagen expression in scleral fibroblasts, while α-KG can elevated collagen expression under HYP conditions. Transcriptome analysis unveiled the related genes and signaling pathways of hypoxia and α-KG affect scleral collagen expression and the results were verified by RT-qPCR. CONCLUSION: The potential molecular mechanisms through which hypoxia and α-KG influencing myopia is unraveled and three novel genes TLCD4, TBC1D4, and EPHX3 are identified. These findings provide a new perspective on the prevention and treatment of myopia via regulating collagen expression.

Abstract Viral encephalitis is characterized by inflammation of the brain parenchyma caused by a variety of viruses, among which the Japanese encephalitis (JE) virus (JEV) is a typical representative arbovirus. Neuronal death, neuroinflammation, and breakdown of the blood brain barrier (BBB) constitute vicious circles of JE progression. Currently, there is no effective therapy to prevent this damage. Growth arrest specific gene 6 (GAS6) is a secreted growth factor that binds to the TYRO3, AXL, and MERTK (TAM) family of receptor tyrosine kinases and has been demonstrated to participate in neuroprotection and suppression of inflammation in many central nervous system (CNS) diseases which has great potential for JE intervention. In this study, we found that GAS6 expression in the brain was decreased and was reversely correlated with viral load and neuronal loss. Mice with GAS6/TAM signalling deficiency showed higher mortality and accelerated neuroinflammation during peripheral JEV infection, accompanied by BBB breakdown. GAS6 directly promoted the expression of tight junction proteins in bEnd.3 cells and strengthened BBB integrity, partly via AXL. Mice administered GAS6 were more resistant to JEV infection due to increased BBB integrity, as well as decreased viral load and neuroinflammation. Thus, targeted GAS6 delivery may represent a strategy for the prevention and treatment of JE especially in patients with impaired BBB.

Abstract Background Anemia frequently occurs in patients with hip fractures and represents a risk factor that can potentially be altered. To evaluate the association between admission anemia and complications in older hip fracture patients while exploring the potential impact of anemia on complications from the perspective of overall, operation and non-operation. Methods This retrospective study enrolled in-patients over 60 years old with hip fractures from January 2020 to November 2023. At admission, anemic patients were identified as having a hemoglobin level below 12 g/dL in females and 13 g/dL in males. Anemia was further classified as mild, moderate, or severe. Data encompassing demographics, comorbidities, medications, information on fracture and surgery, and complications were collected. Results A total of 462/679 patients had anemia, including 348, 105, and 9 with mild, moderate, and severe anemia, respectively. A total of 281 individuals experienced complications, including 212 and 69 with and without operation, respectively. Multivariate regression analysis identified anemia as a greater risk for acute heart failure (OR = 2.056, p = 0.037, 95% CI 1.043–4.052) than non-anemia. Moderate to severe anemia was a significant risk factor for any complication (OR = 1.584, p = 0.028, 95% CI 1.050–2.390), ≥ 2 (OR = 2.364, p = 0.001, 95% CI 1.443–3.872) or 3 (OR = 2.311, p = 0.022, 95% CI 1.131–4.720) complications, delirium (OR = 2.301, p = 0.018, 95% CI 1.156–4.579), venous thromboembolism (OR = 2.031, p = 0.042, 95% CI 1.025–4.025), and acute heart failure (OR = 2.095, p = 0.016, 95% CI 1.145–3.834), compared with mild to non-anemia. Similar results were observed in operated patients, while anemia and its severity were not associated with complications in non-operated patients. Conclusion Moderate to severe anemia caused complications in elderly hip fracture patients, but it was not observed in non-operated individuals. These findings would support orthopedic physicians’ hierarchical management of anemic patients.

Abstract Combining the FDA Adverse Event Reporting System (FAERS) and the Cancer Genome Atlas (TCGA) databases, we aim to explore the factors that influence anti-programmed cell death protein-1 inhibitors/programmed death-ligand-1 (PD-1/PD-L1) related severe cardiac adverse events (cAEs). We obtained anti-PD-1/PD-L1 adverse event reports from January 2014 to December 2022 from the FAERS database. Disproportionality analysis was performed to find anti-PD-1/PD-L1-related cAEs using the proportional reporting ratio (PRR). We were exploring influencing factors based on multivariate logistic regression analysis. Finally, we utilized a strategy that combines FAERS and TCGA databases to explore the potential immune and genetic influencing factors associated with anti-PD-1/PD-L1-related severe cAEs. Reports of severe cAEs accounted for 7.10% of the overall anti-PD-1/PD-L1 adverse event reports in the FAERS database. Immune-mediated myocarditis (PRR = 77.01[59.77–99.23]) shows the strongest toxic signal. The elderly group (65–74: OR = 1.34[1.23–1.47], ≥ 75: OR = 1.64[1.49–1.81]), male (OR = 1.14[1.05–1.24]), anti-PD-L1 agents (OR = 1.17[1.03–1.33]), patients with other adverse events (OR = 2.38[2.17–2.60]), and the concomitant use of proton pump inhibitor (OR = 1.29[1.17–1.43]), nonsteroidal anti-inflammatory drugs (OR = 1.17[1.04–1.31]), or antibiotics (OR = 1.24[1.08–1.43]) may increase the risk of severe cAEs. In addition, PD-L1 mRNA (Rs = 0.71, FDR = 2.30 × 10− 3) and low-density lipoprotein receptor-related protein 3 (LRP3) (Rs = 0.82, FDR = 2.17 × 10− 2) may be immune and genetic influencing factors for severe cAEs. Severe cAEs may be related to antigen receptor-mediated signalling pathways. In this study, we found that age, gender, anti-PD-1/PD-L1 agents, concomitant other adverse events, concomitant medication, PD-L1 mRNA, and LRP3 may be influencing factors for anti-PD-1/PD-L1-related severe cAEs. However, our findings still require a large-scale prospective cohort validation.

Abstract Background Retinal ischemia/reperfusion (IR) injury is a common pathological process in many ophthalmic diseases. Interleukin-1β (IL-1β) is an important inflammatory factor involved in the pathology of retinal IR injury, but the mechanism by which IL-1β is regulated in such injury remains unclear. Caspase-11 non-canonical inflammasomes can regulate the synthesis and secretion of IL-1β, but its role in retinal IR injury has not been elucidated. This study aimed to evaluate the role of caspase-11 non-canonical inflammasomes in retinal IR injury. Methods Retinal IR injury was induced in C57BL/6J mice by increasing the intraocular pressure to 110 mmHg for 60 min. The post-injury changes in retinal morphology and function and in IL-1β expression were compared between caspase-11 gene knockout (caspase-11−/−) mice and wild-type (WT) mice. Morphological and functional changes were evaluated using hematoxylin–eosin staining and retinal whole mount staining and using electroretinography (ERG), respectively. IL-1β expression in the retina was measured using enzyme-linked immunosorbent assay (ELISA). The levels of caspase-11-related protein were measured using western blot analysis. The location of caspase-11 in the retina was determined via immunofluorescence staining. Mouse type I astrocytes C8-D1A cells were used to validate the effects of caspase-11 simulation via hypoxia in vitro. Small-interfering RNA targeting caspase-11 was constructed. Cell viability was evaluated using the MTT assay. IL-1β expression in supernatant and cell lysate was measured using ELISA. The levels of caspase-11-related protein were measured using western blot analysis. Results Retinal ganglion cell death and retinal edema were more ameliorated, and the ERG b-wave amplitude was better after retinal IR injury in caspase-11−/− mice than in WT mice. Further, caspase-11−/− mice showed lower protein expressions of IL-1β, cleaved caspase-1, and gasdermin D (GSDMD) in the retina after retinal IR injury. Caspase-11 protein was expressed in retinal glial cells, and caspase-11 knockdown played a protective role against hypoxia in C8-D1A cells. The expression levels of IL-1β, cleaved caspase-1, and GSDMD were inhibited after hypoxia in the si-caspase-11 constructed cells. Conclusions Retinal IR injury activates caspase-11 non-canonical inflammasomes in glial cells of the retina. This results in increased protein levels of GSDMD and IL-1β and leads to damage in the inner layer of the retina.

Abstract The Hippo-Yes-associated protein (Hippo-YAP) signaling pathway, a conserved pathway that regulates organ size, participates in tumor progression. However, there are few comprehensive analyses of tumor prognosis and immunity. In the present study, TCGA, GTEx, GEO, TIMER2, STRING, GSCA, ImmuCellAI, and other bioinformatics tools were used to reveal the involvement of the Hippo-YAP signaling pathway in the prognosis and immunity of pan-cancers. The obtained results showed that mRNA expression differences of Hippo-YAP pathway genes between normal samples and tumor samples in pan-cancers and some genes (such as TEAD4, MAP4K4, and STK3) might affect the prognosis of patients with skin cutaneous melanoma (SKCM) and pancreatic adenocarcinoma (PAAD). Furthermore, mutation and methylation of the Hippo-YAP signaling pathway genes in normal and primary tumor tissues differ in various cancers (KIRP, BRCA). Additionally, the relationship between the tumor microenvironment, molecular pathways, and the Hippo-YAP pathway indicated that it might lead to a suppressive immune microenvironment that affects the efficacy of immunotherapy. This is a pan-cancer overview of the Hippo-YAP signaling pathway genes, which explores the aberrant expression or mutation of this pathway that regulates the tumor microenvironment and immunotherapy.

Abstract SABRE is emerging as a fast, simple and low-cost hyperpolarization method because of its ability to regenerate enhanced NMR signals. Generally, SABRE hyperpolarization has been performed predominantly manually, leading to variations in reproducibility and efficiency. Recent advances in SABRE include the development of automated shuttling systems to address previous inconsistencies. However, the operational complexity of such systems and the challenges of integration with existing workflows hinder their widespread adoption. This work presents a fully automated lab workstation based on a benchtop NMR spectrometer, specifically designed to facilitate SABRE of different nuclei across different polarization fields. We demonstrated the capability of this system through a series of routine SABRE experimental protocols, including consecutive SABRE hyperpolarization with high reproducibility (average standard deviation of 1.03%), optimization polarization of 13C nuclei respect to the polarization transfer field, and measurement of polarization buildup rate or decay time across a wide range of magnetic fields. Furthermore, we have iteratively optimized the durations for pulsed SABRE-SHEATH 13C pyruvate. The constructed SABRE workstation offers full automation, high reproducibility, and functional diversification, making it a practical tool for conducting routine SABRE hyperpolarization experiments. It provides a robust platform for high-throughput and reliable SABRE and X-SABRE hyperpolarization studies.

Abstract Fully π-conjugated polymers with rigid aromatic units are promising for flexible optoelectronic devices, but their inherent brittleness poses a challenge for achieving high-performance, intrinsically stretchable fully π-conjugated polymer. Here, we are establishing an external-plasticizing strategy using semiconductor fluid plasticizers (Z1 and Z2) to enhance the optoelectronic, morphological, and stretchable properties of fully π-conjugated polymer films for flexible light-emitting diodes. The synergistic effect of hierarchical structure and optoelectronic properties of Z1 in poly(9,9-di-n-octylfluorene-alt-benzothiadiazole) (F8BT) films enable excellent stretchable deformability (~25%) and good conductivity. PLEDs based on F8BT/Z1 films show stable electroluminescence and efficiency under 15% stretch and 100 cycles at 10% strain, revealing outstanding stress tolerance. This strategy is also improving the stretchable properties of polymers like poly(9,9-di-n-octylfluorenyl-2,7-diyl) (PFO) and poly(2-methoxy-5(2′-ethyl)hexoxy-phenylenevinylene) (Super Yellow), demonstrating its general applicability. Therefore, this strategy can provide effective guidance for designing high-performance stretchable fully π-conjugated polymers films for flexible electronic devices.

In this work, we aim to investigate the origin of the magnetic carriers in the lunar crust and the intensity of the ancient dynamo field. The magnetization and depth range of magnetic carriers are studied under a weak and a strong magnetic anomaly in Mare Tranquillitatis and in Oceanus Procellarum, respectively, where the surface ages are 3.6 and 3.3 billion years. A sophisticated three-dimensional amplitude inversion software program from a geophysical survey is used to reconstruct the distributions of magnetization in the lunar crust. Because no globally measured surface magnetic field exists for the Moon, a crustal magnetic anomaly model with a grid resolution of 0.2° is used. The depth range of the magnetic source is fixed by the boundary identified by a relative criterion, which is 20% of the recovered maximum magnetization. The central burial depths of the magnetic carriers are approximately 15 km and 25 km under Reiner Gamma and Mare Tranquillitatis, respectively. The volumes of the two magnetic sources are at scales of 104 and 105 km3, respectively. The aforementioned differences may imply a hotter crust under Reiner Gamma than Mare Tranquillitatis by 3.3 billion years. The results support the view that the magma intrusions magnetized by an ancient magnetic field could be the origin of magnetic anomalies under Reiner Gamma and Mare Tranquillitatis. Compared with previous works, the maximum magnetization of 3 A/m under Reiner Gamma supports the intensity of the field being several microteslas.

Abstract Background Obesity and metabolic syndrome (MetS) have become urgent worldwide health problems, predisposing patients to unfavorable myocardial status and thyroid dysfunction. Low-carbohydrate diet (LCD) and time-restricted eating (TRE) have been confirmed to be effective methods for weight management and improving MetS, but their effects on the myocardium and thyroid are unclear. Methods We conducted a secondary analysis in a randomized clinical diet-induced weight-loss trial. Participants (N = 169) diagnosed with MetS were randomized to the LCD group, the 8 h TRE group, or the combination of the LCD and TRE group for 3 months. Myocardial enzymes and thyroid function were tested before and after the intervention. Pearson’s or Spearman’s correlation was assessed between functions of the myocardium and thyroid and cardiometabolic parameters at baseline. Results A total of 162 participants who began the trial were included in the intention-to-treat (ITT) analysis, and 57 participants who adhered to their assigned protocol were involved in the per-protocol (PP) analysis. Relative to baseline, lactate dehydrogenase, creatine kinase MB, hydroxybutyrate dehydrogenase, and free triiodothyronine (FT3) declined, and free thyroxine (FT4) increased after all 3 interventions (both analyses). Creatine kinase (CK) decreased only in the TRE (− 18 [44] U/L, P

Introduction: Sepsis-induced cardiac injury is the leading cause of death in patients. Recent studies have reported that reactive oxygen species (ROS)-mediated ferroptosis and macrophage-induced inflammation are the two main key roles in the process of cardiac injury. The combination of ferroptosis and inflammation inhibition is a feasible strategy in the treatment of sepsis-induced cardiac injury. Objectives: In the present study, ceria nanozyme coordination with curcumin (CeCH) was designed by a self-assembled method with human serum albumin (HSA) to inhibit ferroptosis and inflammation of sepsis-induced cardiac injury. Methods and results: The formed CeCH obtained the superoxide dismutase (SOD)-like and catalase (CAT)-like activities from ceria nanozyme to scavenge ROS, which showed a protective effect on cardiomyocytes in vitro. Furthermore, it also showed ferroptosis inhibition to reverse cell death from RSL3-induced cardiomyocytes, denoted from curcumin. Due to the combination therapy of ceria nanozyme and curcumin, the formed CeCH NPs could also promote M2 macrophage polarization to reduce inflammation in vitro. In the lipopolysaccharide (LPS)-induced sepsis model, the CeCH NPs could effectively inhibit ferroptosis, reverse inflammation, and reduce the release of pro-inflammatory factors, which markedly alleviated the myocardial injury and recover the cardiac function. Conclusion: Overall, the simple self-assembled strategy with ceria nanozyme and curcumin showed a promising clinical application for sepsis-induced cardiac injury by inhibiting ferroptosis and inflammation.

The effects of Lactobacillus plantarum in microencapsulation (LPM) on intestinal development in layer chicks were investigated in this study, as well as the colonization of L. plantarum in the gut. A total of 480 healthy Hy-Line Brown layer chicks at 0 d old were randomly divided into 4 groups (8 replicates each treatment), and the diets of these birds were supplemented with nothing (control), L. plantarum (0.02 g/kg feed; 109 CFU/kg feed), LPM (1.0 g/kg feed; 109 CFU/kg feed) and wall material of LPM (WM; 0.98 g/kg feed), respectively. Compared to control, LPM improved growth performance and intestinal development of layer chicks, evidenced by significantly increased body weight, average daily gain, average daily feed intake, villus height, villus height/crypt depth, as well as weight and length of the duodenum, jejunum and ileum (P < 0.05). These results could be attributed to the increased colonization of L. plantarum in the gut, which was verified by significant increases in lactic acid content, viable counts in chyme and mucosa (P < 0.05), as well as a visible rise in number of strains labeled with fluorescein isothiocyanate. Meanwhile, the relative abundances of Lactobacillus and Bifidobacterium significantly increased in response to microencapsulated L. plantarum supplementation (P < 0.05), accompanied by the significant up-regulation of colonization related genes (P < 0.05), encoding solute carrier family, monocarboxylate transporter, activin A receptor, succinate receptor and secretogranin II. To sum up, microencapsulated L. plantarum supplementation promoted intestinal development, which could be attributed to the enhancement of L. plantarum colonization in the intestine through the mutual assistance of Bifidobacterium and interactions with colonization related transmembrane proteins.

Severe left ventricular dysfunction and ventricular wall motion abnormalities predispose individuals to thrombosis and thromboembolism. Thromboembolism is one of the main causes of increased mortality in patients with heart failure and reduced ejection fraction (HFrEF). However, regarding thromboembolism due to HFrEF in sinus rhythm, most cases to date have reported ischemic strokes, and repeated embolization of peripheral arteries has been reported not uncommon. Herein, we report the case of a 48-year-old man with a definite diagnosis of sinus rhythm HFrEF and recurrent peripheral arterial embolization within a short period. The condition is caused by severe left ventricular systolic dysfunction and abnormal left ventricular wall motion, resulting in blood stasis and abnormal blood composition, with or without left ventricular thrombosis, and can lead to thromboembolism. Current guidelines state that patients with heart failure and clear indication(s) for anticoagulation (e.g., atrial fibrillation, heart valve replacement) should be administered appropriate anticoagulation therapy. However, controversy persists regarding whether patients with HFrEF in sinus rhythm can benefit from anticoagulation therapy. This case highlights the utility and necessity of anticoagulation for the prevention of intracardiac thrombosis and the treatment of peripheral arterial embolism in patients with HFrEF in sinus rhythm.

AbstractContext Sepsis-induced acute lung injury (ALI) is a severe condition with limited effective therapeutics; nicotinamide mononucleotide (NMN) has been reported to exert anti-inflammatory activities.Objective This study explores the potential mechanisms by which NMN ameliorates sepsis-induced ALI in vivo and in vitro.Materials and methods Cultured MH-S cells and a murine model were used to evaluate the effect of NMN on sepsis-induced ALI. MH-S cells were stimulated with LPS (1 μg/mL) and NMN (500 μM) for 12 h grouping as control, LPS, and LPS + NMN. Cell viability, apoptotic status, and M1/2 macrophage-related markers were detected. The mice were pretreated intraperitoneally with NMN (500 mg/kg) and/or EX-527 (5 mg/kg) 1 h before LPS injection and randomized into 7 groups (n = 8): control, LPS, LPS + NMN, NMN, LPS + NMN + EX-527 (a SIRT1 inhibitor), LPS + EX-527, and EX-527. After 12 h, lung histopathology, W/D ratio, MPO activity, NAD+ and ATP levels, M1/2 macrophage-related markers, and expression of the SIRT1/NF-κB pathway were detected.Results In MH-S cells, NMN significantly decreased the apoptotic rate from 12.25% to 5.74%. In septic mice, NMN improved the typical pathologic findings in lungs and reduced W/D ratio and MPO activity, but increased NAD+ and ATP levels. Additionally, NMN suppressed M1 but promoted M2 polarization, and upregulated the expression of SIRT1, with inhibition of NF-κB-p65 acetylation and phosphorylation. Furthermore, inhibition of SIRT1 reversed the effects of NMN-induced M2 macrophage polarization.Conclusions NMN protects against sepsis-induced ALI by promoting M2 macrophage polarization via the SIRT1/NF-κB pathway, it might be an effective strategy for preventing or treating sepsis-induced ALI.

Abstract To investigate the impact of different 5ʹ untranslated regions (UTRs) on mRNA vaccine translation efficiency, five dual-reporter gene expression plasmids with different 5ʹUTRs were constructed. The corresponding mRNA transcripts were transcribed and capped in vitro. By comparing the expression levels of reporter genes with different 5ʹUTRs, we identified the 5ʹUTR associated with the highest expression level. Subsequently, HIVgp145 mRNA vaccines containing various 5ʹUTRs were constructed and verified. The results demonstrated that mRNA 3 (β-globin 5ʹUTR) displayed the greatest number of green fluorescence-positive cells and the highest luciferase fluorescence intensity in the reporter gene expression system. Further, among the HIVgp145 mRNA vaccines with different 5ʹUTRs, mRNA 7 (β-globin 5ʹUTR) exhibited the highest level of expression. These findings indicate that it is feasible to use the 5ʹUTR of β-globin in an mRNA vaccine, laying the foundation for animal immunogenicity testing.

Abstract Background Adverse atherogenic lipid profile is associated with an increased risk of major adverse cardiac events in patients after acute coronary syndrome (ACS). Knowledge regarding the impact of statins on lipid profile remains limited. Methods We retrospectively analysed multicenter, real-world data from the Chinese Cardiovascular Association Database-iHeart Project. Patients with a primary diagnosis of ACS from 2014 to 2021 during index hospitalisation and having at least one lipid panel record after discharge within 12 months were enrolled. We analysed target achievement of atherogenic lipid profile, including apolipoprotein B (

Abstract Olaparib has been approved as a therapeutic option for metastatic pancreatic ductal adenocarcinoma patients with BRCA1/2 mutations. However, a significant majority of pancreatic cancer patients have inherent resistance or develop tolerance to olaparib. It is crucial to comprehend the molecular mechanism underlying olaparib resistance to facilitate the development of targeted therapies for pancreatic cancer. In this study, we conducted an analysis of the DepMap database to investigate gene expression variations associated with olaparib sensitivity. Our findings revealed that NLRP4 upregulation contributes to increased resistance to olaparib in pancreatic cancer cells, both in vitro and in vivo. RNA sequencing and Co-IP MS analysis revealed that NLRP4 is involved in the DNA damage response and autophagy pathway. Our findings confirmed that NLRP4 enhances the capacity for DNA repair and induces the production of significant levels of reactive oxygen species (ROS) and autophagy in response to treatment with olaparib. Specifically, NLRP4-generated mitochondrial ROS promote autophagy in pancreatic cancer cells upon exposure to olaparib. However, NLRP4-induced ROS do not affect DNA damage. The inhibition of mitochondrial ROS using MitoQ and autophagy using chloroquine (CQ) may render cells more susceptible to the effects of olaparib. Taken together, our findings highlight the significant roles played by NLRP4 in the processes of autophagy and DNA repair when pancreatic cancer cells are treated with olaparib, thereby suggesting the potential therapeutic utility of olaparib in pancreatic cancer patients with low NLRP4 expression.

Abstract Research question Does luteinizing hormone (LH) levels on human chorionic gonadotropin (HCG) trigger day (LHHCG) affect the clinical outcomes of patients with diminished ovarian reserve (DOR) undergoing gonadotropin-releasing hormone antagonist (GnRH-ant) protocol? Methods Retrospective analysis fresh embryo transfer cycles of DOR patients who underwent GnRH-ant protocol from August 2019 to June 2023. The participants were divided into different groups according to LHHCG level and age. The clinical data and outcomes were compared between groups. Results In patients with DOR, the HCG positive rate (59.3% versus 39.8%, P = 0.005), embryo implantation rate (34.5% versus 19.7%, P = 0.002), clinical pregnancy rate (49.2% versus 28.4%, P = 0.003), live birth rate (41.5% versus 22.7%, P = 0.005) in LHHCG < 2.58 IU/L group were significantly higher than LHHCG ≥ 2.58 IU/L group. There was no significant correlation between LHHCG level and clinical pregnancy in POSEIDON group 3. In POSEIDON group 4, the HCG positive rate (52.8% versus 27.0%, P = 0.015), embryo implantation rate (29.2% versus 13.3%, P = 0.023), clinical pregnancy rate (45.3% versus 18.9%, P = 0.010) in LHHCG < 3.14 IU/L group were significantly higher than LHHCG ≥ 3.14 IU/L group. Logistic regression analysis indicated that LHHCG level was an independent influencing factor for clinical pregnancy in POSEIDON group 4 patients (OR = 3.831, 95% CI: 1.379–10.643, P

Abstract Background Nutrient-rich cheese supplements were demonstrated to have improvements in markers of sarcopenia in healthy elders. However, the potential effects of cheese in individuals with possible sarcopenia remain unknown. Method This 90-day randomized controlled trial (RCT) included 68 women aged 60–80 years with possible sarcopenia in China, who were randomly assigned to three groups: Control group (CG), Original cheese group (OG: 9.0 g protein; 322.8 mg calcium), and Golden cheese group (GG: 12.7 g protein; 802.1 mg calcium). OG and GG were instructed to consume their habitual diet along with 4 slices of supplied cheese, while CG was directed to maintain their usual dietary habits. Face-to-face interviews, anthropometric measurements, and blood sample collection were conducted at baseline, midway (60 days), and the end of the trial. Result At the end of the trial, the primary outcome, changes of Skeletal Muscle Mass Index (SMI) were found to be higher in OG (0.18 ± 0.02 kg/m2) and GG (0.14 ± 0.02 kg/m2) compared to CG (0.09 ± 0.02 kg/m2). The secondary outcome, changes of handgrip strength were higher in GG (1.82 ± 4.16 kg) than CG (-0.61 ± 3.78 kg). There were no significant differences in makers for muscle function between three groups (P > 0.05). In the self-comparison, Creatinine/Cystatin C significantly increased in both OG and GG. In addition, OG had a significant increase in changes of free and total carnitine compared to CG. Conclusion Both golden and original cheese supplementation enhanced muscle strength and mass in older women with possible sarcopenia. The mechanism behind this effect may be linked to muscle cell energy metabolism. Trial registration The present study was registered in the Chinese Clinical Trial Registry with the registration number ChiCTR2300078720 (retrospectively registered, 20231215).

Abstract Background Moral distress occurs in daily nursing work and plagues nurses. Improving the level of moral courage is one of the main strategies to reduce moral distress, and low levels of moral courage may lead to nurse burnout, increased turnover, and reduced quality of care. Methods Nine electronic databases in Chinese and English were searched for the level of moral courage among nurses, including PubMed, Web of Science, EMBASE, CINAHL, CNKI, Wan fang, Wei pu, CBM and Cochrane Library, for the period from the date of database creation to April 5, 2023. The Agency for Healthcare Research and Quality (AHRQ) was used to assess the methodological quality of the included studies, followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and the Meta-analysis and Systematic Reviews of Observational Studies guidelines, and data from the included studies were meta-analyzed in STATA version 15 using a fixed-effects model. Results Seventeen cross-sectional studies of moderate or high quality met the eligibility criteria and involved 7718 nurses, and the Nurses’ Moral Courage Scale (NMCS) was used to measure the self-assessed moral courage level of nurses. Eleven of these studies reported total scores for nurses’ moral courage, and the meta-analysis results showed a pooled mean score of 78.94 (95% CI: 72.17, 85.72); Fourteen studies reported mean entry scores for nurses’ moral courage, and the meta-analysis results showed a pooled mean score of 3.93 (95% CI: 3.64, 4.23). Conclusion The results of the meta-analysis showed that nurses’ moral courage levels were in the medium to high range, among the nurses who seemed to be male, non-nursing managers, high school education, had not experienced ethical issues, and considering resignation had lower levels of moral courage. The results of the meta-analysis may provide some reference for nursing managers and even hospital administrators to develop strategies to optimize nursing quality.

Abstract Nanosizing confers unique functions in materials such as graphene and quantum dots. Here, we present two nanoscale-covalent organic frameworks (nano-COFs) that exhibit exceptionally high activity for photocatalytic hydrogen production that results from their size and morphology. Compared to bulk analogues, the downsizing of COFs crystals using surfactants provides greatly improved water dispersibility and light-harvesting properties. One of these nano-COFs shows a hydrogen evolution rate of 392.0 mmol g−1 h−1 (33.3 μmol h−1), which is one of the highest mass-normalized rates reported for a COF or any other organic photocatalysts. A reverse concentration-dependent photocatalytic phenomenon is observed, whereby a higher photocatalytic activity is found at a lower catalyst concentration. These materials also show a molecule-like excitonic nature, as studied by photoluminescence and transient absorption spectroscopy, which is again a function of their nanoscale dimensions. This charts a new path to highly efficient organic photocatalysts for solar fuel production.

Abstract Background Deoxyribonuclease 2 (DNase II) plays a key role in clearing cytoplasmic double-stranded DNA (dsDNA). Deficiency of DNase II leads to DNA accumulation in the cytoplasm. Persistent dsDNA in neurons is an early pathological hallmark of senescence and neurodegenerative diseases including Alzheimer’s disease (AD). However, it is not clear how DNase II and neuronal cytoplasmic dsDNA influence neuropathogenesis. Tau hyperphosphorylation is a key factor for the pathogenesis of AD. The effect of DNase II and neuronal cytoplasmic dsDNA on neuronal tau hyperphosphorylation remains unclarified. Methods The levels of neuronal DNase II and dsDNA in WT and Tau-P301S mice of different ages were measured by immunohistochemistry and immunolabeling, and the levels of DNase II in the plasma of AD patients were measured by ELISA. To investigate the impact of DNase II on tauopathy, the levels of phosphorylated tau, phosphokinase, phosphatase, synaptic proteins, gliosis and proinflammatory cytokines in the brains of neuronal DNase II-deficient WT mice, neuronal DNase II-deficient Tau-P301S mice and neuronal DNase II-overexpressing Tau-P301S mice were evaluated by immunolabeling, immunoblotting or ELISA. Cognitive performance was determined using the Morris water maze test, Y-maze test, novel object recognition test and open field test. Results The levels of DNase II were significantly decreased in the brains and the plasma of AD patients. DNase II also decreased age-dependently in the neurons of WT and Tau-P301S mice, along with increased dsDNA accumulation in the cytoplasm. The DNA accumulation induced by neuronal DNase II deficiency drove tau phosphorylation by upregulating cyclin-dependent-like kinase-5 (CDK5) and calcium/calmodulin activated protein kinase II (CaMKII) and downregulating phosphatase protein phosphatase 2A (PP2A). Moreover, DNase II knockdown induced and significantly exacerbated neuron loss, neuroinflammation and cognitive deficits in WT and Tau-P301S mice, respectively, while overexpression of neuronal DNase II exhibited therapeutic benefits. Conclusions DNase II deficiency and cytoplasmic dsDNA accumulation can initiate tau phosphorylation, suggesting DNase II as a potential therapeutic target for tau-associated disorders. Graphical Abstract Scheme depicting the possible mechanism by which DNase II deficiency induces cognitive impairment in mice. DNase II deficiency induces tau phosphorylation by regulating kinases CDK5 and CaMKII as well as phosphatase PP2A through accumulation of undigested damaged DNA in the cytoplasm of neurons. Then phosphorylated tau induces synaptic loss, neuroinflammation, and neuronal apoptosis, eventually rendering cognitive impairment in mice.

ObjectivePhotoelectric volumetric tracing (PPG) exhibits high sensitivity and specificity in flap monitoring. Deep learning (DL) is capable of automatically and robustly extracting features from raw data. In this study, we propose combining PPG with 1D convolutional neural networks (1D-CNN) to preliminarily explore the method’s ability to distinguish the degree of embolism and to localize the embolic site in skin flap arteries. MethodsData were collected under normal conditions and various embolic scenarios by creating vascular emboli in a dermatome artery model and a rabbit dermatome model. These datasets were then trained, validated, and tested using 1D-CNN. ResultsAs the degree of arterial embolization increased, the PPG amplitude upstream of the embolization site progressively increased, while the downstream amplitude progressively decreased, and the gap between the upstream and downstream amplitudes at the embolization site progressively widened. 1D-CNN was evaluated in the skin flap arterial model and rabbit skin flap model, achieving average accuracies of 98.36% and 95.90%, respectively. ConclusionThe combined monitoring approach of DL and PPG can effectively identify the degree of embolism and locate the embolic site within the skin flap artery.

Bacteria, as the major component of the human microbiome, have been shown to play important physiological roles in human health and disease development. However, a growing body of research suggests that fungi, which make up less than 1% of the human microbiome, also have a significant impact on human health, particularly in early life. Fungal colonization is strongly associated with the onset of future childhood diseases such as infectious diseases, allergic diseases, and intestinal diseases. Factors influencing early life, such as mode of birth and use of antibiotics, may be involved in the development of related diseases by affecting fungal colonization, but more research is needed to summarize this. This article reviews the characteristics of the fungal composition in the first 1 000 days of life, the related factors influencing the colonization of the early life fungal community, and the association between fungal dysbiosis and childhood diseases, providing a reference for the prevention and control of related childhood diseases.

Abstract Objective This study aimed at evaluating the effects of online and offline hybrid weight management approach based on the Fogg behavior model on total gestational weight gain and perinatal outcomes. Methods Pregnant women in Hainan, the southernmost province of China, were recruited into a randomized controlled trial, which was designed to develop a WeChat platform for pregnancy weight management, and implement individualized and continuous pregnancy weight management services for pregnant women under the guidance of the Fogg behavior model. All pregnant women participating in the study were included in the full analysis set (FAS) for analysis. The pregnant women who completed the intervention and provided all outcome indicators were included in the per protocol set (PPS) for outcome evaluation. Results Fifty-eight pregnant women were included in FAS analysis, and 52 pregnant women were finally included in PPS analysis. There was no statistically significant difference (P > 0.05) between the two groups at baseline. The gestational weight gain of the intervention group was significantly lower than that of the control group (P

Abstract Natural killer (NK) cell-based therapies have made great progress in treating both hematological and solid tumors. Their unique mechanism of action does not rely on antigen presentation to recognize and eliminate tumor cells, making them a promising approach for cancer immunotherapy. In this review, we present a comprehensive summary of the latest clinical data of the novel NK cell-based therapies from the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, highlighting the potential of these advancements to revolutionize the treatment of hematologic malignancies and solid tumors.

Abstract Background Tree rings play an important role in reconstructing past climate. Growth differences among individual trees due to microclimatic conditions and local disturbances are averaged in developing tree-ring chronologies. Here, we addressed the problem of averaging by investigating growth synchrony in individual trees. We used tree-ring data of 1046 juniper trees from 32 sites on the Tibetan Plateau and 538 pine trees from 20 sites in the subtropical region of eastern China and calculated the tree-growth synchrony index (TGS). Results Our results showed that both the TGS index and tree-ring index could be indicators of interannual variation of climatic factors. The TGS index identified 20% more climatic extremes than tree-ring index over the last 50 years that high synchrony indicates extreme climate forcing in controlling forest growth. Conclusions The TGS index can identify extreme climatic events effectively than tree-ring index. This study provides a novel perspective for climate reconstruction, especially in the realm of tree growth response to extreme climate. Our findings contribute to understanding of the spatiotemporal dynamics and the causes of historical climate extremes and provide guidance for protecting trees from climate extremes in the future.

Abstract Lipotoxicity is a well-established phenomenon that could exacerbate damage to islet β-cells and play a significant role in the development of type 2 diabetes, the underlying mechanisms of which, however, remain unclear. In lipotoxic conditions, secretagogin (SCGN), an EF-hand calcium-binding protein abundantly expressed in islets, is found to undergo downregulation. In light of this, we aim to explore the role of SCGN in lipotoxicity-induced β-cell injury. Our findings show that exposure to ox-LDL in vitro or long-term high-fat diets (HFD) in vivo decreases SCGN expression and induces pyroptosis in β-cells. Moreover, restoring SCGN partially reverses the pyroptotic cell death under ox-LDL or HFD treatments. We have observed that the downregulation of SCGN facilitates the translocation of ChREBP from the cytosol to the nucleus, thereby promoting TXNIP transcription. The upregulation of TXNIP activates the NLRP3/Caspase-1 pathway, leading to pyroptotic cell death. In summary, our study demonstrates that lipotoxicity leads to the downregulation of SCGN expression in islet β-cells, resulting in ChREBP accumulation in the nucleus and subsequent activation of the NLRP3/Caspase-1 pyroptotic pathway. Thus, administering SCGN could be a potential therapeutic strategy to alleviate β-cell damage induced by lipotoxicity in type 2 diabetes.

Abstract Membrane proteins are considered the major source of drug targets and are indispensable for drug design and disease prevention. However, traditional biomechanical experiments are costly and time-consuming; thus, many computational methods for predicting membrane protein types are gaining popularity. The position-specific scoring matrix (PSSM) method is an excellent method for describing the evolutionary information of protein sequences. In this study, we propose an improved capsule neural network (ICNN) model based on a capsule neural network to acquire sufficient relevant information from the PSSM. Furthermore, accounting for the complementarity between traditional machine learning and deep learning, we propose a hybrid framework that combines both approaches to predict protein types. This framework trains 41 baseline models based on the PSSM. The optimal subset features, selected after traversal, are fused using a two-level decision-level feature fusion approach. Subsequently, comparisons are made using three combined strategies within an ensemble learning framework. The experimental results demonstrate that solely relying on PSSM input, the proposed method not only surpasses the optimal methods by 1.52 $$\%$$ % , 2.26 $$\%$$ % and 2.67 $$\%$$ % on Dataset1, Dataset2, and Datasets3, respectively, but also exhibits superior generalizability. Furthermore, the code and dataset can be free download at https://github.com/ruanxiaoli/membrane-protein-types .

Abstract Heat extremes frequently hit different regions synchronously during boreal summer over the Eurasian continent. A remarkable coupling is first revealed between Eurasian heat extreme occurrence and individual extratropical intraseasonal oscillation (EISO). Further, the combined EISOs facilitate and largely increase the occurrence probabilities of synchronous Eurasian heat extremes. These dominant combined EISOs together contribute 20–45% to the total heat extreme days over the five Eurasian regions where the climatological heat extremes occur most frequently. A multi-model hindcast further shows that the subseasonal prediction exhibits higher skills for synchronous heat extremes over the combined-EISO hotspot regions when the associated combined EISOs are active, supporting the notion that the monitoring and prediction of EISOs are crucial for heat extremes’ early warning. Skillful prediction of EISOs opens a pathway for heat extremes’ prediction by extending it from the weather to the subseasonal timescales.

Abstract Background Maintaining the structural and functional integrity of the blood–brain barrier (BBB) is vital for neuronal equilibrium and optimal brain function. Disruptions to BBB performance are implicated in the pathology of neurodegenerative diseases. Main body Early indicators of multiple neurodegenerative disorders in humans and animal models include impaired BBB stability, regional cerebral blood flow shortfalls, and vascular inflammation associated with BBB dysfunction. Understanding the cellular and molecular mechanisms of BBB dysfunction in brain disorders is crucial for elucidating the sustenance of neural computations under pathological conditions and for developing treatments for these diseases. This paper initially explores the cellular and molecular definition of the BBB, along with the signaling pathways regulating BBB stability, cerebral blood flow, and vascular inflammation. Subsequently, we review current insights into BBB dynamics in Alzheimer’s disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. The paper concludes by proposing a unified mechanism whereby BBB dysfunction contributes to neurodegenerative disorders, highlights potential BBB-focused therapeutic strategies and targets, and outlines lessons learned and future research directions. Conclusions BBB breakdown significantly impacts the development and progression of neurodegenerative diseases, and unraveling the cellular and molecular mechanisms underlying BBB dysfunction is vital to elucidate how neural computations are sustained under pathological conditions and to devise therapeutic approaches.

Abstract Background Allii Macrostemonis Bulbus is also named Xiebai in China. It is an edible vegetable, and also a famous herb for treating coronary heart disease. Allium chinense G. Don (ACGD) and Allium macrostemon Bunge (AMB) are it botanical sources. The aim of this study was to explore the cardioprotective effects, and decipher the visual spatial distribution and absolute content of primary metabolites derived from these two herbs. Methods H9c2 cells were used to perform the hypoxia-reoxygenation (H/R)-induced myocardial injury model. Their protective effects were evaluated by apoptosis levels. Furthermore, matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry imaging approach (MALDI-TOF MSI) was carried out to present the spatial location of primary metabolites including fatty acids, amino acids, carotenoids, and vitamins in these two Allium herbs. Multiple analytical methods were applied to perform quantitative analysis of these primary metabolites in AMB and ACGD bulbs by liquid chromatography tandem mass spectrometry (LC–MS). Results First, AMB and ACGD extracts both could increase the cell viability in H9c2 cells, and attenuate H/R-induced injury. They markedly decreased apoptosis, accompanied by activating the BCL-2/BAX pathway. Further, MALDI-TOF MSI-based relative quantification results showed several amino acids, fatty acids, carotenoids, and vitamins were largely rich in the tunics and outside scales of fresh bulbs, while some primary metabolites were abundant in their developing flower buds. Absolute quantification results displayed total contents of amino acids in ACGD bulbs were higher than those in AMB, while total contents of fatty acids and vitamins provides opposite trends in these two Allium herbs. The total contents of carotenoids and trace elements showed no significant differences between AMB and ACGD samples. Conclusions This study would be helpful to understand the myocardial injury protection effects of these two Allium herbs, and the spatial accumulation and quantitative content levels of their main nutrients. Graphical Abstract