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Abstract Background Endometriosis is well known as a chronic inflammatory disease. The development of endometriosis is heavily influenced by the estrogen receptor β (ERβ), while NOD-like receptors (NLRs) family CARD domain-containing 5 (NLRC5) exhibits anti-inflammatory properties during endometriosis. However, whether NLRC5-mediated anti-inflammation is involved in the ERβ-mediated endometriosis is still uncertain. This study aimed to assess that relation. Methods Nine cases of eutopic endometrial tissue and ten cases of ectopic endometrial tissue were collected from patients with endometriosis, and endometrial samples from ten healthy fertile women were analyzed, and the expression levels of ERβ were quantified using immunohistochemistry (IHC). Subsequently, we constructed mouse model of endometriosis by intraperitoneal injection. We detected the expression of ERβ, NLRC5, tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and IL-10 and measured the volume of ectopic lesions in mice with endometriosis. In vitro, human endometrial stromal cells (hESCs) were transfected respectively with ERβ-overexpressing and NLRC5-overexpressing plasmids. We then assessed the expression of ERβ and NLRC5 using quantitative real-time PCR (qRT-PCR) and western blot analysis. Furthermore, we measured the concentrations of TNF-α, IL-6, and IL-10 in the cell culture supernatant through enzyme-linked immunosorbent assay (ELISA). Additionally, we evaluated the migration and invasion ability of hESCs using transwell and wound healing assays. Results Inhibition of NLRC5 expression promotes the development of ectopic lesions in mice with endometriosis, upregulates the expression of pro-inflammatory factors TNF-α and IL-6, and downregulates the expression of anti-inflammatory factor IL-10. The high expression of NLRC5 in endometriosis depended on the ERβ overexpression. And ERβ promoted the migration of hESCs partially depend on inflammatory microenvironment. Lastly, NLRC5 overexpression inhibited ERβ-mediated development and inflammatory response of endometriosis. Conclusions Our results suggest that the innate immune molecule NLRC5-mediated anti-inflammation participates in ERβ-mediated endometriosis development, and partly clarifies the pathological mechanism of endometriosis, expanding our knowledge of the specific molecules related to the inflammatory response involved in endometriosis and potentially providing a new therapeutic target for endometriosis.

Abstract Background Breast cancer (BC) is the most common malignant tumor in women worldwide, and further elucidation of the molecular mechanisms involved in BC pathogenesis is essential to improve the prognosis of BC patients. RNA Binding Motif Protein 8 A (RBM8A), with high affinity to a myriad of RNA transcripts, has been shown to play a crucial role in genesis and progression of multiple cancers. We attempted to explore its functional significance and molecular mechanisms in BC. Methods Bioinformatics analysis was performed on publicly available BC datasets. qRT-PCR was used to determine the expression of RBM8A in BC tissues. MTT assay, clone formation assay and flow cytometry were employed to examine BC cell proliferation and apoptosis in vitro. RNA immunoprecipitation (RIP) and RIP-seq were used to investigate the binding of RBM8A/EIF4A3 to the mRNA of IGF1R/IRS-2. RBM8A and EIF4A3 interactions were determined by co-immunoprecipitation (Co-IP) and immunofluorescence. Chromatin immunoprecipitation (Ch-IP) and dual-luciferase reporter assay were carried out to investigate the transcriptional regulation of RBM8A by TEAD4. Xenograft model was used to explore the effects of RBM8A and TEAD4 on BC cell growth in vivo. Results In this study, we showed that RBM8A is abnormally highly expressed in BC and knockdown of RBM8A inhibits BC cell proliferation and induces apoptosis in vitro. EIF4A3, which phenocopy RBM8A in BC, forms a complex with RBM8A in BC. Moreover, EIF4A3 and RBM8A complex regulate the expression of IGF1R and IRS-2 to activate the PI3K/AKT signaling pathway, thereby promoting BC progression. In addition, we identified TEAD4 as a transcriptional activator of RBM8A by Ch-IP, dual luciferase reporter gene and a series of functional rescue assays. Furthermore, we demonstrated the in vivo pro-carcinogenic effects of TEAD4 and RBM8A by xenograft tumor experiments in nude mice. Conclusion Collectively, these findings suggest that TEAD4 novel transcriptional target RBM8A interacts with EIF4A3 to increase IGF1R and IRS-2 expression and activate PI3K/AKT signaling pathway, thereby further promoting the malignant phenotype of BC cells.

Lauric acid (LA) has the possibility to improve milk production in dairy cows by improving mammary gland development, however, the mechanism by which it might regulate mammary gland development is unclear. The influence of LA on milk production, nutrient digestibility and the expression of proteins related to mammary gland development in dairy cows were evaluated. Forty primiparous Holstein dairy cows were divided into 4 groups in a randomized block design. Four treatments included the control (0 g/d LA per cow), low-LA (100 g/d LA per cow), medium-LA (200 g/d LA per cow), and high-LA (300 g/d LA per cow). Yields of milk, fat-corrected milk, and energy-corrected milk quadratically increased (P

Urban scenescapes are significantly influenced by cultural groups representing different ethnicities. In order to foster a cohesive and inclusive urban environment, it is crucial to comprehend the scale, type, and distribution of scenes associated with ethnicity. With the aim of exploring Tibetan cultural scenescapes in Chinese cities, this study employed the theory of scenes to develop a socio-spatial research method. By focusing on the five downtown districts of Chengdu as the study area, the study evaluated the effectiveness of urban facilities in expressing Tibetan culture and delineated the scenescapes related to Tibetan ethnicity in the designated region. This study’s findings indicate the following: 1) different urban facilities exhibited notable variation in their cultural performance; 2) currently, seven distinct scene clusters showcase Tibetan culture in downtown Chengdu; 3) these scene clusters can be categorised into three types. Based on the findings, this study has proposed strategies for planning scene clusters and designing facilities, with the overarching objective of fostering an inclusive and multicultural urban environment.

Objective: The objective of the study was to explore the regulatory mechanism of the Xiaozheng Tongluo method on lipid metabolism in liver tissue based on the sterol regulatory element-binding protein-2/(SREBP2)/3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR)/low-density lipoprotein receptor (LDLR) signaling pathway. Materials and Methods: C57BL/6 mice were selected as the blank group. The apolipoprotein E-deficient (ApoE-/-) mice were randomly divided into the model group, traditional Chinese medicine (TCM) group, and control group. The general condition of the mice was determined by the mouse’s state and liver weight. Liver hematoxylin and eosin staining and Oil Red O staining were used to observe the pathological changes and lipid droplet deposition of the liver. The protein expression levels of SREBP2, HMGCR, and LDLR were detected by Western blotting and polymerase chain reaction. Results: (1) The rats in the model group were in poor condition, and their liver weight increased significantly. Compared with the model group, the condition of the TCM group and the control group improved to varying degrees, and their liver weight decreased significantly. (2) Compared with the normal group, the hepatocytes in the model group were arranged in a disorderly manner, and the red-stained lipids of stem cells increased significantly. Compared with the model group, the degree of liver lesions in the control group and TCM group was reduced, and the red-stained lipid of hepatocytes was significantly reduced. (3) Compared with the blank group, the expression of SREBP2 and HMGCR protein in the model group increased significantly, and the expression of LDLR protein decreased significantly (P < 0.05). Compared with the model group, the expression of SREBP2 and HMGCR protein in the TCM group decreased significantly, and the expression of LDLR protein increased significantly (P < 0.05). Conclusions: The method detailed in this paper can increase the expression of SREBP2 and HMGCR protein and decrease the expression of LDLR protein, thus regulating liver cholesterol metabolism and delaying the progression of atherosclerosis.

Abstract Background Early-stage breast cancer (BC) presents a certain risk of recurrence, leading to variable prognoses and complicating individualized management. Yet, preoperative noninvasive tools for accurate prediction of disease-free survival (DFS) are lacking. This study assessed the potential of strain elastography (SE) and diffuse optical tomography (DOT) for non-invasive preoperative prediction of recurrence in T1 BC and developed a prediction model for estimating the probability of DFS. Methods A total of 565 eligible patients with T1 invasive BC were enrolled prospectively and followed to investigate the recurrence. The associations between imaging features and DFS were evaluated and a best-prediction model for DFS was developed and validated. Results During the median follow-up period of 10.8 years, 77 patients (13.6%) developed recurrences. The fully adjusted Cox proportional hazards model showed a significant trend between an increasing strain ratio (SR) (P

The study aims to investigate the stability of high fill slopes and their impact on oil and gas pipelines at the foot of the slopes in a key construction project located in Anning City, Yunnan Province. The project formed a high fill slope with a length of nearly 1.6km and a maximum height of about 42 m in early 2023. Due to site planning constraints, four oil and gas pipelines were buried parallel at the foot of the high-fill slope, with the closest pipeline being only 7 m away from the foot of the slope, posing a serious threat to the safety of the oil and gas pipelines. FLAC3D software was employed to analyze the influence of the fill slope on the pipelines at the foot of the slope, and to explore the stability of the slope with the installation of five rows of CFG piles at the toe. The results show that the potential failure surface exists only within the artificial fill, above the oil and gas pipelines. The basic stability factor of the fill slope is 1.305, indicating basic stability under extreme rainfall conditions. Under natural conditions, the pipeline meets the stability requirements, but may lead to deformation and rupture under heavy rainfall conditions. With the addition of five rows of CFG piles at the slope toe, pipeline deformation and ellipticity meet the specification requirements under heavy rainfall conditions, and the safety and stability coefficient of the slope increases by 4.2%, yet fails to meet the specification safety reserve requirements. Further preventive measures are recommended to ensure the safety reserve of the fill slope.

Abstract Venous thromboembolism (VTE) is a prevalent complication among patients with cancer, contributing significantly to morbidity and mortality. However, the relationship between VTE-related genes (VRGs) and their potential impact on prognosis, immune response, and therapeutic targets in various cancer types remains unclear. Based on the coagulation and complement pathways, we identified hub VRGs that play a role in regulating the immune response in cancer. Specifically, coagulation factor III (F3), plasminogen activator (PLAT) and complement C1s (C1S) were identified as genes that exhibit high expression levels, positively correlating with tumor stemness and copy number variations, while inversely correlating with methylation levels, in particular cancer types. Pan-cancer survival analysis revealed detrimental effects of these VRGs in several cancer types, notably in glioblastoma and lower grade glioma (GMBLGG). Further analysis using receiver operating characteristic (ROC) curves demonstrated a high accuracy of F3, PLAT and C1S in predicting outcomes in GBMLGG, with area under the curve (AUC) values ranging from 0.78 to 0.9. Validation of the prognostic value of these three genes in GMBLGG was conducted using an independent Gene Expression Omnibus (GEO) dataset. Additionally, gene–drug association analysis identified ciclosporin, ouabain and 6- mercaptopurine, which all exhibit immunosuppressive properties, as potential therapeutic options for tumor patients exhibiting high F3, PLAT or C1S expression, respectively. In summary, our findings provide a bioinformatics perspective on VRGs in pan-cancer, highlighting the pivotal roles of F3, PLAT and C1S, which could potentially be therapeutically exploited and targeted in several cancers, especially in GBMLGG.

Abstract Background Whether endobiliary radiofrequency ablation (EB-RFA) changes the standard role of stent placement in treating unresectable malignant biliary obstruction (MBO) remains unclear. The aim of this study is to compare percutaneous EB-RFA and metal stent placement (RFA-Stent) with metal stent placement alone (Stent) in treating unresectable MBO using a propensity score matching (PSM) analysis. Methods From June 2013 to June 2018, clinical data from 163 patients with malignant biliary obstruction who underwent percutaneous RFA-Stent or stenting alone were retrospectively analyzed using a nearest-neighbor algorithm to one-to-one PSM analysis to compare primary and secondary stent patency (PSP, SSP), overall survival (OS) and complications between the two groups. Results Before matching, for whole patients, RFA-Stent resulted in longer median PSP (8.0 vs. 5.1 months, P = 0.003), SSP (9.8 vs. 5.1 months, P

Abstract The free-field switching of the perpendicular magnetization by the out-of-plane polarized spin current induced spin-orbit torque makes it a promising technology for developing high-density memory and logic devices. The materials intrinsically with low symmetry are generally utilized to generate the spin current with out-of-plane spin polarization. However, the generation of the out-of-plane polarized spin current by engineering the symmetry of materials has not yet been reported. Here, we demonstrate that paramagnetic CaRuO3 films are able to generate out-of-plane polarized spin current by engineering the crystal symmetry. The non-uniform oxygen octahedral tilt/rotation along film’s normal direction induced by oxygen octahedral coupling near interface breaks the screw-axis and glide-plane symmetries, which gives rise to a significant out-of-plane polarized spin current. This spin current can drive field-free spin-orbit torque switching of perpendicular magnetization with high efficiency. Our results offer a promising strategy based on crystal symmetry design to manipulate spin current and could have potential applications in advanced spintronic devices.

Abstract Background Chinese cherry [Cerasus pseudocerasus (Lindl.) G.Don] (syn. Prunus pseudocerasus Lindl.) is an economically important fruiting cherry species with a diverse range of attractive colors, spanning from the lightest yellow to the darkest black purple. However, the MYB transcription factors involved in anthocyanin biosynthesis underlying fruit color variation in Chinese cherry remain unknown. Results In this study, we characterized the R2R3-MYB gene family of Chinese cherry by genome-wide identification and compared it with those of 10 Rosaceae relatives and Arabidopsis thaliana. A total of 1490 R2R3-MYBs were classified into 43 subfamilies, which included 29 subfamilies containing both Rosaceae MYBs and AtMYBs. One subfamily (S45) contained only Rosaceae MYBs, while three subfamilies (S12, S75, and S77) contained only AtMYBs. The variation in gene numbers within identical subfamilies among different species and the absence of certain subfamilies in some species indicated the species-specific expansion within MYB gene family in Chinese cherry and its relatives. Segmental and tandem duplication events primarily contributed to the expansion of Chinese cherry R2R3-CpMYBs. The duplicated gene pairs underwent purifying selection during evolution after duplication events. Phylogenetic relationships and transcript profiling revealed that CpMYB10 and CpMYB4 are involved in the regulation of anthocyanin biosynthesis in Chinese cherry fruits. Expression patterns, transient overexpression and VIGS results confirmed that CpMYB10 promotes anthocyanin accumulation in the fruit skin, while CpMYB4 acts as a repressor, inhibiting anthocyanin biosynthesis of Chinese cherry. Conclusions This study provides a comprehensive and systematic analysis of R2R3-MYB gene family in Chinese cherry and Rosaceae relatives, and identifies two regulators, CpMYB10 and CpMYB4, involved in anthocyanin biosynthesis in Chinese cherry. These results help to develop and utilize the potential functions of anthocyanins in Chinese cherry.

Abstract Receptor-interacting protein kinase 1 (RIPK1) is a therapeutic target in treating neurodegenerative diseases and cancers. RIPK1 has three distinct functional domains, with the center domain containing a receptor-interacting protein homotypic interaction motif (RHIM), which mediates amyloid formation. The functional amyloid formed by RIPK1 and/or RIPK3 is a crucial intermediate in regulating cell necroptosis. In this study, the amyloid structure of mouse RIPK1, formed by an 82-residue sequence centered at RHIM, is presented. It reveals the “N”-shaped folding of the protein subunit in the fibril with four β-strands. The folding pattern is shared by several amyloid structures formed by proteins with RHIM, with the central β-strand formed by the most conserved tetrad sequence I/VQI/VG. However, the solid-state NMR results indicate a structural difference between mouse RIPK1 and mouse RIPK3. A change in the structural rigidity is also suggested by the observation of weakened signals for mouse RIPK3 upon mixing with RIPK1 to form the RIPK1/RIPK3 complex fibrils. Our results provide vital information to understand the interactions between different proteins with RHIM, which will help us further comprehend the regulation mechanism in cell necroptosis.

Abstract Background The present study is to evaluate the clinical characteristics of patients with temporomandibular disorders (TMD). Methods A total of 3362 TMD patients were included. Each participant had complete medical records according to the diagnostic criteria for temporomandibular disorders (DC/TMD). The clinical characteristics including symptoms and signs in relation to age and gender were analyzed. Results The mean age of the patients seeking care was 29.89 ± 13.73Y, and 68.6% of patients were aged 16–35 years. The female-to-male ratio of patients was 2.2: 1, and the average age of males was significantly lower than that of females. The prevalence of clicking symptoms decreased with age, while the prevalence of pain symptoms and limitations in jaw movement increased with age. Females were more likely to have limitations in jaw movement than males. Among the patients with pain, the average visual analogue scale (VAS) was 2.96 ± 1.23. The average VAS score of acute TMD patients (≤ 3 months) was significantly higher than that of chronic TMD patients (> 3 months). Conclusions The majority of TMD patients seeking care were young people. The number and average age of female patients was higher than the males. Female patients were more likely to have limitations in jaw movement than males.

Abstract Small cell lung cancer (SCLC) is a recalcitrant cancer characterized by early metastasis, rapid tumor growth and poor prognosis. In recent decades, the epidemiology, initiation and mutation characteristics of SCLC, as well as abnormal signaling pathways contributing to its progression, have been widely studied. Despite extensive investigation, fewer drugs have been approved for SCLC. Recent advancements in multi-omics studies have revealed diverse classifications of SCLC that are featured by distinct characteristics and therapeutic vulnerabilities. With the accumulation of SCLC samples, different subtypes of SCLC and specific treatments for these subtypes were further explored. The identification of different molecular subtypes has opened up novel avenues for the treatment of SCLC; however, the inconsistent and uncertain classification of SCLC has hindered the translation from basic research to clinical applications. Therefore, a comprehensives review is essential to conclude these emerging subtypes and related drugs targeting specific therapeutic vulnerabilities within abnormal signaling pathways. In this current review, we summarized the epidemiology, risk factors, mutation characteristics of and classification, related molecular pathways and treatments for SCLC. We hope that this review will facilitate the translation of molecular subtyping of SCLC from theory to clinical application.

Abstract This study spanned 6 years and 4 generations, involving the progressive crossbreeding of South African Kalahari Goat (SK) and Guizhou Black Goat (GB) over three generations, followed by cross fixation F3 with F1 in the fourth generation, accompanied by the use of molecular markers technology to select a high fertility population, resulting in the creation of a hybrid goat, BKF4 (11/16 SK lineage and 5/16 GB lineage). A comparative evaluation of the BKF4 hybrid breed and its parental breeds was conducted. Reproductive and production parameters of GB, SK, and BKF4 goat groups were monitored, including lambing rate (LR), survival rate (SR), daily weight gain at 3 months of age (DWG), and adult body weight (ABW) (n = 110, 106, 112 per group). In addition, dressing percentage (DP) (n = 12 per group) and analyses of amino acids (n = 8, 6, 10 per group) and fatty acids (n = 6 per group) were conducted to evaluate meat quality indicators. Results: (1) Reproductive and production performance: The index of LR reached 199%, significantly higher than GB and SK (p ≤ 0.001), with a SR of 95.0%, markedly higher than SK (p ≤ 0.001); DWG was 276.5 g, ABW reached 56.6 kg and with a dressing percentage (DP) of 54.5%, they are significantly surpassing GB (p ≤ 0.001). (2) Regarding meat quality: pH45-value and crude protein content (CP) increased, while intramuscular fat content increased compared to GB and ash content decreased. The amino acid composition was similar to GB, but the taste was more similar to SK. However, there were some negative impacts on fatty acid composition and functionality. (3) PCA analysis revealed that: BKF4 exhibited superior meat quality compared to GB and SK, influenced by two key factors contributing 83.49% and 16.51% to the explained variance, respectively. The key factors affecting meat quality include intramuscular fat (IMF), nutrient index (NI), PUFAs/MUFAs, n-6FAs, and drip loss (DL).

Abstract Background This study aimed to evaluate the effectiveness and safety of recombinant human endostatin (Rh-endostatin) plus programmed cell death 1 (PD-1) inhibitors and chemotherapy as first-line treatment for advanced or metastatic non-small cell lung cancer (NSCLC) in a real-world setting. Methods This was a retrospective study on patients with EGFR/ALK-negative, advanced or metastatic NSCLC. Patients received Rh-endostatin plus PD-1 inhibitors and chemotherapy every three weeks for 4 to 6 cycles. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. Results A total of 68 patients were included in this retrospective analysis. As of data cutoff (December 13, 2022), the median follow-up of 21.4 months (interquartile range [IQR], 8.3-44.4 months). The median PFS and OS was 22.0 (95% confidence interval [CI]: 16.6-27.4) and 31.0 months (95% CI: 23.4-not evaluable [NE]), respectively. The ORR was 72.06% (95% CI: 59.85-82.27%), and DCR was 95.59% (95% CI: 87.64-99.08%). Patients with stage IIIB/IIIC NSCLC had significantly longer median PFS (23.4 vs. 13.2 months), longer median OS (not reached vs. 18.0 months), and higher ORR (89.2% vs. 51.6%) than those with stage IV NSCLC (all p ≤ 0.001). The ORR was higher in patients with high PD-L1 expression (tumor proportion score [TPS] ≥ 50%) than in those with low PD-L1 expression or positive PD-L1 expression (75% vs. 50%, p = 0.025). All patients experienced treatment-related adverse events (TRAEs), and ≥ grade 3 TRAEs occurred in 16 (23.53%) patients. Conclusions Rh-endostatin combined with PD-1 inhibitors plus chemotherapy as first-line treatment yielded favorable effectiveness with a manageable profile in patients with advanced or metastatic NSCLC, representing a promising treatment modality.

Abstract Catalytic methods to couple alcohol and alkene feedstocks are highly valuable in synthetic chemistry. The direct oxidative coupling of primary alcohols and alkenes offers a streamlined approach to ketone synthesis. Currently, available methods are based on transition metal-catalyzed alkene hydroacylation, which involves the generation of an electrophilic aldehyde intermediate from primary alcohol dehydrogenation. These methods generally require high reaction temperatures and a high loading of precious metal catalysts and are predominantly effective for branch-selective reactions with electron-rich alkenes. Herein, we designed a dual photo/cobalt-catalytic method to manipulate the reactivity of nucleophilic ketyl radicals for the synthesis of ketones from primary alcohols and alkenes in complementary reactivity and selectivity. This protocol exhibits exceptional scope across both primary alcohols and alkenes with high chemo- and regio-selectivity under mild reaction conditions. Mechanism investigations reveal the essential role of cobalt catalysis in enabling efficient catalysis and broad substrate scope.

Abstract The rising prevalence of diabetes mellitus has casted a spotlight on one of its significant sequelae: cognitive impairment. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, originally developed for diabetes management, are increasingly studied for their cognitive benefits. These benefits may include reduction of oxidative stress and neuroinflammation, decrease of amyloid burdens, enhancement of neuronal plasticity, and improved cerebral glucose utilization. The multifaceted effects and the relatively favorable side-effect profile of SGLT2 inhibitors render them a promising therapeutic candidate for cognitive disorders. Nonetheless, the application of SGLT2 inhibitors for cognitive impairment is not without its limitations, necessitating more comprehensive research to fully determine their therapeutic potential for cognitive treatment. In this review, we discuss the role of SGLT2 in neural function, elucidate the diabetes-cognition nexus, and synthesize current knowledge on the cognitive effects of SGLT2 inhibitors based on animal studies and clinical evidence. Research gaps are proposed to spur further investigation.

Abstract Background Dry powder inhalers (DPIs) rely on both internal resistance and patients’ inspiratory capacity for effective operation. Optimal inspiratory technique is crucial for DPI users. This study assessed the accuracy and repeatability of two available devices, PF810® and In-Check DIAL®, and analyzed their measurement errors and consistency in detecting inspiratory capacity. Methods The accuracy and repeatability of peak inspiratory flow (PIF) and forced inspiratory vital capacity (FIVC) against various internal resistances of the two devices were assessed using standard waveforms generated by a breathing simulator. The agreement of PIF measurements between the two devices in healthy volunteers and chronic obstructive pulmonary disease (COPD) patients was analyzed with the intraclass correlation coefficient and Bland–Altman graphical analysis. Results PF810® showed great accuracy and repeatability in measuring PIF, except for square waveforms at the lowest flow rate (20 L/min). In-Check DIAL® exhibited poor accuracy against high resistance levels. In scenarios with no resistance, In-Check DIAL® had significantly smaller measurement errors than PF810®, but larger errors against high resistance levels. The two devices showed excellent agreement (ICC > 0.80, P

Abstract Background Sterol side-chain reductase 2 (SSR2) is a key enzyme in the synthesis of plant cholesterol pathway. Despite the importance of watermelon as a horticultural cash crop, the SSR2 gene in watermelon has not been previously studied or reported. Results In this study, 28 SSR2 genes were identified in the watermelon genome. The physicochemical properties of 28 ClaSSR proteins were predicted by bioinformatics methods, and the gene structure, conserved motif, chromosome localization, phylogenetic analysis, cis-acting elements, expression patterns, promoter activity analysis and subcellular localization of ClaSSRs were studied. The 28 ClaSSRs were unevenly distributed on 11 chromosomes, and phylogenetic analysis showed that they could be grouped into 4 groups with other related Cucurbitaceae homologous genes. Analysis of gene structure and motifs revealed similarities in exons/introns and motifs between members of the same group, further supporting phylogenetic results. The RT–qPCR results showed variations in ClaSSRs expression during watermelon fruit development. The analysis of promoter activity for ClaSSR25 showed strong activity. Subcellular localization studies confirmed that ClaSSR25 is mainly located in the cytoplasm, which aligns with the predicted outcomes. We additionally estimated the network of protein–protein interactions for ClaSSR25 and analyzed proteins that could potentially interact with ClaSSR25 in melon and Arabidopsis thaliana. Conclusions We conducted bioinformatics analysis and expression analysis of members of the watermelon SSR2 gene family in this work, and the outcomes set the stage for further investigations into the watermelon SSR2 gene. Graphical Abstract

AIM: To investigate the impact of hsa_circ_0007482 on the proliferation and apoptosis of human pterygium fibroblasts (HPFs) and its correlation with the severity grades of pterygium. METHODS: Pterygium and normal conjunctival tissues were collected from the superior area of the same patient's eye (n=33). The correlation between pterygium severity and hsa_circ_0007482 expression using quantitative reverse-transcription polymerase chain reaction (RT-qPCR) were analyzed. Three distinct siRNA sequences targeting hsa_circ_0007482, along with a negative control sequence, were transfected into HPFs. Cell proliferation was assessed using the cell counting kit-8. Expression levels of Ki67, proliferating cell nuclear antigen (PCNA), Cyclin D1, Bax, B-cell lymphoma-2 (Bcl-2), and Caspase-3 were measured via RT-qPCR. Immunofluorescence staining was employed to detect Ki67 and vimentin expressions. Apoptosis was evaluated using flow cytometry. RESULTS: Hsa_circ_0007482 expression was significantly higher in pterygium tissues compared to normal conjunctival tissues (P

Introduction: Morphological abnormalities of erythrocytes/red blood cells (RBCs), e.g., increased acanthocytes, in Parkinson’s disease (PD) have been reported previously, although the underlying mechanisms remain to be characterized. In this study, the potential roles of α-synuclein (α-syn), a protein critically involved in PD and highly abundant in RBCs, were studied in PD patients as well as in a PD mouse model. Methods: Transgenic [PAC-Tg (SNCAA53T), A53T] mice overexpressing A53T mutant α-syn and SNCA knockout mice were employed to characterize the effect of α-syn on RBC morphology. In addition to A53T and SNCA knockout mice, the morphology of RBCs of PD patients was also examined using scanning electron microscopy. The potential roles of α-syn were further investigated in cultured RBCs and mice. Results: Morphological abnormalities of RBCs and increased accumulation of aggregated α-syn on the RBC membrane were observed in PD patients. A similar phenomenon was also observed in A53T mice. Furthermore, while mice lacking α-syn expression showed a lower proportion of acanthocytes, treating RBCs derived from SNCA knockout mice with aggregated α-syn resulted in a higher percentage of acanthocytes. In a follow-up proteomic investigation, several major classes of proteins were identified as α-syn-associated proteins on the RBC membrane, seven of which were calcium-binding proteins. Applying aggregated α-syn to the RBC membrane directly induced extracellular calcium influx along with morphological changes; both observations were adequately reversed by blocking calcium influx. Conclusions: This study demonstrated that α-syn plays a critical role in PD-associated morphological abnormalities of RBCs, at least partially via a process mediated by extracellular calcium influx.

Rapid development of checkpoint inhibitors has provided significant breakthroughs for cancer stem cell (CSC) therapy, while the therapeutic efficacy is restricted by hypoxia-mediated tumor immune evasion, especially hypoxia-induced CD47 overexpression in CSCs. Herein, we developed a genetically engineered CSC membrane-coated hollow manganese dioxide (hMnO2@gCMs) to elicit robust antitumor immunity by blocking CD47 and alleviating hypoxia to ultimately achieve the eradication of CSCs. The hMnO2 core effectively alleviated tumor hypoxia by inducing decomposition of tumor endogenous H2O2, thus suppressing the CSCs and reducing the expression of CD47. Cooperating with hypoxia relief-induced downregulation of CD47, the overexpressed SIRPα on gCM shell efficiently blocked the CD47-SIRPα “don't eat me” pathway, synergistically eliciting robust antitumor-mediated immune responses. In a B16F10-CSC bearing melanoma mouse model, the hMnO2@gCMs showed an enhanced therapeutic effect in eradicating CSCs and inhibiting tumor growth. Our work presents a simple, safe, and robust platform for CSC eradication and cancer immunotherapy.

Co-infection with porcine reproductive and respiratory syndrome virus (PRRSV) and Haemophilus parasuis (HPS) has severely restricted the healthy development of pig breeding. Exploring disease resistance of non-coding RNAs in pigs co-infected with PRRSV and HPS is therefore critical to complement and elucidate the molecular mechanisms of disease resistance in Kele piglets and to innovate the use of local pig germplasm resources in China. RNA-seq of lungs from Kele piglets with single-infection of PRRSV or HPS and co-infection of both pathogens was performed. Two hundred and twenty-five differentially expressed long non-coding RNAs (DElncRNAs) and 30 DEmicroRNAs (DEmiRNAs) were identified and characterized in the PRRSV and HPS co-infection (PRRSV–HPS) group. Compared with the single-infection groups, 146 unique DElncRNAs, 17 unique DEmiRNAs, and 206 target differentially expressed genes (DEGs) were identified in the PRRSV–HPS group. The expression patterns of 20 DEmiRNAs and DElncRNAs confirmed by real-time quantitative polymerase chain reaction (RT-qPCR) were consistent with those determined by high-throughput sequencing. In the PRRSV–HPS group, the target DEGs were enriched in eight immune Gene Ontology terms relating to two unique DEmiRNAs and 16 DElncRNAs, and the unique target DEGs participated the host immune response to pathogens infection by affecting 15 immune-related Kyoto Encyclopedia of Genes and Genomes enrichment pathways. Notably, competitive endogenous RNA (ceRNA) networks of different groups were constructed, and the ssc-miR-671-5p miRNA was validated as a potential regulatory factor to regulate DTX4 and AEBP1 genes to achieve innate antiviral effects and inhibit pulmonary fibrosis by dual-luciferase reporter assays. These results provided insight into further study on the molecular mechanisms of resistance to PRRSV and HPS co-infection in Kele piglets.

Abstract Ventricular septal rupture (VSR) is a mechanical complication of acute myocardial infarction (AMI), and its mortality has not decreased significantly in recent decades. However, no clinical model has been developed to predict short-term mortality in patients with post-infarction VSR (PIVSR). This study aimed to develop a nomogram to predict the 30-day mortality by using the clinical characteristics of hospitalized patients with PIVSR. The least absolute shrinkage and selection operator (LASSO) and multivariate logistic regression analysis was used to construct a nomogram by R. The model was evaluated by the area under the curve (AUC), calibration curve and decision curve analysis (DCA). The bootstrap method was used to validate the model internally. As a result, a nomogram was constructed by using six variables, including CRRT, mechanical ventilation, PPCI, WBC, PASP and methods of treatment. The AUC of the prediction model was 0.96 (0.93, 0.98). The prediction model was well calibrated. The DCA showed that if the threshold probability was between 15% and 95%, the nomogram model would provide a net benefit. The well-constructed and evaluated nomogram can be beneficial to clinicians to predict the risk of death within 30 days in patients with PIVSR.

Abstract Background High-grade gliomas (HGGs) have a rapid relapse and short survival. Studies have identified many clinical characteristics and biomarkers associated with progression-free survival (PFS) and over-survival (OS). However, there has not yet a comprehensive study on survival after the first progression (SAP). Methods From CGGA and TCGA, 319 and 308 HGGs were confirmed as the first progression. The data on clinical characteristics and biomarkers were analyzed in accordance with OS, PFS, and SAP. Results Analysis of 319 patients from CGGA, significant predictors of improved OS/PFS/SAP were WHO grade, MGMT promoter methylation, and Ki-67 expression in univariate analysis. Further multivariate analysis showed MGMT promoter methylation and Ki-67 expression were independent predictors. However, an analysis of 308 patients from TCGA found MGMT promoter methylation is the only prognostic marker. A longer SAP was observed in patients with methylated MGMT promoter after standard chemoradiotherapy. In our data, HGGs could be divided into low, intermediate, and high-risk groups for SAP by MGMT methylation and Ki-67 expression. Conclusions Patients with MGMT promoter methylation have a prolonger SAP after standard chemoradiotherapy. HGGs could be divided into low, intermediate, and high-risk groups for SAP according to MGMT status and Ki-67 expression.

Abstract Objectives To compare color Doppler ultrasound and contrast-enhanced ultrasound (CEUS) in evaluating vascular invasion in pancreatic ductal adenocarcinoma (PDAC). Materials and methods This retrospective study included 210 patients with PDAC who were evaluated by color Doppler ultrasound, CEUS, and contrast-enhanced computed tomography (CECT) at our institution between January 2017 and December 2020. Pathologic results were used as the gold standard in patients who underwent surgical and intraoperative exploration. For nonsurgical patients, CECT results were used as the reference standard. The vessels evaluated included those in the peripancreatic arterial system and venous system. The diagnostic performances of color Doppler ultrasound and CEUS for vascular invasion were compared. Results In 51 patients who underwent surgery and intraoperative exploration, color Doppler ultrasound and CEUS differed only in assessing venous system invasion in patients with PDAC of the pancreatic body and tail, with the former being superior to the latter. In 159 nonsurgical patients, there was no difference between CEUS and color Doppler ultrasound in assessing superior mesenteric arteriovenous invasion. CEUS was superior to color Doppler ultrasound in evaluating the celiac artery and its branches, with an accuracy of up to 97.8% for some vessels. Color Doppler ultrasound was ideal for evaluating the splenic and portal veins. Conclusion CEUS is more suitable for the evaluation of peripancreatic arteries than color Doppler. CEUS combined with color Doppler ultrasound can be used as a potential supplement to CECT and is also expected to be used to evaluate vascular invasion of PDAC after chemotherapy. Critical relevance statement Contrast-enhanced US and color Doppler in the assessment of vascular invasion in pancreatic ductal adenocarcinoma have their respective advantages, through standardized ultrasound processes are expected to improve the efficiency of inspection. Key Points Contrast-enhanced US has unique advantages in assessing pancreatic ductal adenocarcinoma invasion of the celiac artery. Doppler imaging is of high value in assessing venous system invasion. Standardization of ultrasound imaging procedures for pancreatic ductal adenocarcinoma is expected to improve efficiency. Graphical Abstract

Abstract In the last decade, laboratory-scale single-junction perovskite solar cells have achieved a remarkable power conversion efficiency exceeding 26.1%. However, the transition to industrial-scale production has unveiled a significant efficiency gap. The central challenge lies in the difficulty of achieving uniform, high-quality perovskite films on a large scale. To tackle this issue, various innovative strategies for manipulating crystallization have emerged in recent years. Based on an in-depth fundamental understanding of the nucleation and growth mechanisms in large-area perovskite films prepared through blade/slot-die coating methods, this review offers a critical examination of crystallization manipulation strategies for large-area perovskite solar modules. Lastly, we explore future avenues aimed at enhancing the efficiency and stability of large-area PSMs, thereby steering the field toward commercially viable applications.

Abstract The tumor microenvironment (TME) plays a pivotal role in the onset, progression, and treatment response of cancer. Among the various components of the TME, cancer-associated fibroblasts (CAFs) are key regulators of both immune and non-immune cellular functions. Leveraging single-cell RNA sequencing (scRNA) data, we have uncovered previously hidden and promising roles within this specific CAF subgroup, paving the way for its clinical application. However, several critical questions persist, primarily stemming from the heterogeneous nature of CAFs and the use of different fibroblast markers in various sample analyses, causing confusion and hindrance in their clinical implementation. In this groundbreaking study, we have systematically screened multiple databases to identify the most robust marker for distinguishing CAFs in lung cancer, with a particular focus on their potential use in early diagnosis, staging, and treatment response evaluation. Our investigation revealed that COL1A1, COL1A2, FAP, and PDGFRA are effective markers for characterizing CAF subgroups in most lung adenocarcinoma datasets. Through comprehensive analysis of treatment responses, we determined that COL1A1 stands out as the most effective indicator among all CAF markers. COL1A1 not only deciphers the TME signatures related to CAFs but also demonstrates a highly sensitive and specific correlation with treatment responses and multiple survival outcomes. For the first time, we have unveiled the distinct roles played by clusters of CAF markers in differentiating various TME groups. Our findings confirm the sensitive and unique contributions of CAFs to the responses of multiple lung cancer therapies. These insights significantly enhance our understanding of TME functions and drive the translational application of extensive scRNA sequence results. COL1A1 emerges as the most sensitive and specific marker for defining CAF subgroups in scRNA analysis. The CAF ratios represented by COL1A1 can potentially serve as a reliable predictor of treatment responses in clinical practice, thus providing valuable insights into the influential roles of TME components. This research marks a crucial step forward in revolutionizing our approach to cancer diagnosis and treatment.

Abstract Background Malnutrition is linked to a higher risk of unfavorable outcomes in various illnesses. The present investigation explored the correlation between inadequate nutritional condition and outcomes in older individuals diagnosed with hyperlipidemia. Methods The geriatric nutritional risk index (GNRI) was used to evaluate the nutritional status. All patients were divided into two groups according to GNRI. A Kaplan-Meier analysis was used to assess the survival rates of different groups at risk of malnutrition. In addition, GNRI was used in COX proportional risk regression models to evaluate its predictive effect on both overall mortality and cardiovascular mortality among patients with hyperlipidemia. Furthermore, the study employed restricted cubic splines (RCS) to examine the nonlinear correlation between GNRI and mortality. Results The study included 4,532 elderly individuals diagnosed with hyperlipidemia. During a median follow-up duration of 139 months, a total of 1498 deaths from all causes and 410 deaths from cardiovascular causes occurred. The Kaplan-Meier analysis demonstrated significantly poorer survival among individuals at risk of malnutrition, as indicated by the GNRI. In the malnutrition risk group, the modified COX proportional hazards model revealed that a decrease in GNRI was associated with a higher risk of all-cause mortality (HR=1.686, 95% CI 1.212-2.347) and cardiovascular mortality (HR=3.041, 95% CI 1.797-5.147). Furthermore, the restricted cubic splines revealed a non-linear association between GNRI and both all-cause mortality and cardiovascular mortality (p-value for non-linearity = 0.0039, p-value for non-linearity=0.0386). Conclusions In older patients with hyperlipidemia, lower levels of GNRI are associated with mortality. The GNRI could potentially be used to predict all-cause mortality and cardiovascular mortality.

Abstract The accurate prediction of photovoltaic (PV) power is crucial for planning, constructing, and scheduling high‐penetration distributed PV power systems. Traditional point prediction methods suffer from instability and lack reliability, which can be effectively addressed through interval prediction. This study proposes a short‐term PV power interval prediction method based on the framework of sparrow search algorithm (SSA)‐variational mode decomposition (VMD)‐convolutional neural network (CNN)‐gate recurrent unit (GRU). First, PV data undergo similar day clustering based on permutation entropy and VMD is applied to solar radiation signals with high correlation. Then, the hyperparameters of GRU are optimized by SSA according to the comprehensive evaluation indicator of interval prediction proposed in this study. Subsequently, quantile prediction results are obtained based on CNN‐GRU using the optimal parameters from SSA optimization. Finally, the prediction interval is composed of multiple quantile prediction results. A MATLAB R2022b program is developed to compare different prediction methods. The results demonstrate that compared to single neural network methods, the proposed method effectively improves the coverage width‐based criterion. In the interval prediction of sunny and rainy similar days, the comprehensive evaluation indicators of the proposed method are only 54.3% and 37.4% of the single GRU, respectively, indicating significantly improved interval prediction accuracy.

Abstract The function of Family With Sequence Similarity 83, Member A (FAM83A) in lung squamous cell carcinoma (LUSC) is largely unknown. Here, we detected its prognostic and regulation roles in LUSC. Bioinformatics methods were applied initially to predict the expression level and prognostic value of FAM83A mRNA in LUSC. In vitro experiments, such as western blot, colony formation and cell viability assay, lipid Reactive oxygen species (ROS), malondialdehyde (MDA), reduced glutathione (GSH)/oxidized glutathione disulfide (GSSG), and 4-hydroxy-2-nonenal (4-HNE) assay, were used to investigate its mechanism. In vivo experiments were further conducted to validate the mechanism. Results from TCGA and Oncomine databases revealed significantly higher FAM83A mRNA expression levels in LUSC than in normal lung tissue. TCGA and GEO databases and our database revealed that FAM83A expression level was an independent prognostic factor for both overall survival and progression-free survival. Besides, FAM83A was significantly associated with a higher ability of growth and clonogenicity. Mechanistically, in vitro and in vivo experiments revealed that FAM83A could promote LUSC cell growth by inhibiting ferroptosis via activating the Wnt/β-catenin signaling pathway. The rescue experiment demonstrated that inhibition of the Wnt/β-catenin pathway counteracted the function of FAM83A. FAM83A is overexpressed in LUSC and could serve as a prognosis prediction biomarker for LUSC. FAM83A promotes LUSC cell growth by inhibiting ferroptosis via activating the Wnt/β-catenin signaling pathway, which provides a new potential therapeutic target for LUSC treatment.

Abstract Pain is a very common and complex medical problem that has a serious impact on individuals’ physical and mental health as well as society. Non-steroidal anti-inflammatory drugs and opioids are currently the main drugs used for pain management, but they are not effective in controlling all types of pain, and their long-term use can cause adverse effects that significantly impair patients’ quality of life. Mesenchymal stem cells (MSCs) have shown great potential in pain treatment. However, limitations such as the low proliferation rate of MSCs in vitro and low survival rate in vivo restrict their analgesic efficacy and clinical translation. In recent years, researchers have explored various innovative approaches to improve the therapeutic effectiveness of MSCs in pain treatment. This article reviews the latest research progress of MSCs in pain treatment, with a focus on methods to enhance the analgesic efficacy of MSCs, including engineering strategies to optimize the in vitro culture environment of MSCs and to improve the in vivo delivery efficiency of MSCs. We also discuss the unresolved issues to be explored in future MSCs and pain research and the challenges faced by the clinical translation of MSC therapy, aiming to promote the optimization and clinical translation of MSC-based analgesia therapy. Graphical Abstract

Abstract Objective To evaluate the safety and efficacy of the granisetron transdermal delivery system (GTDS) combined with Dexamethasone for preventing chemotherapy-induced nausea and vomiting (CINV) in patients receiving Capecitabine plus Oxaliplatin (CapeOX) therapy. Design Open-label, prospective, multi-center phase II trial. Setting Three institutions. Participants Fifty-four patients scheduled to receive CapeOX chemotherapy. Interventions Participants received GTDS (3.1 mg applied to the upper arm 48 h before chemotherapy, replaced on day 5, and discarded on day 12) and Dexamethasone. Main outcome measures The primary endpoint was the complete control rate of CINV. Secondary endpoints included the duration of delayed complete control, complete control rate in the acute phase, safety, and quality of life. Results The complete control rate for delayed CINV over the entire period (25–480 h) was 72.7% (95% CI 0.57–0.88). The duration of delayed complete control was 17.2 ± 4.5 days, with 51.5% of patients experiencing no nausea during the delayed phase. The complete control rate in the acute phase was 81.8% (95% CI 0.69–0.95). No serious adverse events related to the antiemetic regimen were reported. Conclusion Prolonged administration of GTDS is safe and effective for preventing CINV in patients with gastrointestinal malignancies treated with CapeOX. Trial Registration ClinicalTrials.gov registry (NCT05325190); registered on October 10, 2021.

Abstract This research study demonstrates an efficient scheme for early detection of cardiorespiratory complications in pandemics by Utilizing Wearable Electrocardiogram (ECG) sensors for pattern generation and Convolution Neural Networks (CNN) for decision analytics. In health-related outbreaks, timely and early diagnosis of such complications is conclusive in reducing mortality rates and alleviating the burden on healthcare facilities. Existing methods rely on clinical assessments, medical history reviews, and hospital-based monitoring, which are valuable but have limitations in terms of accessibility, scalability, and timeliness, particularly during pandemics. The proposed scheme commences by deploying wearable ECG sensors on the patient’s body. These sensors collect data by continuously monitoring the cardiac activity and respiratory patterns of the patient. The collected raw data is then transmitted securely in a wireless manner to a centralized server and stored in a database. Subsequently, the stored data is assessed using a preprocessing process which extracts relevant and important features like heart rate variability and respiratory rate. The preprocessed data is then used as input into the CNN model for the classification of normal and abnormal cardiorespiratory patterns. To achieve high accuracy in abnormality detection the CNN model is trained on labeled data with optimized parameters. The performance of the proposed scheme is evaluated and gauged using different scenarios, which shows a robust performance in detecting abnormal cardiorespiratory patterns with a sensitivity of 95% and specificity of 92%. Prominent observations, which highlight the potential for early interventions include subtle changes in heart rate variability and preceding respiratory distress. These findings show the significance of wearable ECG technology in improving pandemic management strategies and informing public health policies, which enhances preparedness and resilience in the face of emerging health threats.

Abstract Objective To investigate the distribution and activation of B-cell subpopulations in rheumatoid arthritis (RA) patients treated with Janus kinase inhibitors (JAKis) and to analyze their correlation with disease remission. Methods Peripheral blood samples were collected from 23 adult healthy controls and 58 RA patients, 31 of whom were treated with JAKis and assessed during a 24-month follow-up. The number of peripheral B-cell subpopulations (including naive B cells, nonswitched memory B (NSMB) cells, switched memory B cells, and double-negative B cells), their activation, and phosphorylation of SYK and AKT upon B-cell receptor (BCR) stimulation in each population were analyzed by flow cytometry. Results Compared with that in healthy controls, the frequency of NSMB cells was significantly lower in new-onset untreated RA patients. However, expression of CD40, CD80, CD95, CD21low and pAKT significantly increased in these NSMB cells. Additionally, the number of NSMB cells correlated negatively with DAS28-ESR and IgG and IgA levels in these patients; expression of CD80, CD95 and CD21low on NSMB cells correlated positively with DAS28-ESR and IgG and IgA levels. After treatment with JAKis, the serum IgG concentration significantly decreased in RA patients in remission, but CD40, CD95 and pAKT levels in NSMB cells significantly decreased. Conclusion RA patients present different B-cell subpopulations, in which the frequency of NSMB cells is negatively associated with disease activity. However, treatment with JAKis can inhibit activation of NSMB cells, restore the balance of kinase phosphorylation, and facilitate disease remission in RA patients.

Abstract This study was aimed to explore the longitudinal association of five early life factors (breastfeeding, maternal smoking around birth, birth weight, being born in a multiple birth, and adoption) during the in-utero, perinatal, and early childhood development stages with incidence of depression and anxiety in adults aged 40–69 years. We used data from the UK biobank, 5,02,394 participants aged 40–69 years were recruited between 2006 and 2010. Participants provided information on early life exposures through touchscreen questionnaires or verbal interviews at baseline. The primary outcomes, depression, and anxiety, were defined according to the International Classification of Diseases, 10th Revision. Hazard ratios (HR) and 95% confidence intervals (CI) for each factor were reported. During a median follow-up of 13.6 years, 16,502 (3.55%) participants developed depression, and 15,507 (3.33%) developed anxiety. After adjusting for potential confounders, increased risk of depression was found to be significantly associated with non-breastfeeding (HR, 1.08; 95% CI, 1.04–1.13), maternal smoking around birth (HR, 1.19; 95% CI, 1.14–1.23), being born in multiple births (HR, 1.16; 95% CI, 1.05–1.27), low birth weight (HR, 1.14; 95% CI, 1.07–1.22), and being an adoptee (HR, 1.42; 95% CI, 1.28–1.58). Increased risk of anxiety was associated with non-breastfeeding (HR, 1.09; 95% CI, 1.04–1.13), maternal smoking around birth (HR, 1.11; 95% CI, 1.07–1.16), being born in a multiple births (HR, 1.05; 95% CI, 0.95–1.17), low birth weight (HR, 1.12; 95% CI, 1.05–1.20), and being an adoptee (HR, 1.25; 95% CI, 1.10–1.41). Each of these five early life factors can be considered as early life risk factors for incident depression and anxiety in adulthood independently. The dose-response relationship was also observed, suggesting that with an increase in the number of early life risk factors, the likelihood of experiencing depression and anxiety also increased. These findings highlighted the imperative consideration of early life factors in comprehending the susceptibility to mental health disorders later in life, including non-breastfeeding, maternal smoking around birth, being born in multiple births, low birth weight, and being an adoptee.

Abstract The vector forces at the human-mattress interface are not only crucial for understanding the distribution of vertical and shear forces exerted on the human body during sleep but also serves as a significant input for biomechanical models of sleeping positions, whose accuracy determines the credibility of predicting musculoskeletal system loads. In this study, we introduce a novel method for calculating the interface vector forces. By recording indentations after supine and lateral positions using a vacuum mattress and 3D scanner, we utilize image registration techniques to align body pressure distribution with the mattress deformation scanning images, thereby calculating the vector force values for each unit area (36.25 mm × 36.25 mm). This method was validated through five participants attendance from two perspectives, revealing that (1) the mean summation of the vertical force components is 98.67% ± 7.21% body weight, exhibiting good consistency, and mean ratio of horizontal component force to body weight is 2.18% ± 1.77%. (2) the predicted muscle activity using the vector forces as input to the sleep position model aligns with the measured muscle activity (%MVC), with correlation coefficient over 0.7. The proposed method contributes to the vector force distribution understanding and the analysis of musculoskeletal loads during sleep, providing valuable insights for mattress design and evaluation.

Abstract Objectives This study investigated the quantitative assessment and application of Synthetic MRI (SyMRI) for preoperative brain development in children with congenital heart disease (CHD). Methods Forty-three CHD patients aged 2–24 months were prospectively included in the observation group, and 43 healthy infants were included in the control group. The SyMRI scans were processed by postprocessing software to obtain T1, T2, and PD maps. The values of T1, T2, and PD in different brain regions were compared with the scores of the five ability areas of the Gesell Development Scale by Pearson correlation analysis. Results In the observation group, the T1 values of the posterior limb of the internal capsule (PLIC), Optic radiation (PTR), cerebral peduncle, centrum semiovale, occipital white matter, temporal white matter, and dentate nucleus were greater than those in the control group. In the observation group, the T2 values of the PLIC, PTR, frontal white matter, occipital white matter, temporal white matter, and dentate nucleus were greater than those in the control group. Pearson correlation analysis revealed that the observation group had significantly lower Development Scale scores. In the observation group, the T2 value of the splenium of the corpus callosum was significantly positively correlated with the personal social behavior score. The AUCs for diagnosing preoperative brain developmental abnormalities in children with CHD using T1 values of the temporal white matter and dentate nucleus were both greater than 0.60. Conclusions Quantitative assessment using SyMRI can aid in the early detection of preoperative brain development abnormalities in children with CHD. Critical relevance statement T1 and T2 relaxation values from SyMRI can be considered as a quantitative imaging marker to detect abnormalities, allowing for early clinical evaluation and timely intervention, thereby reducing neurodevelopmental disorders in these children. Key Points T1 and T2 relaxation values by SyMRI are related to myelin development. Evaluated development quotient markers were lower in the observation compared to the control group. SyMRI can act as a reference indicator for brain development in CHD children. Graphical Abstract

Abstract Valproic acid (VPA) is one of the most effective antiepileptic drugs, and exposing animals to VPA during gestation has been used as a model for autism spectrum disorder (ASD). Numerous studies have shown that impaired synaptic transmission in the cerebellar cortical circuits is one of the reasons for the social deficits and repetitive behavior seen in ASD. In this study, we investigated the effect of VPA exposure during pregnancy on tactile stimulation-evoked cerebellar mossy fiber-granule cell (MF-GC) synaptic transmission in mice anesthetized with urethane. Three-chamber testing showed that mice exposed to VPA mice exhibited a significant reduction in social interaction compared with the control group. In vivo electrophysiological recordings revealed that a pair of air-puff stimulation on ipsilateral whisker pad evoked MF-GC synaptic transmission, N1, and N2. The evoked MF-GC synaptic responses in VPA-exposed mice exhibited a significant increase in the area under the curve (AUC) of N1 and the amplitude and AUC of N2 compared with untreated mice. Cerebellar surface application of the selective N-methyl-D-aspartate (NMDA) receptor blocker D-APV significantly inhibited facial stimulation-evoked MF-GC synaptic transmission. In the presence of D-APV, there were no significant differences between the AUC of N1 and the amplitude and AUC of N2 in the VPA-exposed mice and those of the untreated mice. Notably, blockade of the GluN2A subunit-containing, but not the GluN2B subunit-containing, NMDA receptor, significantly inhibited MF-GC synaptic transmission and decreased the AUC of N1 and the amplitude and AUC of N2 in VPA-exposed mice to levels similar to those seen in untreated mice. In addition, the GluN2A subunit-containing NMDA receptor was expressed at higher levels in the GC layer of VPA-treated mice than in control mice. These results indicate that gestational VPA exposure in mice produces ASD-like behaviors, accompanied by increased cerebellar MF-GC synaptic transmission and an increase in GluN2A subunit-containing NMDA receptor expression in the offspring.

Zhigancao decoction is a traditional prescription for treating irregular pulse and palpitations in China. As the monarch drug of Zhigancao decoction, the bioactive molecules of licorice against heart diseases remain elusive. We established the HRESIMS-guided method leading to the isolation of three novel bicyclic peptides, glycnsisitins A–C (1–3), with distinctive C–C and C–O–C side-chain-to-side-chain linkages from the roots of Glycyrrhiza uralensis (Licorice). Glycnsisitin A demonstrated stronger cardioprotective activity than glycnsisitins B and C in an in vitro model of doxorubicin (DOX)-induced cardiomyocyte injury. Glycnsisitin A treatment not only reduced the mortality of heart failure (HF) mice in a dose-dependent manner but also significantly attenuated DOX-induced cardiac dysfunction and myocardial fibrosis. Gene set enrichment analysis (GSEA) of the differentially expressed genes indicated that the cardioprotective effect of glycnsisitin A was mainly attributed to its ability to maintain iron homeostasis in the myocardium. Mechanistically, glycnsisitin A interacted with transferrin and facilitated its binding to the transferrin receptor (TFRC), which caused increased uptake of iron in cardiomyocytes. These findings highlight the key role of bicyclic peptides as bioactive molecules of Zhigancao decoction for the treatment of HF, and glycnsisitin A constitutes a promising therapeutic agent for the treatment of HF.

Objective: To increase the yield of Sophora flavescens polysaccharides and elucidate their antioxidant and hypolipidemic properties, this study optimised the polysaccharide extraction process through orthogonal experiments, followed by evaluation of their antioxidant and hypolipidemic activities in vitro. Methods: Using polysaccharide yield as the primary metric, this study performed orthogonal experiments to optimise the extraction process, building on preliminary one-way experiments. This study investigated the effect of extraction temperature, number of extractions, material-liquid ratio and extraction time on the polysaccharide yield of Sophora flavescens. Furthermore, this study evaluated the in vitro antioxidant activity of the polysaccharides by investigating their scavenging potential against DPPH radicals, hydroxyl radicals and superoxide anion radicals. In addition, the in vitro hypolipidemic activity of the polysaccharides was evaluated by their binding affinity to sodium cholate (SC), sodium taurocholate (STC), sodium glycylcholate (SGC) and mixed bile salts (MBS). Results: The optimal conditions for the extraction of Sophora flavescens polysaccharide were determined as follows: a temperature of 85 ℃, a material-liquid ratio of 1:35 (g:mL), and an extraction duration of 3.5 hours, yielding an average polysaccharide content of 3.07%±0.07%. The scavenging efficiencies of Sophora flavescens polysaccharides against DPPH radicals, hydroxyl radicals, and superoxide anion radicals at a concentration of 5 mg/mL were measured at 60.1%±3.6%, 39.6%±3.1% and 45.1%±4.1%, respectively. Furthermore, the binding affinities of Sophora flavescens polysaccharides to SC, STC, SGC and MBS at a concentration of 10 mg/mL were determined to be 34.4%±0.75%, 45.4%±0.15%, 19.7%±0.94% and 37.7%±0.64%, respectively. Conclusion: Sophora flavescens polysaccharide exhibits notable in vitro antioxidant and hypolipidemic activities. This investigation furnishes a foundational understanding for the potential development and exploitation of Sophora flavescens polysaccharide.

Carbapenem-resistant Acinetobacter baumannii (CRAB) is a Priority 1 (Critical) pathogen urgently requiring new antibiotics. Polymyxins are a last-line option against CRAB-associated infections. This transcriptomic study utilized a CRAB strain to investigate mechanisms of bacterial killing with polymyxin B, colistin, colistin B, and colistin/sulbactam combination therapy. After 4 h of 2 mg/L polymyxin monotherapy, all polymyxins exhibited common transcriptomic responses which primarily involved disruption to amino acid and fatty acid metabolism. Of the three monotherapies, polymyxin B induced the greatest number of differentially expressed genes (DEGs), including for genes involved with fatty acid metabolism. Gene disturbances with colistin and colistin B were highly similar (89 % common genes for colistin B), though effects on gene expression were generally lower (0–1.5-fold in most cases) with colistin B. Colistin alone (2 mg/L) or combined with sulbactam (64 mg/L) resulted in rapid membrane disruption as early as 1 h. Transcriptomic analysis of this combination revealed that the effects were driven by colistin, which included disturbances in fatty acid synthesis and catabolism, and inhibition of nutrient uptake. Combination therapy produced substantially higher fold changes in 72 % of DEGs shared with monotherapy, leading to substantially greater reductions in fatty acid biosynthesis and increases in biofilm, cell wall, and phospholipid synthesis. This indicates synergistic bacterial killing with the colistin/sulbactam combination results from a systematic increase in perturbation of many genes associated with bacterial metabolism. These mechanistic insights enhance our understanding of bacterial responses to polymyxin mono- and combination therapy and will assist to optimize polymyxin use in patients.

Cervical cancer remains a significant global public health concern, often exhibits cisplatin resistance in clinical settings. Hypoxia, a characteristic of cervical cancer, substantially contributes to cisplatin resistance. To evaluate the therapeutic efficacy of cisplatin in patients with cervical cancer and to identify potential effective drugs against cisplatin resistance, we established a hypoxia-inducible factor-1 (HIF-1)-related risk score (HRRS) model using clinical data from patients treated with cisplatin. Cox and LASSO regression analyses were used to stratify patient risks and prognosis. Through qRT-PCR, we validated nine potential prognostic HIF-1 genes that successfully predict cisplatin responsiveness in patients and cell lines. Subsequently, we identified fostamatinib, an FDA-approved spleen tyrosine kinase inhibitor, as a promising drug for targeting the HRRS-high group. We observed a positive correlation between the IC50 values of fostamatinib and HRRS in cervical cancer cell lines. Moreover, fostamatinib exhibited potent anticancer effects on high HRRS groups in vitro and in vivo. In summary, we developed a hypoxia-related gene signature that suggests cisplatin response prediction in cervical cancer and identified fostamatinib as a potential novel treatment approach for resistant cases.

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.

Coal gangue, which accumulates in the open air, is modified by immersion in rain, and exhibits different tendencies to spontaneous combustion in different areas of precipitation. To study the role and influence of moisture on the oxidation and spontaneous combustion of coal gangue, we used high-sulfur coal gangue prone to spontaneous combustion in the Qipanjing area of Inner Mongolia. First, the coal gangue is soaked with different moisture content (moisture content: 0, 15%, 30%, 50%, 100%). After soaking for 45 days, the coal gangue is naturally air dried. The dried gangue samples were put into the self-made programmed temperature experiment furnace to conduct experiments on the pre-treated coal gangue samples (the temperature rise rate was set at 3℃/min, and the temperature rise range was set at 30−390 ℃). The gas the temperature points of the coal gangue in each stage was collected by air collecting bag (each rise of 15 ℃ was a stage). Finally, the collected gas was passed into the GC-4000A gas chromatograph. By comparing the O2 consumption、the volume fraction of CO, CH4, C2H4, C2H6 and other index gases produced by coal gangue treated with different moisture content, the results show that: The low temperature oxidation of coal gangue is the best when the moisture content is 15%, the initial formation temperature of CO, CH4, C2H4, C2H6 and other indicator gases is the lowest, and the concentration of various indicator gases is the highest when the temperature is 390℃. When the moisture content exceeds 50%, under the action of moisture dissolution, a large number of combustible substances in the coal gangue are carried and dispersed by moisture, resulting in a significant decrease in the concentration of various indicator gases generated when the moisture content of the coal gangue rises to 390 ℃, even lower than that of the control experimental group without moisture immersion and redrying treatment. When the coal gangue is immersed in water, the initial temperature points of the various index gases are reduced by about 15 ℃.

Objective To investigate the effects of dual-wavelength pulsed dye laser on the proliferation and apoptosis of hemangioma vascular endothelial cells (HemECs). Methods The isolated HemECs were randomly divided into four groups: pulsed dye laser group (PDL, 595 nm wavelength), Nd∶YAG laser (1 064 nm wavelength) group, dual-wavelength group (595 nm PDL+1 064 nm Nd∶YAG) and control group (no laser treatment). After 1, 3, and 7 d of treatment, the proliferation and apoptosis rate of HemECs were detected using CCK-8 and flow cytometry,respectively. The expression levels of angiogenesis related proteins, VEGF and bFGF, were detected with Western blotting. Results Compared with the control group, laser treatment made HemECs longer and sparser. After one day of treatment, the dual-wavelength laser significantly inhibited HemEC proliferation (P=0.015). However, neither PDL nor Nd∶YAG significantly changed proliferation rate of HemECs (P>0.05 vs. controls). After 3 and 7 days of treatment, the proliferation activity, expression levels of VEGF and bFGF proteins of HemECs were markedly decreased in the all laser-treated groups (P

Tendinopathy leads to low-grade tissue inflammation and chronic damage, which progresses due to pathological imbalance in angiogenesis. Reducing early pathological vascularization may be a new approach in helping to regenerate tendon tissue. Conventional stem cell therapy and tissue engineering scaffolds have not been highly effective at treating tendinopathy. In this study, tissue engineered stem cells (TSCs) generated using human umbilical cord mesenchymal stem cells (hUC-MSCs) were combined with microcarrier scaffolds to limit excessive vascularization in tendinopathy. By preventing VEGF receptor activation through their paracrine function, TSCs reduced in vitro angiogenesis and the proliferation of vascular endothelial cells. TSCs also decreased the inflammatory expression of tenocytes while promoting their anabolic and tenogenic characteristics. Furthermore, local injection of TSCs into rats with collagenase-induced tendinopathy substantially reduced early inflammation and vascularization. Mechanistically, transcriptome sequencing revealed that TSCs could reduce the progression of pathological angiogenesis in tendon tissue, attributed to Rap1-mediated vascular inhibition. TSCs may serve as a novel and practical approach for suppressing tendon vascularization, and provide a promising therapeutic agent for early-stage clinical tendinopathy.

In order to study the transformation law of active functional groups in the low-temperature oxidation process of coal gangue spontaneous combustion and its relationship with gas release, the experimental system composed of Fourier transform infrared spectrometer and programmed temperature control device was used to analyze the spectral experimental data of coal gangue samples at 30-350 °C in air atmosphere. The Spearman method was used to study the correlation between gas release and functional groups. The results showed that the content of hydroxyl groups in the spontaneous combustion process showed an overall upward trend, the content of aliphatic hydrocarbons in the oxidation reaction was high and the reaction was active, and the oxygen-containing functional groups were affected by aliphatic hydrocarbons in the oxidation. The amount of CH4 gas released increases with the increase of aliphatic hydrocarbon −CH2−, substituted aromatic hydrocarbon C−H and hydroxyl content. CO gas increases with the increase of carbonyl and aromatic hydrocarbon C−H content, and decreases with the increase of oxygen-containing functional group content. The release of CO2 gas during oxidation mainly increases with the increase of hydroxyl and carbonyl content, showing a very high correlation.