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Abstract Botryosphaeria dothidea is the main fungal pathogen responsible for causing Chinese hickory (Carya cathayensis) dry rot disease, posing a serious threat to the Chinese hickory industry. Understanding the molecular basis of B. dothidea infection and the host’s resistance mechanisms is crucial for controlling and managing the ecological impact of Chinese hickory dry rot disease. This study utilized ultrastructural observations to reveal the process of B. dothidea infection and colonization in Chinese hickory, and investigated the impact of B. dothidea infection on Chinese hickory biochemical indicators and plant hormone levels. Through high-throughput transcriptome sequencing, the gene expression profiles associated with different stages of B. dothidea infection in Chinese hickory and their corresponding defense responses were described. Additionally, a series of key genes closely related to non-structural carbohydrate metabolism, hormone metabolism, and plant-pathogen interactions during B. dothidea infection in Chinese hickory were identified, including genes encoding DUF, Myb_DNA-binding, and ABC transporter proteins. These findings provide important insights into elucidating the pathogenic mechanisms of B. dothidea and the resistance genes in Chinese hickory.

Abstract Background Cellular senescence can be induced in mammalian tissues by multiple stimuli, including aging, oncogene activation and loss of tumor suppressor genes, and various types of stresses. While senescence is a tumor suppressing mechanism when induced within premalignant or malignant tumor cells, senescent cells can promote cancer development through increased secretion of growth factors, cytokines, chemokines, extracellular matrix, and degradative enzymes, collectively known as senescence-associated secretory phenotype (SASP). Previous studies indicated that senescent cells, through SASP factors, stimulate tumor cell invasion that is a critical step in cancer cell metastasis. Methods In the current study, we investigated the effect of senescent cells on the motility of breast cancer cells, which is another key step in cancer cell metastasis. We analyzed the motility of breast cancer cells co-cultured with senescent cells in vitro and metastasis of the breast cancer cells co-injected with senescent cells in orthotopic xenograft models. We also delineated the signaling pathway mediating the effect of senescent cells on cancer cell motility. Results Our results indicate that senescent cells stimulated the migration of breast cancer cells through secretion of GM-CSF and bFGF, which in turn induced activation of the JNK pathway in cancer cells. More importantly, senescent cells promoted breast cancer metastasis, with a minimum effect on the primary tumor growth, in orthotopic xenograft mouse models. Conclusions These results have revealed an additional mechanism by which senescent cells promote tumor cell metastasis and tumor progression, and will potentially lead to identification of novel targets for cancer therapies that suppress metastasis, the major cause of cancer mortality.

Abstract Intestinal cancer (IC) poses a significant global health challenge that drives continuous efforts to explore effective treatment modalities. Conventional treatments for IC are effective, but are associated with several limitations and drawbacks. Chinese herbal medicine (CHM) plays an important role in the overall cancer prevention and therapeutic strategies. Recent years have seen a growing body of research focus on the potential of CHM in IC treatment, showing promising results in managing IC and mitigating the adverse effects of radiotherapy and chemotherapy. This review provides updated information from preclinical research and clinical observation on CHM’s role in treatment of IC, offering insights into its comprehensive management and guiding future prevention strategies and clinical practice.

Abstract Background Winter rapeseed, the sole overwintering oilseed crop in northern China, emphasizes winter resilience, yet epigenetic regulatory mechanisms governing overwintering memory remain poorly understood. Results In this study, the root collar tissues from the robust cold-resistant variety Longyou-7 were sampled during the pre-winter period (S1), overwintering periods (S2–S5), and re-greening period (S6), to analyze overall genomic DNA methylation levels using high-performance liquid chromatography (HPLC). The result showed that DNA methylation level exceeded 80% in the S1 stage. Throughout the overwintering periods, methylation levels displayed a decreasing trend in S3, followed by an increase in S5, and a pronounced decrease in S6. Consequently, S1, S3, S5, and S6 periods were chosen for whole-genome bisulfite sequencing analyses to elucidate the overwintering memory mechanisms of Longyou-7. The result revealed that DNA methylation primarily occurs in the CG context in Longyou-7. However, methylation of mC sites is most prevalent in the CHH type, gradually decreasing during overwintering periods. Analysis of methylation patterns in specific genomic regions of Longyou-7 showed that the highest methylation levels in the intergenic region. Moreover, mC sites in repeats and transposon elements are distributed differently across the three contexts. Subsequently, differentially methylated regions and promoters of Longyou-7 were identified during various periods compared to the S1 stage, followed by joint analysis with transcriptome sequencing. Functional enrichment analysis highlighted the involvement of most overlapping genes in the MAPK signaling pathway, plant hormone signal transduction, and starch and sucrose metabolism pathways. Changes in candidate gene expression within these three pathways correlated closely with DNA methylation levels. Conclusions Our findings underscored the critical role of DNA methylation in regulating the expression of overwintering memory genes in winter rapeseed. These results offer a comprehensive insights into the epigenetic regulatory mechanisms governing winter rapeseed's overwintering memory, while identified overwintering memory genes served as crucial genetic resources for multifaceted breeding of winter-resistant varieties. Graphical Abstract

Objective To explore the inhibitory effect of daphnetin (Dap) on gastric cancer cells and its mechanism. Methods Gastric cancer AGS cells were treated with Dap at concentrations of 0, 30, 60, 90, 120, and 150 μmol/L, and the effect on cell viability was evaluated after 48 h using the MTT assay. AGS cells were divided into groups A to E, and each group was treated with Dap at concentrations of 0, 30, 60, 90, 120, and 150 μmol/L, respectively, for 48 h. Each group was observed for changes in cell count and morphology using optical microscopy and crystal violet staining. DCF staining was used to evaluate the effect of Dap on intracellular reactive oxygen species (ROS) levels in AGS cells in groups A to D, while JC-1 staining was used to evaluate the effect of Dap on the level of mitochondrial membrane potential (MMP) in AGS cells in groups A to D. Western blot was conducted to measure the expression levels of LC3 and P62 proteins in AGS cells in groups A to D, and changes in autophagic flux in AGS cells were measured by Ad-mCherry-GFP-LC3B staining. Results Dap significantly inhibited AGS cell viability in a concentration-dependent manner (F=321.50,t=12.44-34.77,P

Abstract Immune checkpoint inhibitors (ICIs) have become an important cornerstone of many tumour treatments. However, the toxicity profile of immune-chemotherapy combination treatment approaches among older adult cancer patients is still unclear. Patients with any cancer who received camrelizumab-based immunotherapy were eligible for inclusion. The primary endpoints were adverse events (AEs) and immune-related adverse events (irAEs), which were defined based on Naranjo's algorithm. Patients were stratified by age (≥ 70 years and

Abstract Third-generation EGFR tyrosine kinase inhibitors (TKIs), exemplified by osimertinib, have demonstrated promising clinical efficacy in the treatment of non-small cell lung cancer (NSCLC). Our previous work has identified ASK120067 as a novel third-generation EGFR TKI with remarkable antitumor effects that has undergone New Drug Application (NDA) submission in China. Despite substantial progress, acquired resistance to EGFR-TKIs remains a significant challenge, impeding the long-term effectiveness of therapeutic approaches. In this study, we conducted a comprehensive investigation utilizing high-throughput proteomics analysis on established TKI-resistant tumor models, and found a notable upregulation of branched-chain amino acid transaminase 1 (BCAT1) expression in both osimertinib- and ASK120067-resistant tumors compared with the parental TKI-sensitive NSCLC tumors. Genetic depletion or pharmacological inhibition of BCAT1 impaired the growth of resistant cells and partially re-sensitized tumor cells to EGFR TKIs. Mechanistically, upregulated BCAT1 in resistant cells reprogrammed branched-chain amino acid (BCAA) metabolism and promoted alpha ketoglutarate (α-KG)-dependent demethylation of lysine 27 on histone H3 (H3K27) and subsequent transcriptional derepression of glycolysis-related genes, thereby enhancing glycolysis and promoting tumor progression. Moreover, we identified WQQ-345 as a novel BCAT1 inhibitor exhibiting antitumor activity both in vitro and in vivo against TKI-resistant lung cancer with high BCAT1 expression. In summary, our study highlighted the crucial role of BCAT1 in mediating resistance to third-generation EGFR-TKIs through epigenetic activation of glycolysis in NSCLC, thereby supporting BCAT1 as a promising therapeutic target for the treatment of TKI-resistant NSCLC.

Abstract Bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) have been shown to promote angiogenesis after ischemic stroke, in which microRNAs (miRs) are believed to play an important role in exosome-mediated therapeutic effects, though the mechanism is still not clear. In this study, a series of molecular biological and cellular assays, both in vitro and in vivo, were performed to elucidate the role of exosomal miR-486 in angiogenesis following cerebral ischemic and its molecular mechanisms. Our results revealed that BMSC-Exos significantly improved neurological function and increased microvessel density in ischemic stroke rats. In vitro assays showed that BMSC-Exos promoted the proliferation, migration, and tube formation ability of oxygen–glucose deprivation/reoxygenation (OGD/R) injured rat brain microvascular endothelial cells (RBMECs). Importantly, BMSC-Exos increased the expression of miR-486 and phosphorylated protein kinase B (p-Akt) and down-regulated the protein level of phosphatase and tensin homolog (PTEN) in vivo and in vitro. Mechanistic studies demonstrated that transfection with miR-486 mimic enhanced RBMECs angiogenesis and increased p-Akt expression, while inhibited PTEN expression. On the other hand, the miR-486 inhibitor induced an opposite effect, which could be blocked by PTEN siRNA. It was thus concluded that exosomal miR-486 from BMSCs may enhance the functional recovery by promoting angiogenesis following cerebral ischemic injury, which might be related to its regulation of the PTEN/Akt pathway.

Abstract Background The pregnant women with intrahepatic cholestasis were at high risk of fetal distress, preterm birth and unexpected stillbirth. Intrahepatic cholestasis of pregnancy (ICP) was mainly caused by disorder of bile acid metabolism, whereas the specific mechanism was obscure. Methods We performed proteomics analysis of 10 ICP specimens and 10 placenta specimens from patients without ICP through data-independent acquisition (DIA) technique to disclose differentially expressed proteins. We executed metabolomic analysis of 30 ICP specimens and 30 placenta specimens from patients without ICP through UPLC-MS/MS to identify differentially expressed metabolites. Enrichment and correlation analysis was used to obtain the direct molecular insights of ICP development. The ICP rat models were constructed to validate pathological features. Results The heatmap of proteomics analysis showed the top 30 up-regulated and 30 down-regulated proteins. The metabolomic analysis revealed 20 richer and 4 less abundant metabolites in ICP samples compared with placenta specimens from patients without ICP, and enrichment pathways by these metabolites included primary bile acid biosynthesis, cholesterol metabolism, bile secretion, nicotinate and nicotinamide metabolism, purine metabolism and metabolic pathways. Combined analysis of multiple omics results demonstrated that bile acids such as Glycohyocholic acid, Glycine deoxycholic acid, beta-Muricholic acid, Noncholic acid, cholic acid, Gamma-Mercholic Acid, alpha-Muricholic acid and Glycochenodeoxycholic Aicd were significantly associated with the expression of GLRX3, MYL1, MYH7, PGGT1B, ACTG1, SP3, LACTB2, C2CD5, APBB2, IPO9, MYH2, PPP3CC, PIN1, BLOC1S1, DNAJC7, RASAL2 and ATCN3 etc. The core protein ACAT2 was involved in lipid metabolic process and animal model showed that ACAT2 was up-regulated in placenta and liver of pregnant rats and fetal rats. The neonates had low birth weight and Safranin O-Fast green FCF staining of animal models showed that poor osteogenic and chondrogenic differentiation of fetal rats. Conclusion Multiple metabolites-alpha-Muricholic acid, beta-Muricholic acid, Glycine deoxycholic acid and Glycochenodeoxycholic Acid etc. were perfect biomarkers to predict occurrence of ICP. Bile acids were significantly associated with varieties of protein expression and these proteins were differentially expressed in ICP samples. Our study provided several biomarkers for ICP detection and potential therapeutic targets for ICP development.

Abstract Extreme cold exposure has been widely considered as a cardiac stress and may result in cardiac function decompensation. This study was to examine the risk factors that contribute to changes in cardiovascular indicators of cardiac function following extreme cold exposure and to provide valuable insights into the preservation of cardiac function and the cardiac adaptation that occur in real‐world cold environment. Seventy subjects were exposed to cold outside (Mohe, mean temperature −17 to −34°C) for one day, and were monitored by a 24‐h ambulatory blood pressure device and underwent echocardiography examination before and after extreme cold exposure. After exposure to extreme cold, 41 subjects exhibited an increase in ejection fraction (EF), while 29 subjects experienced a decrease. Subjects with elevated EF had lower baseline coefficients of variation (CV) in blood pressure compared to those in the EF decrease group. Additionally, the average real variability (ARV) of blood pressure was also significantly lower in the EF increase group. Multivariate regression analysis indicated that both baseline CV and ARV of blood pressure were independent risk factors for EF decrease, and both indicators proved effective for prognostic evaluation. Correlation analysis revealed a correlation between baseline blood pressure CV and ARV, as well as EF variation after exposure to extreme cold environment. Our research clearly indicated that baseline cardiovascular indicators were closely associated with the changes in EF after extreme cold exposure. Furthermore, baseline blood pressure variability could effectively predict alterations in left cardiac functions when individuals were exposed to extreme cold environment.

Abstract Background The global prevalence of autoimmune hepatitis (AIH) is increasing due in part to the lack of effective pharmacotherapies. Growing evidence suggests that fibroblast growth factor 4 (FGF4) is crucial for diverse aspects of liver pathophysiology. However, its role in AIH remains unknown. Therefore, we investigated whether FGF4 can regulate M1 macrophage and thereby help treat liver inflammation in AIH. Methods We obtained transcriptome-sequencing and clinical data for patients with AIH. Mice were injected with concanavalin A to induce experimental autoimmune hepatitis (EAH). The mechanism of action of FGF4 was examined using macrophage cell lines and bone marrow-derived macrophages. Results We observed higher expression of markers associated with M1 and M2 macrophages in patients with AIH than that in individuals without AIH. EAH mice showed greater M1-macrophage polarization than control mice. The expression of M1-macrophage markers correlated positively with FGF4 expression. The loss of hepatic Fgf4 aggravated hepatic inflammation by increasing the abundance of M1 macrophages. In contrast, the pharmacological administration of FGF4 mitigated hepatic inflammation by reducing M1-macrophage levels. The efficacy of FGF4 treatment was compromised following the in vivo clearance of macrophage populations. Mechanistically, FGF4 treatment activated the phosphatidylinositol 3-kinase (PI3K)–protein kinase B (AKT)-signal pathway in macrophages, which led to reduced M1 macrophages and hepatic inflammation. Conclusion We identified FGF4 as a novel M1/M2 macrophage-phenotype regulator that acts through the PI3K–AKT-signaling pathway, suggesting that FGF4 may represent a novel target for treating inflammation in patients with AIH.

Objective To explore the relationship between serum hypoxia inducible factor-1α (HIF-1α) and renal interstitial lesions in primary IgA nephropathy (IgAN). Methods From August 2017 to August 2021, retrospective analysis was performed for 142 IgAN patients. The relevant clinical data were collected and serum HIF-1αlevel was detected. They were divided into two groups according to the severity of renal interstitial lesions. Proportion of renal tubulointerstitial lesions ≤25% was mild group while >25% severe group. Inter-group differences in various parameters were examined by multiple factors. Correlations between serum HIF-1α and risk factors of kidney disease progression were analyzed. ResultsNo statistically significant inter-group differences existed in gender, 24 h urine protein quantification, body mass index (BMI), serum albumin, low-density lipoprotein cholesterol, triglycerides or hypertension (P>0.05). As compared with mild group, age [(44.45±9.65) year vs (38.36±11.09) year], blood creatinine [(116.28±44.75) μmol/L vs (84.82±42.06) μmol/L], blood uric acid [(389.03±104.57) μmol/L vs (353.39±90.01) μmol/L], serum HIF-1α[(213.53±68.86) pg/L vs (141.13±60.61) pg/L] were higher (P

Abstract Background Subarachnoid hemorrhage (SAH) is a subtype of hemorrhagic stroke characterized by high mortality and low rates of full recovery. This study aimed to investigate the epidemiological characteristics of SAH between 1990 and 2021. Methods Data on SAH incidence, mortality, and disability-adjusted life-years (DALYs) from 1990 to 2021 were obtained from the Global Burden of Disease Study (GBD) 2021. Estimated annual percentage changes (EAPCs) were calculated to evaluate changes in the age-standardized rate (ASR) of incidence and mortality, as well as trends in SAH burden. The relationship between disease burden and sociodemographic index (SDI) was also analyzed. Results In 2021, the incidence of SAH was found to be 37.09% higher than that in 1990; however, the age-standardized incidence rates (ASIRs) showed a decreased [EAPC: -1.52; 95% uncertainty interval (UI) -1.66 to -1.37]. Furthermore, both the number and rates of deaths and DALYs decreased over time. It was observed that females had lower rates compared to males. Among all regions, the high-income Asia Pacific region exhibited the highest ASIR (14.09/100,000; 95% UI 12.30/100,000 − 16.39/100,000) in 2021, with an EPAC for ASIR

Abstract Background Acute thrombotic events play a major role in various cardiovascular diseases. Therefore, direct thrombus imaging can be proved beneficial for early diagnosis and prompt therapy of thrombosis. Our study investigated targeted dual‐modality cyclic arginine‐glycine‐aspartic micro bubbles (cRGD‐MBs) for direct imaging of thrombi by fluorescence and ultrasound. Methods cRGD‐MBs were prepared by mechanical vibration and chemical chelation methods. Results Coulter counter analysis demonstrated that the cRGD‐MBs were well dispersed, with diameters ranging from 1 to 3 μm. They emitted bright red fluorescence under an excitation wavelength of 660 nm. In vivo fluorescence and ultrasound imaging revealed that cRGD‐MBs accumulated at the site of thrombus in the carotid artery with significant fluorescence and ultrasonic signal. Conclusions This study showed that novel microbubble cRGD‐MBs were successfully synthesized, and that these could potentially be used as contrast agents for immediate diagnosis of acute thrombus in vivo.

Abstract Dysregulated epigenetic states are a hallmark of cancer and often arise from genetic alterations in epigenetic regulators. This includes missense mutations in histones, which, together with associated DNA, form nucleosome core particles. However, the oncogenic mechanisms of most histone mutations are unknown. Here, we demonstrate that cancer-associated histone mutations at arginines in the histone H3 N-terminal tail disrupt repressive chromatin domains, alter gene regulation, and dysregulate differentiation. We find that histone H3R2C and R26C mutants reduce transcriptionally repressive H3K27me3. While H3K27me3 depletion in cells expressing these mutants is exclusively observed on the minor fraction of histone tails harboring the mutations, the same mutants recurrently disrupt broad H3K27me3 domains in the chromatin context, including near developmentally regulated promoters. H3K27me3 loss leads to de-repression of differentiation pathways, with concordant effects between H3R2 and H3R26 mutants despite different proximity to the PRC2 substrate, H3K27. Functionally, H3R26C-expressing mesenchymal progenitor cells and murine embryonic stem cell-derived teratomas demonstrate impaired differentiation. Collectively, these data show that cancer-associated H3 N-terminal arginine mutations reduce PRC2 activity and disrupt chromatin-dependent developmental functions, a cancer-relevant phenotype.

Abstract Background Psoriasis is a long-term inflammatory skin disease. A novel herbal formula containing nine Chinese herbal medicines, named Inflammation Skin Disease Formula (ISDF), has been prescribed in clinics for decades. Aims To investigate the efficacy and action mechanisms of ISDF on psoriasis using imiquimod (IMQ) and Interleukin-23 (IL-23)-induced models in mice and reveal the pharmacokinetics profile of ISDF in rats. Methods Topical administration of IMQ and intradermal injection with IL-23 respectively induced skin lesions like psoriasis on the dorsal area of Balb/c and C57 mice. The mice's body weight, skin thickness, and psoriasis area and severity index (PASI) were assessed weekly. SD rats were used in the pharmacokinetics study and the contents of berberine and baicalin were determined. Results The PASI scores and epidermal thickness of mice were markedly decreased after ISDF treatment in both models. ISDF treatment significantly decreased the contents of IL-17A and IL-22 in the serum of IMQ- and IL-23-treated mice. Importantly, ISDF markedly downregulated IL-4, IL-6, IL-1β, and tumor necrosis factor α (TNF-α) gene expression, and the phosphorylation of NF-κB p65, JNK, ERKs and MAPK p38 in IMQ-treated mice. The protein phosphorylation of Jak1, Jak2, Tyk2 and Stat3 was significantly mitigated in the ISDF-treated groups. The absorption of baicalin and berberine of ISDF through the gastrointestinal tract of rats was limited, and their distribution and metabolism in rats were also very slow, which suggested ISDF could be used in the long-term application. Conclusions ISDF has a strong anti-psoriatic therapeutic effect on mouse models induced with psoriasis through IMQ and IL-23, which is achieved by inhibiting the activation of the Jak/Stat3-activated IL-23/Th17 axis and the downstream NF-κB signalling and MAPK signalling pathways. ISDF holds great potential to be a therapy for psoriasis and should be further developed for this purpose.

ObjectiveThe causal link between detrimental behaviors and cognitive performance remains unclear. This research seeks to investigate the causal impact of adjustable lifestyle factors on cognitive deterioration, including frequency of alcohol intake, onset of smoking, and sedentary activities like prolonged television viewing.MethodsThis research combines large-scale genetic data obtained from univariable and multivariable Mendelian randomization analyses with experimental findings obtained from animal models.ResultsOur findings reveal that the odds ratio (OR) for cognitive function deterioration was 0.445 (inverse variance weighted [IVW] 95% CI: 0.370 to 0.536, p

The growth rate of young ruminants has been associated with production performance in later life, with recent studies highlighting the importance of rumen microbes in supporting the health and growth of ruminants. However, the specific role of rumen epithelium bacteria and microbiota-host interactions in influencing the early life growth rate of ruminants remains poorly understood. In this study, we investigated the rumen fermentation pattern, microbiota characteristics, and global gene expression profiles of the rumen epithelium in 6-month-old goats with varying growth rates. Our results showed that goats with high average daily gain (HADG) exhibited higher rumen propionate concentrations. Goats with low average daily gain (LADG) had the higher relative abundances of rumen epithelium bacteria genera U29-B03 and Quinella, while exhibiting a lower relative abundance of Lachnospiraceae UCG-009. In the rumen fluid, the relative abundances of bacteria genus Alloprevotella were lower and Desulfovibrio were higher in LADG goats compared to HADG goats. Additionally, the relative abundance of fungal genus Symmetrospora was lower in LADG goats compared to HADG goats. Transcriptome analysis showed that 415 genes were differentially expressed between LADG and HADG goats, which were enriched in functions related to cell junction and cell adhesion, etc. Correlation analysis revealed that rumen epithelium bacteria genera UCG-005 and Candidatus Saccharimonas were negatively associated, while Lachnospiraceae NK3A20 group and Oscillospiraceae NK4A214 group were positively associated with average daily gain (ADG) and genes related to barrier function. The rumen fluid bacteria genus Alloprevotella was positively correlated, while Desulfovibrio was negatively correlated with rumen propionate and ammoniacal nitrogen (NH3-N) concentrations, as well as genes related to barrier function and short chain fatty acids (SCFAs) transport. In summary, our study reveals that the higher ruminal fermentation efficiency, improved rumen epithelial barrier functions, and enhanced SCFAs transport in HADG goats could be attributed to the rumen microbiota, particularly the rumen epithelium bacteria, such as Lachnospiraceae and Oscillospiraceae NK4A214 group.

Objective To report 3 cases of Guillain-Barré syndrome (GBS) caused by heat stroke (HS) and review the relevant literatures, and summarize the clinical characteristics of GBS caused by HS. Methods and Results The three patients were all diagnosed and treated by The Second Affiliated Hospital of Nanchang University in August 2022. The clinical manifestations were mainly weakness of limbs and dysarticulation after recovery of consciousness disorder of HS, disappearance of tendon reflex as shown by physical examination, extensive peripheral nerve damage mainly caused by axonal damage and motor nerve involvement as shown by EMG. Cerebrospinal fluid protein cell segregation phenomenon was present in Case 1 and Case 2, and the clinical diagnosis was GBS caused by HS. The muscle strength was better than before after immunotherapy, but obvious neurological dysfunction was still found after one year follow-up. Conclusions GBS caused by HS is a severe condition, often appearing within 3 weeks after HS. Immunotherapy leads to varying degrees of improvement in muscle strength; however, significant neurological dysfunction still persist, resulting in a poorer prognosis compared to general GBS.

To characterize the chromosomes of the four species of Polygonatum Miller, 1754, used in traditional Chinese medicine, P. cyrtonema Hua, 1892, P. kingianum Collett et Hemsley, 1890, P. odoratum (Miller, 1768) Druce, 1906, and P. sibiricum Redouté, 1811, and have an insight into the karyotype variation of the genus Polygonatum, fluorescence in situ hybridization (FISH) with 5S and 45S rDNA oligonucleotide probes was applied to analyze the karyotypes of 9 populations of the four species. Detailed molecular cytogenetic karyotypes of the 9 populations were established for the first time using the dataset of chromosome measurements and FISH signals of 5S and 45S rDNA. Four karyotype asymmetry indices, CVCI, CVCL, MCA and Stebbins’ category, were measured to elucidate the asymmetry of the karyotypes and karyological relationships among species. Comparison of their karyotypes revealed distinct variations in the karyotypic parameters and rDNA patterns among and within species. The basic chromosome numbers detected were x = 9, 11 and 13 for P. cyrtonema, x = 15 for P. kingianum, x = 10 and 11 for P. odoratum, and x = 12 for P. sibiricum. The original basic chromosome numbers of the four species were inferred on the basis of the data of this study and previous reports. All the 9 karyotypes were of moderate asymmetry and composed of metacentric, submetacentric and subtelocentric chromosomes or consisted of two of these types of chromosomes. Seven populations have one locus of 5S rDNA and two loci of 45S rDNA, and two populations added one 5S or 45S locus. The karyological relationships among the four species revealed by comparison of rDNA patterns and PCoA based on x, 2n, TCL, CVCI, MCA and CVCL were basically accordant with the phylogenetic relationships revealed by molecular phylogenetic studies. The mechanisms of both intra- and inter-specific dysploidy in Polygonatum were discussed based on the data of this study and literature.

Abstract Nao-an Dropping Pill (NADP) is a Chinese patent medicine which commonly used in clinic for ischemic stroke (IS). However, the material basis and mechanism of its prevention or treatment of IS are unclear, then we carried out this study. 52 incoming blood components were resolved by UHPLC-MS/MS from rat serum, including 45 prototype components. The potential active prototype components hydroxysafflor yellow A, ginsenoside F1, quercetin, ferulic acid and caffeic acid screened by network pharmacology showed strongly binding ability with PIK3CA, AKT1, NOS3, NFE2L2 and HMOX1 by molecular docking. In vitro oxygen–glucose deprivation/reperfusion (OGD/R) experimental results showed that NADP protected HA1800 cells from OGD/R-induced apoptosis by affecting the release of LDH, production of NO, and content of SOD and MDA. Meanwhile, NADP could improve behavioral of middle cerebral artery occlusion/reperfusion (MCAO/R) rats, reduce ischemic area of cerebral cortex, decrease brain water and glutamate (Glu) content, and improve oxidative stress response. Immunohistochemical results showed that NADP significantly regulated the expression of PI3K, Akt, p-Akt, eNOS, p-eNOS, Nrf2 and HO-1 in cerebral ischemic tissues. The results suggested that NADP protects brain tissues and ameliorates oxidative stress damage to brain tissues from IS by regulating PI3K/Akt/eNOS and Nrf2/HO-1 signaling pathways.

Abstract Molybdenum and its alloys are known for their superior strength among body-centered cubic materials. However, their widespread application is hindered by a significant decrease in ductility at lower temperatures. In this study, we demonstrate the achievement of exceptional ductility in a Mo alloy containing rare-earth La2O3 nanoparticles through rotary-swaging, a rarity in Mo-based materials. Our analysis reveals that the large ductility originates from substantial variations in the electronic density of states, a characteristic intrinsic to rare-earth elements. This characteristic can accelerate the generation of oxygen vacancies, facilitating the amorphization of the oxide-matrix interface. This process promotes vacancy absorption and modification of dislocation configurations. Furthermore, by inducing irregular shapes in the La2O3 nanoparticles through rotary-swaging, incoming dislocations interact with them, creating multiple dislocation sources near the interface. These dislocation sources act as potent initiators at even reduced temperatures, fostering diverse dislocation types and intricate networks, ultimately enhancing dislocation plasticity.

Background Adolescent non-suicidal self-injury has become an increasingly serious mental health problem, and its course is protracted, causing serious burdens to patients, families and society. Intervention of non-suicidal self-injury in adolescents requires a comprehensive intervention model, and the practice of online intervention management in China is still in its infancy. Objective To investigate the intervention effect of "Internet+" dialectical behavior therapy (DBT) on suicidal ideation, cognitive emotion regulation, and alleviation of depression in adolescent patients with non-suicidal self-injury. Methods A total of 120 adolescent patients with non-suicidal self-injury who were discharged from the Second Affiliated Hospital of Xinxiang Medical University from May 2021 to May 2022 were selected and randomly divided into the control group (n=60) and intervention group by randomized controlled single-blind method (n=60). The control group received drug intervention, telephone follow-up and psychological counseling, the intervention group implemented a one-year "Internet+" DBT training based on the control group, which was divided into 4 modules of mindfulness training, interpersonal effectiveness training, emotion regulation training and pain tolerance training. Before the intervention, 6 months and 12 months after the intervention, the Self-rating Idea of Suicide Scale (SIOSS), Chinese version of Cognitive Emotion Regulation Questionnaire, (CERQ-C) and Montgomery and Asberg Depression Rating Scale (MADRS) were used to evaluate the suicidal ideation, cognitive emotion regulation, and depression status of the two groups of patients. Repeated measures analysis of variance was used to compare the health status of the two groups at different time points. Results Finally, 57 cases in the control group and 55 cases in the intervention group completed the study. There was an interaction between group and time on SIOSS, CERQ-C, and MADRS scores (P0.001). The difference was statistically significant when comparing the self-blame, acceptance, and contemplation dimensions of the CERQ-C scores before and after intervention within the control group (P

Abstract Background Rose (Rosa hybrida) is a globally recognized ornamental plant whose growth and distribution are strongly limited by drought stress. The role of Mediator, a multiprotein complex crucial for RNA polymerase II-driven transcription, has been elucidated in drought stress responses in plants. However, its physiological function and regulatory mechanism in horticultural crop species remain elusive. Results In this study, we identified a Tail module subunit of Mediator, RhMED15a-like, in rose. Drought stress, as well as treatment with methyl jasmonate (MeJA) and abscisic acid (ABA), significantly suppressed the transcript level of RhMED15a-like. Overexpressing RhMED15a-like markedly bolstered the osmotic stress tolerance of Arabidopsis, as evidenced by increased germination rate, root length, and fresh weight. In contrast, the silencing of RhMED15a-like through virus induced gene silencing in rose resulted in elevated malondialdehyde accumulation, exacerbated leaf wilting, reduced survival rate, and downregulated expression of drought-responsive genes during drought stress. Additionally, using RNA-seq, we identified 972 differentially expressed genes (DEGs) between tobacco rattle virus (TRV)-RhMED15a-like plants and TRV controls. Gene Ontology (GO) analysis revealed that some DEGs were predominantly associated with terms related to the oxidative stress response, such as ‘response to reactive oxygen species’ and ‘peroxisome’. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment highlighted pathways related to ‘plant hormone signal transduction’, in which the majority of DEGs in the jasmonate (JA) and ABA signalling pathways were induced in TRV-RhMED15a-like plants. Conclusion Our findings underscore the pivotal role of the Mediator subunit RhMED15a-like in the ability of rose to withstand drought stress, probably by controlling the transcript levels of drought-responsive genes and signalling pathway elements of stress-related hormones, providing a solid foundation for future research into the molecular mechanisms underlying drought tolerance in rose.

Abstract Background Several observational studies demonstrated that pregnant individuals with COVID-19 had a higher risk of preeclampsia and preterm birth. We aimed to determine whether women with COVID-19 diagnosis had adverse pregnancy outcomes. Methods A two-sample Mendelian randomization (MR) analysis in this study was used to evaluate the casual relationships between COVID-19 infection and obstetric-related diseases based on genome-wide association studies (GWAS) dataset. Inverse-variance weighted (IVW), MR-Egger and MR-PRESSO were used to infer the connection and estimate the pleiotropy respectively. Results The significant connection was observed between COVID-19 and placental disorders with betaIVW of 1.57 and odds ratio (OR) of 4.81 (95% confidence interval [CI]: 1.05–22.05, p = 0.04). However, there were no associations between COVID-19 infection and gestational diabetes mellitus (GDM) (OR = 1.12; 95% CI: 0.85–1.45, p = 0.41), other disorders of amniotic fluid and membranes (OR = 0.90; 95% CI: 0.61–1.32, p = 0.59), Intrahepatic Cholestasis of Pregnancy (ICP) (OR = 1.42; 95% CI: 0.85–2.36, p = 0.18), birth weight (OR = 1.02; 95% CI: 0.99–1.05, p = 0.19), gestational hypertension (OR = 1.00; 95% CI: 1.00–1.00, p = 0.85), spontaneous miscarriages (OR = 1.00; 95% CI: 0.96–1.04, p = 0.90) and stillbirth (OR = 1.00; 95% CI: 0.98–1.01, p = 0.62). Conclusion There was no direct causal relationship between COVID-19 infection and maternal and neonatal poor outcomes. Our study could alleviate the anxiety of pregnant women under the COVID-19 pandemic conditions partly.

Abstract Radix Fici Simplicissimae (RFS) is widely studied, and is in demand for its value in medicines and food products, with increased scientific focus on its cultivation and breeding. We used ultra-high-performance liquid chromatography quadrupole-orbitrap mass spectrometry-based metabolomics to elucidate the similarities and differences in phytochemical compositions of wild Radix Fici Simplicissimae (WRFS) and cultivated Radix Fici Simplicissimae (CRFS). Untargeted metabolomic analysis was performed with multivariate statistical analysis and heat maps to identify the differences. Eighty one compounds were identified from WRFS and CRFS samples. Principal component analysis and orthogonal partial least squares discrimination analysis indicated that mass spectrometry could effectively distinguish WRFS from CRFS. Among these, 17 potential biomarkers with high metabolic contents could distinguish between the two varieties, including seven phenylpropanoids, three flavonoids, one flavonol, one alkaloid, one glycoside, and four organic acids. Notably, psoralen, apigenin, and bergapten, essential metabolites that play a substantial pharmacological role in RFS, are upregulated in WRFS. WRFS and CRFS are rich in phytochemicals and are similar in terms of the compounds they contain. These findings highlight the effects of different growth environments and drug varieties on secondary metabolite compositions and provide support for targeted breeding for improved CRFS varieties.

Abstract Metastasis is a bottleneck in cancer treatment. Studies have shown the pivotal roles of long noncoding RNAs (lncRNAs) in regulating cancer metastasis; however, our understanding of lncRNAs in gastric cancer (GC) remains limited. RNA-seq was performed on metastasis-inclined GC tissues to uncover metastasis-associated lncRNAs, revealing upregulated small nucleolar RNA host gene 26 (SNHG26) expression, which predicted poor GC patient prognosis. Functional experiments revealed that SNHG26 promoted cellular epithelial–mesenchymal transition and proliferation in vitro and in vivo. Mechanistically, SNHG26 was found to interact with nucleolin (NCL), thereby modulating c-Myc expression by increasing its translation, and in turn promoting energy metabolism via hexokinase 2 (HK2), which facilitates GC malignancy. The increase in energy metabolism supplies sufficient energy to promote c-Myc translation and expression, forming a positive feedback loop. In addition, metabolic and translation inhibitors can block this loop, thus inhibiting cell proliferation and mobility, indicating potential therapeutic prospects in GC.

Abstract Background The neural cells in the brains of patients with Parkinson’s disease (PWP) display aberrant synchronized oscillatory activity within the beta frequency range. Additionally, enhanced gamma oscillations may serve as a compensatory mechanism for motor inhibition mediated by beta activity and also reinstate plasticity in the primary motor cortex affected by Parkinson’s disease. Transcranial alternating current stimulation (tACS) can synchronize endogenous oscillations with exogenous rhythms, thereby modulating cortical activity. The objective of this study is to investigate whether the addition of tACS to multidisciplinary intensive rehabilitation treatment (MIRT) can improve symptoms of PWP so as to enhance the quality of life in individuals with Parkinson’s disease based on the central-peripheral-central theory. Methods The present study was a randomized, double-blind trial that enrolled 60 individuals with Parkinson’s disease aged between 45 and 70 years, who had Hoehn-Yahr scale scores ranging from 1 to 3. Participants were randomly assigned in a 1:1 ratio to either the tACS + MIRT group or the sham-tACS + MIRT group. The trial consisted of a two-week double-blind treatment period followed by a 24-week follow-up period, resulting in a total duration of twenty-six weeks. The primary outcome measured the change in PDQ-39 scores from baseline (T0) to 4 weeks (T2), 12 weeks (T3), and 24 weeks (T4) after completion of the intervention. The secondary outcome assessed changes in MDS-UPDRS III scores at T0, the end of intervention (T1), T2, T3, and T4. Additional clinical assessments and mechanistic studies were conducted as tertiary outcomes. Discussion The objective of this study is to demonstrate that tACS can enhance overall functionality and improve quality of life in PWP, based on the framework of MIRT. Additionally, it seeks to establish a potential correlation between these therapeutic effects and neuroplasticity alterations in relevant brain regions. The efficacy of tACS will be assessed during the follow-up period in order to optimize neuroplasticity and enhance its potential impact on rehabilitation efficiency for PWP. Trial registration Chinese Clinical Trial Registry ChiCTR2300071969. Registered on 30 May 2023.

Abstract What is static charge? Despite the long history of research, the identity of static charge and mechanism by which static is generated by contact electrification are still unknown. Investigations are challenging due to the complexity of surfaces. This study involves the molecular-scale analysis of contact electrification using highly well-defined surfaces functionalized with a self-assembled monolayer of alkylsilanes. Analyses show the elementary molecular steps of contact electrification: the exact location of heterolytic cleavage of covalent bonds (i.e., Si-C bond), exact charged species generated (i.e., alkyl carbocation), and transfer of molecular fragments. The strong correlation between charge generation and molecular fragments due to their signature odd-even effects further shows that contact electrification is based on cleavage of covalent bonds and transfer of ionic molecular fragments. Static charge is thus an alkyl carbocation; in general, it is an ionic molecular fragment. This mechanism based on cleavage of covalent bonds is applicable to general types of insulating materials, such as covalently bonded polymers. The odd-even effect of charging caused by the difference of only one atom explains the highly sensitive nature of contact electrification.

The effects of ultrasound treatment (20 kHz, 0, 150, 300, 450, 600 W, 6 min) on the gel properties of PSE (pale, soft, and exudative)-like chicken myofibrillar protein (MP) emulsion gels were studied. When the ultrasound power increased from 0 W to 600 W, the water-holding capacity (WHC) and gel strength of PSE-like MP emulsion gel increased by 45.01% and 37.5%, respectively (p

A traditional Chinese herbal medicine formula named Huang-Lian-Jie-Du Decoction (HLJDD) has been used to cure various inflammatory diseases with a long history. However, one component of HLJDD Gardeniae fructus has remarkable liver and kidney toxicities. Therefore, it was altered with Dictamni cortex to form a modified HLJDD (MHLJDD). In this study, we aimed to evaluate the sub-chronic toxicity of the active fraction of MHLJDD (MHLJDD-F) in rats. Adult rats of both sexes were intragastrically administered with vehicle or MHLJDD-F (at the dose of 170, 340, and 680 mg/kg/day) once daily for 90 days. Half of the rats from each group were kept for an additional 30-day period to observe the drug withdrawal effect. The signs of toxicity and mortality of the rats were observed, and the body weight and food consumption were recorded. Blood was collected for hematological and biochemical analyses and major organs were weighed and harvested for histopathological examinations. The results revealed that no systemic toxicity of MHLJDD-F was found during the experiments. Organ coefficients and pathological alterations of major organs were comparable to the control rats. The no-observed adverse effect level (NOAEL) of MHLJDD-F was found up to 680 mg/kg/day. All these results demonstrated that long-term oral administration of MHLJDD-F did not cause significant toxicity, which is worthy to be widely applied as a new herbal medicine in pre-clinical and clinical studies.

Objective To delineate the efficacy and safety profile of hemodiafiltration with endogenous reinfusion (HFR) for uremic toxin removal in patients undergoing maintenance hemodialysis (MHD).Methods Patients who have been on MHD for a period of at least 3 months were enrolled. Each subject underwent one HFR and one hemodiafiltration (HDF) treatment. Blood samples were collected before and after a single HFR or HDF treatment to test uremic toxin levels and to calculate clearance rate. The primary efficacy endpoint was to compare uremic toxin levels of indoxyl sulfate (IS), λ-free light chains (λFLC), and β2-microglobulin (β2-MG) before and after HFR treatment. Secondary efficacy endpoints was to compare the levels of urea, interleukin-6 (IL-6), P-cresol, chitinase-3-like protein 1 (YKL-40), leptin (LEP), hippuric acid (HPA), trimethylamine N-oxide (TMAO), asymmetric dimethylarginine (ADMA), tumor necrosis factor-α (TNF-α), fibroblast growth factor 23 (FGF23) before and after HFR treatment. The study also undertook a comparative analysis of uremic toxin clearance between a single HFR and HDF treatment. Meanwhile, the lever of serum albumin and branched-chain amino acids before and after a single HFR or HDF treatment were compared. In terms of safety, the study was meticulous in recording vital signs and the incidence of adverse events throughout its duration.Results The study enrolled 20 patients. After a single HFR treatment, levels of IS, λFLC, β2-MG, IL-6, P-cresol, YKL-40, LEP, HPA, TMAO, ADMA, TNF-α, and FGF23 significantly decreased (p 0.05), while post-HDF, levels of serum albumin significantly decreased (p = 0.000).Conclusion HFR treatment effectively eliminates uremic toxins from the bloodstream of patients undergoing MHD, especially protein-bound toxins and large middle-molecule toxins. Additionally, it retains essential physiological compounds like albumin and branched-chain amino acids, underscoring its commendable safety profile.

Introduction Heart failure with preserved ejection fraction (HFpEF) is a prevalent comorbidity among patients with end-stage kidney disease. Although sodium-glucose cotransporter 2 inhibitors are validated in treating heart failure and ameliorating left ventricular hypertrophy among non-dialysis patients, the effects on dialysis patients are unknown. We previously investigated the pharmacokinetics of henagliflozin in patients undergoing haemodialysis (HD) or peritoneal dialysis (PD) and clarified its safety.Methods and analysis This multicentre, randomised, double-blind, placebo-controlled trial is being conducted at three hospitals in Shanghai, China. A target of 108 HD or PD patients with HFpEF are randomly allocated to treatment group (henagliflozin 5 mg/day in addition to standard therapy) or control group (placebo with standard therapy) at a ratio of 1:1. All subjects will be followed up for 24 weeks. The primary outcome is change in echocardiography-measured left ventricular mass index. The secondary interests include changes in left atrial volume index, E/e’, e’ and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Intergroup comparisons of change in echocardiography-related outcomes from baseline to 24 weeks are based on a linear regression model adjusted for baseline values (analysis of covariance), and repeated measure analysis of variance with Bonferroni adjustment is employed for comparison of change in NT-proBNP. Subgroup analyses of the primary and secondary outcomes are conducted to determine whether the effect of henagliflozin varies according to dialysis modality. The χ2 method is used to compare the occurrence of adverse events and severe adverse events.Ethics and dissemination This trial has been approved by the Ethics Committee of Renji Hospital, School of Medicine, Shanghai Jiao Tong University (LY2023-127-B). All participants provide written informed consent before screening. The results of the trial will be disclosed completely in international peer-reviewed journals. Both positive and negative results will be reported.Trial registration number ChiCTR2300073169.

Increasingly, progestins are being detected in aquatic environments, especially in aquaculture areas, and concern about their adverse effects on aquatic organisms is growing. However, the mechanisms underlying progestin-induced oxidative stress and the antioxidant response of aquatic invertebrates to progestin exposure are unknown. Researchers recently reported that norgestrel (NGT) likely causes oxidative stress in the clam Mactra veneriformis. In this study, we assessed reactive oxygen species (ROS) levels, antioxidant enzyme activity, malonaldehyde content, ultrastructure, and DNA damage in the digestive gland of M. veneriformis exposed to 7.69 or 756.62 ng/L of NGT for 21 days. We also conducted tandem mass tag-based quantitative proteomic analysis to detect the protein response and gain insights into response mechanisms in clams exposed to NGT. We found that NGT enhanced oxidative phosphorylation via the wingless/integrated signaling pathway and triggered ROS generation. The alterations of antioxidant enzyme activities suggested that these enzymes are involved in scavenging NGT-induced ROS. NGT weakened antioxidant defense by suppressing the antioxidant synthesis-related AMP-activated protein kinase/forkhead box O and sirtuin 1/forkhead box O pathways. Additionally, cell membrane dissolution, mitochondrial cristae rupture, DNA damage, elevation of malonaldehyde content, and oxidation of lipid, protein, and glucose occurred due to compromised redox homeostasis. Our results highlight the oxidative stress, antioxidant response, and oxidative damage induced by NGT in M. veneriformis and shed light on ecological risks of progestins to aquatic invertebrates.

Understanding changes in root traits of high-yielding genotypes that consistently perform during different drought periods is crucial for improving wheat production and yield stability. A 2-year field trial and a pot experiment were conducted to determine the response of root growth and grain yield to early and terminal droughts in old and modern cultivars (FC3: 1960s and CH1: 2010s) under rainfed and irrigated conditions in the field. Rainfed wheat faced terminal drought in 2015–2016 and early drought in 2016–2017. Plants in the pot experiment were exposed to terminal drought, early drought, and well-watered. Both field and pot experiments showed higher grain yield in modern cultivar CH1 compared to FC3. Early and terminal droughts reduced grain yield in both cultivars, with a greater reduction in FC3. CH1 exhibited higher yield stability under drought conditions and experienced less reduction in early drought. Compared to FC3, CH1 produced more root biomass in the early growth stage. At anthesis, CH1 had significantly lower root biomass and root length density in the topsoil layer (00.2 m) and higher in the subsoil layer (0.21.0 m) than FC3, respectively. At maturity, the retention rate of subsoil root biomass in CH1 was higher, especially under early drought (80.2 % in field and 93.9 % in pot experiments). Both cultivars consumed similar seasonal water use, but CH1 reduced pre-anthesis water use and consumed more water after anthesis. This study indicates that modern cultivar had vigorous root growth at early stage. A higher proportion of root biomass preserved in deep soil after anthesis enhanced post-anthesis water use and photosynthetic rate, improved post-anthesis dry matter accumulation, and thus resulted in higher thousand kernel weight. These factors ensure higher yield and yield stability under both early and terminal drought stress.

Summary: The Japanese eel (Anguilla japonica), a flagship anguillid species for conservation, is known for its long-distance-oriented migration. However, our understanding of the genetic architecture underlying long-distance migration and population genomic characteristics of A. japonica is still limited. Here, we generated a high-quality chromosome-level genome assembly and conducted whole-genome resequencing of 218 individuals to explore these aspects. Strong signals of selection were found on genes involved in long-distance aerobic exercise and navigation, which might be associated with evolutionary adaptation to long-distance migrations. Low genetic diversity was detected, which might result from genetic drift associated with demographic declines. Both mitochondrial and nuclear genomic datasets supported the existence of a single panmictic population for Japanese eel, despite signals of single-generation selection. Candidate genes for local selection involved in functions like development and circadian rhythm. The findings can provide insights to adaptative evolution to long-distance migration and inform conservation efforts for A. japonica.

Background: Pancreatic cancer (PanCa), ranked as the 4th leading cause of cancer-related death worldwide, exhibits an dismal 5-year survival rate of less than 5 %. Chronic pancreatitis (CP) is a known major risk factor for PanCa. Brusatol (BRT) possesses a wide range of biological functions, including the inhibition of PanCa proliferation. However, its efficacy in halting the progression from CP to pancreatic carcinogenesis remains unexplored. Methods: We assess the effects of BRT against pancreatic carcinogenesis from CP using an experimentally induced CP model with cerulein, and further evaluate the therapeutic efficacy of BRT on PanCa by employing Krastm4Tyj Trp53tm1Brn Tg (Pdx1-cre/Esr1*) #Dam/J (KPC) mouse model. Results: Our finding demonstrated that BRT mitigated the severity of cerulein-induced pancreatitis, reduced pancreatic fibrosis and decreased the expression of α-smooth muscle actin (α-SMA), which is a biomarker for pancreatic fibrosis. In addition, BRT exerted effects against cerulein-induced pancreatitis via inactivation of NLRP3 inflammasome. Moreover, BRT significantly inhibited tumor growth and impeded cancer progression. Conclusions: The observed effect of BRT on impeding pancreatic carcinogenesis through targeting NLRP3 inflammasome suggests its good potential as a potential agent for treatment of PanCa.

Abstract Therapeutic mRNA vaccines have become powerful therapeutic tools for severe diseases, including infectious diseases and malignant neoplasms. mRNA vaccines encoding tumor‐associated antigens provide unprecedented hope for many immunotherapies that have hit the bottleneck. However, the application of mRNA vaccines is limited because of biological instability, innate immunogenicity, and ineffective delivery in vivo. This study aims to construct a novel mRNA vaccine delivery nanosystem to successfully co‐deliver a tumor‐associated antigen (TAA) encoded by the Wilms' tumor 1 (WT1) mRNA. In this system, named PSB@Nb1.33C/mRNA, photosynthetic bacteria (PSB) efficiently delivers the iMXene‐WT1 mRNA to the core tumor region using photo‐driven and hypoxia‐driven properties. The excellent photothermal therapeutic (PTT) properties of PSB and 2D iMxene (Nb1.33C) trigger tumor immunogenic cell death, which boosts the release of the WT1 mRNA. The released WT1 mRNA is translated, presenting the TAA and amplifying immune effect in vivo. The designed therapeutic strategy demonstrates an excellent ability to inhibit distant tumors and counteract postsurgical lung metastasis. Thus, this study provides an innovative and effective paradigm for tumor immunotherapy, i.e., photo‐immunogene cancer therapy, and establishes an efficient delivery platform for mRNA vaccines, thereby opening a new path for the wide application of mRNA vaccines.

The goal of this study was to evaluate the trace element pollution in a marine ranching area in China based on molecular responses (expression of metallothionein and antioxidant enzyme genes), and biochemical biomarkers (metallothionein content, antioxidant enzyme activities, and malonaldehyde level) in four indicator species. We collected samples of two fish (Lateolabrax maculatus and Sebastes schlegelii), one crustacean (Charybdis japonica), and one gastropod (Rapana venosa) from the western Furong Island marine ranching area and from an adjacent area in March 2022 and measured the trace element content in these indicator species as well as in the seawater and sediment. We found that the bioaccumulation characteristics of trace elements and the response patterns of biomarkers were species specific. Moreover, not every biomarker was significantly correlated with environmental trace element content. We then established two biomarker combinations indicative of trace element pollution in seawater and sediment, respectively, based on the correlation between biomarkers and trace element contents. The selected biomarkers were integrated using integrated biomarker response version 2 (IBRv2). IBRv2 values in the studied marine ranching area were lower than those in the adjacent area. Additionally, these values were consistent with the bioaccumulation of trace elements in the indicator species, the integrated trace element pollution index for seawater, and the potential risk index for sediment. These results show that this multi-biomarker and multi-species IBRv2 approach provided a comprehensive diagnosis of trace element pollution in the marine ranching area. Therefore, its application may be beneficial for marine environmental monitoring and management in view of the ecotoxicological impact of pollutants on organisms.

Study region: Beijing Region Study focus: Limited studies have yet been done on regionalization of multi-performances of rainwater harvesting systems (RHS). In this study, the daily rainfall records from 77 stations are used, and a hydro-economic model is adopted to examine regional water saving, stormwater control and economic performances of RHS by proposing a regionalization approach. New hydrological insights for the region: Higher water saving efficiency (WSE) and reliability (R) of RHS are linked with lower water demand, larger tank size and greater rainfall conditions. Differently, higher stormwater capture efficiency (SCE) is related to higher water demand, larger tank size and lower rainfall. The WSE and R of RHS demonstrate substantial regional differences; their maximized obtainable values closely depend on water demand scenarios and range from 9% to 99%, with smaller values in western mountain area but larger values in northeast suburban and central urban areas. The maximum obtainable values of SCE range from 61% to 100%, with higher values in western mountain area, but lower values in northeast suburban and central urban areas. A 10 m3 tank size can provide the highest benefit-cost ratio of RHS across the Beijing region. The regionalization approach proposed is a useful guidance for the implementation of RHS and sustainable urban water management, and thus it has the potential for wide uses in other regions with high rainfall gradients.

Abstract The antiangiogenic agent apatinib has been shown to clinically improve responses to immune checkpoint inhibitors in several cancer types. Patients with N3 nasopharyngeal carcinoma have a high risk of distant metastasis, however, if the addition of immunotherapy to standard treatment could improve efficacy is unclear. In this phase II clinical trial (ChiCTR2000032317), 49 patients with stage TanyN3M0 nasopharyngeal carcinoma were enrolled and received the combination of three cycles of induction chemotherapy, camrelizumab and apatinib followed by chemoradiotherapy. Here we report on the primary outcome of distant metastasis-free survival and secondary end points of objective response rate, failure-free survival, locoregional recurrence-free survival, overall survival and toxicity profile. After induction therapy, all patients had objective response, including 13 patients (26.5%) with complete response. After a median follow-up of 28.7 months, the primary endpoint of 1-year distant metastasis-free survival was met for the cohort (1-year DMFS rate: 98%). Grade≥3 toxicity appeared in 32 (65.3%) patients, with the most common being mucositis (14[28.6%]) and nausea/vomiting (9[18.4%]). In this work, camrelizumab and apatinib in combination with induction chemotherapy show promising distant metastasis control with acceptable safety profile in patients with stage TanyN3M0 nasopharyngeal carcinoma.

AIM: To quantify changes in radial peripapillary capillary vessel density (ppVD) and the peripapillary retinal nerve fiber layer (pRNFL) in children with type 1 diabetes without clinical diabetic retinopathy by optical coherence tomography angiography (OCTA), providing a basis for early retinopathy in children with type 1 diabetes. METHODS: This was a retrospective study. A total of 30 patients (3–14y) with type 1 diabetes without clinical diabetic retinopathy (NDR group) were included. A total of 30 age-matched healthy subjects were included as the normal control group (CON group). The HbA1c level in the last 3mo was measured once in the NDR group. The pRNFL thickness and ppVD were automatically measured, and the mean pRNFL and ppVD were calculated in the nasal, inferior, temporal, and superior quadrants. The changes in ppVD and pRNFL in the two groups were analyzed. RESULTS: Compared with CON group, the nasal and superior ppVDs decreased in the NDR group (all P0.05). Person and Spearman correlation analysis of ppVD and pRNFL thickness in each quadrant of the NDR group showed a positive correlation between nasal and superior (all P0.05). There was no significant correlation between the HbA1c level and ppVD and pRNFL in any quadrant (all P>0.05). There was no significant correlation between the course of diabetes mellitus and ppVD and pRNFL in any quadrant (all P>0.05). CONCLUSION: ppVD and pRNFL decrease in eyes of children with type 1 diabetes before clinically detectable retinopathy and OCTA is helpful for early monitoring．

Conventional urbanization transforms natural into paved landscapes, posing a significant environmental challenge. Detecting the changes in (im)pervious surfaces in cities, where patches are small and intermingled, is particularly challenging. This study introduces a novel approach to these changes by integrating Coupled Non-negative Matrix Factorization (CNMF) image fusion with an automatic pixel purification algorithm. By fusing low-resolution hyperspectral (30m) with high-resolution panchromatic (5m) PRISMA imagery, we achieved enhanced spatial resolution, crucial for accurate land use and land cover (LULC) classification. We introduced automatic pixel purification as a key innovation method to improve LULC mapping accuracy, sensitive to training pixel selection and mixed pixels. This method, which is tested in Dublin City area, enhanced/ refined spectral signatures and clarity across major LULC classes including bare soil, industrial roofs, grasslands, trees, residential roofs/asphalts, and water bodies, significantly improving classification accuracy by removing outliers and ensuring spectral consistency. The Random Forest (RF) algorithm, applied before and after pixel purification, showed substantial increases in overall accuracy (from 94.04% to 96.69%,) and Kappa coefficient (from 92.60% to 95.91%) for 2021, with similar improvements in 2022. This method enabled accurate differential analysis of (im)pervious surfaces, revealing a 4.08% decrease in pervious (from 33.29 km2 to 28.08 km2) and a 4.09% increase in impervious surfaces (from 79.96 km2 to 82.92 km2) over one year, highlighting the rapid urbanization’s impact on Dublin’s landscape permeability. This study significantly advances LULC classification and urban monitoring, offering valuable insights for sustainable urban development and advocating for its integration into future remote sensing and urban planning initiatives.

Abstract Background Qing-Zao-Jiu-Fei Decoction (QZJFD) is a famous herbal formula commonly prescribed for the treatment of lung-related diseases in the ancient and modern times. Trichosanthis Fructus (TF) and Fritillariae Thunbergii Bulbus (FTB) are widely used for treatment of cough and pulmonary disease. In order to identify a more effective formula for treatment of pulmonary fibrosis, we intend to add TF and FTB in QZJFD to form a modified QZJFD (MQZJFD). In this study, we aims to explore MQZJFD as an innovative therapeutic agent for pulmonary fibrosis using bleomycin (BLM)-treated rats and to unravel the underlying molecular mechanisms. Methods BLM was given to SD rats by intra-tracheal administration of a single dose of BLM (5 mg/kg). QZJFD (3 g/kg) and MQZJFD (1, 2 and 4 g/kg) was given intragastrically daily to rats for 14 days (from day 15 to 28) after BLM administration for 14 consecutive days. Results MQZJFD was found to contain 0.29% of amygdalin, 0.020% of lutin, 0.077% of glycyrrhizic acid and 0.047% of chlorogenic acid. BLM treatment could induce collagen deposition in the lung tissues of rats, indicating that the pulmonary fibrosis rat model had been successfully established. MQZJFD have better effects than the original QZJFD in reducing the pulmonary structure damage and collagen deposition of rat lung fibrosis induced by BLM. MQZJFD could reduce the hydroxyproline content in lung tissues of BLM-treated rats. The biomarkers of fibrosis such as matrix metalloproteinase 9 (MMP9), collagen I and α-smooth muscle actin (α-SMA) were remarkably reduced after treatment with MQZJFD. MQZJFD also have anti-oxidant stress effects by inhibiting the level of malondialdehyde (MDA), but enhancing the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and the level of glutathione (GSH) in the lung tissues of BLM-treated rats. Moreover, the MQZJFD markedly suppressed the over expressions of p-p65/p65 and p-IκBα/IκBα, but upregulated the Nrf2. MQZJFD also suppressed the protein expressions of p-ERK1/2/ERK1/2, p-p38/p38 and p-JNK/JNK in the lung tissues of BLM-treated rats. Conclusions MQZJFD could improve the pulmonary fibrosis induced by BLM in rats via inhibiting the fibrosis and oxidative stress via suppressing the activation of NF-κB/Nrf2 and MAPKs pathways.

Gut dysbiosis, a well-known risk factor to triggers the progression of Alzheimer's disease (AD), is strongly associated with metabolic disturbance. Trimethylamine N-oxide (TMAO), produced in the dietary choline metabolism, has been found to accelerate neurodegeneration in AD pathology. In this study, the cognitive function and gut microbiota of TgCRND8 (Tg) mice of different ages were evaluated by Morris water maze task (MWMT) and 16S rRNA sequencing, respectively. Young pseudo germ-free (PGF) Tg mice that received faecal microbiota transplants from aged Tg mice and wild-type (WT) mice were selected to determine the role of the gut microbiota in the process of neuropathology. Excessive choline treatment for Tg mice was used to investigate the role of abnormal choline metabolism on the cognitive functions. Our results showed that gut dysbiosis, neuroinflammation response, Aβ deposition, tau hyperphosphorylation, TMAO overproduction and cyclin-dependent kinase 5 (CDK5)/transcription 3 (STAT3) activation occurred in Tg mice age-dependently. Disordered microbiota of aged Tg mice accelerated AD pathology in young Tg mice, with the activation of CDK5/STAT3 signaling in the brains. On the contrary, faecal microbiota transplantation from WT mice alleviated the cognitive deficits, attenuated neuroinflammation, Aβ deposition, tau hyperphosphorylation, TMAO overproduction and suppressed CDK5/STAT3 pathway activation in Tg mice. Moreover, excessive choline treatment was also shown to aggravate the cognitive deficits, Aβ deposition, neuroinflammation and CDK5/STAT3 pathway activation. These findings provide a novel insight into the interaction between gut dysbiosis and AD progression, clarifying the important roles of gut microbiota-derived substances such as TMAO in AD neuropathology.

In this study, by virtue of a derivative formula for the ratio of two differentiable functions and with aid of a monotonicity rule, the authors expand a logarithmic expression involving the cosine function into the Maclaurin power series in terms of specific determinants and prove a decreasing property of the ratio of two logarithmic expressions containing the cosine function.

Abstract Background The RNA recognition motif (RRM) is primarily engaged in the processing of mRNA and rRNA following gene transcription as well as the regulation of RNA transport; it is critical in preserving RNA stability. Results In this study, we identified 102 members of the RRM1 gene family in Brassica rapa, which were dispersed across 10 chromosomes with the ninth chromosome being the most extensively distributed. The RRM1 gene family members of Brassica rapa and Arabidopsis thaliana were grouped into 14 subclades (I–XIV) using phylogenetic analysis. Moreover, the results of transcriptome analysis and RT-qPCR indicated that the expression of Brapa05T000840 was upregulated in the cultivars ‘Longyou 7’ and ‘Longyou 99’ following exposure to cold stress at a temperature of 4 °C for 24 h. The levels of expression in the leaves and growth cones of the ‘Longyou 7’ variety were found to be significantly higher than those observed in the ‘Longyou 99’ variety under conditions of low temperature and NaCl stress. It illustrates the involvement of the RRM1 gene in the physiological response to both low temperature and salt stress. In addition, it was observed that the survival rate of transgenic BrRBP (Brapa05T000840) Arabidopsis thaliana plants was notably higher compared to that of wild-type plants when subjected to varying durations of low temperature treatment. Furthermore, the expression of the BrRBP gene in transgenic plants exhibited an upward trend as the duration of low temperature treatment increased, reaching its peak at 24 h. The in-vivo enzymatic activity of reactive oxygen species-scavenging enzymes were found to be significantly elevated in comparison to wild-type plants, suggesting that the BrRBP gene may enhance the cold tolerance of Arabidopsis thaliana. Conclusions This study offers a significant foundation for comprehending the regulation mechanism of the RRM1 gene family in winter Brassica rapa subjected to cold stress, as well as for finding key genes associated with cold resistance.

Sea ice drift is a crucial parameter for sea ice flux, atmospheric and ocean circulation, and ship navigation. Pattern matching is widely used to retrieve sea ice drift from Synthetic Aperture Radar (SAR) data, but it often yields mismatched vectors and coarse spatial resolution. This study presents a framework to enhance the spatial resolution and accuracy of pattern-matching sea ice drift derived from SAR images. The framework employs the Accelerated-KAZE feature extraction method and Brute-Force feature matcher to extract feature-tracking sea ice drift vectors from SAR data, with mismatched vectors subsequently removed. The pattern-matching vectors are then refined by fusing with these feature-tracking vectors, using a Co-Kriging algorithm. Using the sea ice drift product from the Technical University of Denmark space as the pattern-matching vector field for refinement, the framework's effectiveness is evaluated by comparing the refined vectors with buoy displacements and pattern-matching vectors across five selected regions. Results show a reduction in velocity and direction root mean square error (RMSE) by 0.47 km/d (22%) and 4.97° (28%), respectively, and an enhanced spatial resolution from 10 km to 1 km. The findings demonstrate the framework's success in improving the accuracy and resolution of pattern-matching sea ice drift from SAR imagery.