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Abstract Epigenetics governs a chromatin state regulatory system through five key mechanisms: DNA modification, histone modification, RNA modification, chromatin remodeling, and non-coding RNA regulation. These mechanisms and their associated enzymes convey genetic information independently of DNA base sequences, playing essential roles in organismal development and homeostasis. Conversely, disruptions in epigenetic landscapes critically influence the pathogenesis of various human diseases. This understanding has laid a robust theoretical groundwork for developing drugs that target epigenetics-modifying enzymes in pathological conditions. Over the past two decades, a growing array of small molecule drugs targeting epigenetic enzymes such as DNA methyltransferase, histone deacetylase, isocitrate dehydrogenase, and enhancer of zeste homolog 2, have been thoroughly investigated and implemented as therapeutic options, particularly in oncology. Additionally, numerous epigenetics-targeted drugs are undergoing clinical trials, offering promising prospects for clinical benefits. This review delineates the roles of epigenetics in physiological and pathological contexts and underscores pioneering studies on the discovery and clinical implementation of epigenetics-targeted drugs. These include inhibitors, agonists, degraders, and multitarget agents, aiming to identify practical challenges and promising avenues for future research. Ultimately, this review aims to deepen the understanding of epigenetics-oriented therapeutic strategies and their further application in clinical settings.

Abstract The hypothalamus is the coordination center of the sheep (Ovis aries) endocrine system and plays an important role in the reproductive processes of sheep. However, the specific mechanism by which the hypothalamus affects sheep reproductive performance remains unclear. In this study, the hypothalamus tissues of high-reproduction small-tailed Han sheep and low-reproduction Wadi sheep were collected, and full-length transcriptome sequencing by Oxford Nanopore Technologies (ONT) was performed to explore the key functional genes associated with sheep fecundity. The differentially expressed genes (DEGs) were screened and enriched using DESeq2 software through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Approximately 41.75 million clean reads were obtained from the hypothalamus tissues of high- and low-reproduction sheep, after quality control, 32,194,872 high-quality full-length sequences and 2,114 DEGs were obtained, including 1,247 upregulated genes and 867 downregulated genes (P adjust 1). Some DEGs were enriched in oocyte meiosis, progesterone-mediated oocyte maturation, estrogen signaling pathway, GnRH signaling pathway and other development-related signaling pathways. The constructed protein-protein interaction (PPI) networks identified the reproduction-related genes, such as GSK3B, PPP2R1B, and PPP2CB. The results of this study will enrich and supplement the genomic information available for small-tailed Han sheep and Wadi sheep, as well as expand the understanding of the molecular mechanisms underlying the regulation of animal reproduction by the hypothalamus, and they also provided reference data for further investigations on the mechanism of high reproduction in sheep.

Abstract Background Pediatric patients are vulnerable to the threat of carbapenem-resistant Klebsiella pneumoniae (CRKP) due to their limited immunity and few available antibiotics. Especially when these pathogens exhibit hypervirulent phenotypes, they are often associated with poor clinical outcomes. Methods In this study, we investigated a CRKP outbreak in pediatric patients from 2019 to 2021 in a teaching hospital in China based on whole genome sequencing. We sequenced twenty-nine CRKP isolates isolated from unduplicated pediatric patients to understand their genetic relationships, virulence factors, resistance mechanisms, and transmission trajectories. Conjugation experiments were performed to evaluate the horizontal transfer ability of carbapenem resistance determinants in twenty-nine CRKP isolates. We then characterized these isolates for biofilm formation ability and serum resistance. Genetic relatedness, comparison of plasmids, and chromosomal locus variation of CRKP isolates were analyzed by bioinformatics. Results All the isolates were carbapenemase-producers harbouring bla NDM−5. Among them, twenty-eight isolates belonged to the ST2407 group, with the consistent capsular serotype K25. The virulence-related factors: ureA, fim, ybtA, irp1/irp2, and mrkA were prevalent in these isolates. Additionally, most CRKP isolates showed moderately adherent biofilm formation. Although the ST2407 clonal group did not exhibit serum resistance, the heterogeneous level of serum resistance was related to the disruption of oqxR. Conjugation and WGS revealed that the bla NDM−5 carried by the twenty-eight CRKP ST2407 isolates was located on nonconjugative IncX3 plasmids associated with deleting the T4SS-encoding genes. Clonal transmission of CRKP ST2407 in pediatric patients was suggested by the phylogenetic tree. Conclusions Our study provides evidence of the clonal spread of bla NDM−5-producing K. pneumoniae in pediatric patients and the necessity for the T4SS system for horizontal transfer of the IncX3 plasmid carrying bla NDM−5. Additionally, the disruption of oqxR may have affected the serum resistance of CRKP. The results of this study emphasize the importance of continuously monitoring for CRKP infection in pediatric patients to prevent recurrent infections.

Infections with the coronavirus disease 2019 (COVID-19) and disorders of the heart and blood vessels are causally related. To ascertain the causal relationship between COVID-19 and cardiovascular disease (CVD), we carried out a Mendelian randomization (MR) study through a method known as inverse variance weighting (IVW). When analyzing multiple SNPs, MR can meta-aggregate the effects of multiple loci by using IVW meta-pooling method. The weighted median (WM) is the median of the distribution function obtained by ranking all individual SNP effect values according to their weights. WM yields robust estimates when at least 50% of the information originates from valid instrumental variables (IVs). Directed gene pleiotropy in the included IVs is permitted because MR–Egger does not require a regression straight line through the origin. For MR estimation, IVW, WM and MR-Egger were employed. Sensitivity analysis was conducted using funnel plots, Cochran's Q test, MR–Egger intercept test, MR–PRESSO, and leave-one-out analysis. SNPs related to exposure to COVID-19 and CVD were compiled. CVD for COVID-19 infection, COVID-19 laboratory/self-reported negative, and other very severe respiratory diagnosis and population were randomly assigned using MR. The COVID-19 laboratory/self-reported negative results and other very severe respiratory confirmed cases versus MR analysis of CVD in the population (p ​> ​0.05); COVID-19 infection to CVD (p ​= ​0.033, OR ​= ​1.001, 95%CI: 1.000–1.001); and the MR–Egger results indicated that COVID-19 infection was associated with CVD risk. This MR study provides preliminary evidence for the validity of the causal link between COVID-19 infection and CVD.

Abstract SWAT model is one of the primary tools for assessing irrigation district water management and water‐saving measures. However, its incapacity to consider the diverse growth and water requirements of paddy during various growth stages, as well as the insufficient availability of external water sources. This study introduces the Penman‐Monteith equation and Jensen model into the SWAT framework, setting crop coefficients, crop base coefficients, and growth stage sensitivity indices based on the different growth stage. Additionally, modifications are made to the external water source available for irrigation and paddy field leakage modules, establishing a distributed agricultural hydrological model suitable for accurately simulating water balance elements and paddy yield in multi‐source irrigation districts. The Yangshudang watershed in the Zhanghe irrigation district is chosen for the evaluation of the modified model's simulation performance, with a quantitative assessment of water‐saving and yield‐increasing effects. The results demonstrate that the modified model effectively meets the requirements for simulating paddy evapotranspiration of various growth stages, yield, agricultural irrigation water consumptions, and runoff, exhibiting a notable enhancement in performance. As two common water‐saving measures in irrigation areas, intermittent irrigation and irrigation district renovation were used as two water‐saving scenarios in the simulation of the modified SWAT model. Under intermittent irrigation, the watershed experiences a 6.58% reduction in net irrigation water use. In the scenario with irrigation district renovation, the water resources in the watershed are utilized more efficiently. The modified model from this study can be applied for assessing the synergistic effects of irrigation district water‐saving and yield‐increasing measures, providing crucial insights for the formulation of irrigation district water‐saving strategies and water resource optimization plans.

Abstract Cadmium (Cd) is a biologically non-essential heavy metal, a major soil pollutant, and extremely harmful to plants. The phytohormone methyl jasmonate (MeJA) plays an important role in plant heavy-metal resistance. However, the understanding of the effects of MeJA supply level on alleviating Cd toxicity in plants is limited. Here, we investigated how MeJA regulated the development of physiological processes and cell wall modification in Cosmos bipinnatus. We found that low concentrations of MeJA increased the dry weight of seedlings under 120 µM Cd stress by reducing the transport of Cd from roots to shoots. Moreover, a threshold concentration of exogenous MeJA increased the activities of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) in plant roots, the concentration of Cd in the root cell wall, and the contents of pectin and hemicellulose 1 polysaccharides, through converting Cd into pectin-bound forms. These results suggested that MeJA mitigated Cd toxicity by modulating root cell wall polysaccharide and functional group composition, especially through pectin polysaccharides binding to Cd, with effects on Cd transport capacity, specific chemical forms of Cd, and homeostatic antioxidant systems in C. bipinnatus.

Abstract Background The prognosis of brain injury caused by subarachnoid hemorrhage (SAH) is poor. Previous studies showed that abnormal function of RBPs might be involved in brain injury, neuroinflammation and further affect microglia homeostasis. However, no studies have systematically analyzed the genome-wide abnormal expression of RBPs genes in microglia during SAH. Methods RNA-seq data of microglia from the SAH mouse group (SAH) and control sham-operated mouse group (sham) were downloaded from the GEO database in GSE167957, including four samples from the sham group and four samples from the SAH group for subsequent analysis.Utilizing GO and KEGG functional enrichment analyses, we conducted a comprehensive study of differentially expressed genes (DEGs), alternative splicing patterns, and co-expression networks to gain deeper insights into the differential expression of RNA-binding proteins (RBPs) and differential alternative splicing events (ASEs) between the SAH (subarachnoid hemorrhage) and sham groups. This analysis aimed to elucidate the potential mechanisms underlying the aberrant expression of RBPs in microglia during brain injury caused by SAH. Results ASEs and co-expression analyses of differentially expressed RBPs and differential ASEs were carried out in microglia in terms of gene expression. GO and KEGG functional enrichment analysis showed that aberrantly expressed RBPs such as Mcm7, Mtdh, SRSF3, and Hnrnpa2b1 may affect and regulate downstream Csnk1d, Uckl1 and other protein phosphorylation-related genes by alterative splicing. Conclusion RBPs were aberrantly expressed in microglia during the development of brain injury secondary to SAH, regulating alterative splicing of downstream genes and influencing the progression of SAH brain injury in this study. This implies that RBPs are important for the identification of new therapeutic targets for brain injury after SAH.

Acute lung injury (ALI) and acute respiratory distress syndrome are life-threatening conditions induced by inflammatory responses, in which cell-free DNA (cfDNA) plays a pivotal role. This study investigated the therapeutic potential of biodegradable cationic nanoparticles (cNPs) in alleviating ALI. Using a mouse model of lipopolysaccharide-induced ALI, we examined the impact of intravenously administered cNPs. Our findings indicate that cNPs possess robust DNA binding capability, enhanced accumulation in inflamed lungs, and a favorable safety profile in vivo. Furthermore, cNPs attenuate the inflammatory response in LPS-induced ALI mice by scavenging cfDNA, mainly derived from neutrophil extracellular traps, and activating the macrophage-mediated cGAS-STING pathway. The findings suggest a potential treatment for ALI by targeting cfDNA with cNPs. This approach has demonstrated efficacy in mitigating lung injury and merits further exploration.

ABSTRACT Carbapenem-resistant Klebsiella pneumoniae producing metallo-β-lactamase poses a major public health threat worldwide. Imipenemase often coexists with other resistance genes leading to the formation of multidrug-resistant bacteria. In this study, we describe the microbiological and genomic characteristics of the hypervirulent carbapenem-resistant K. pneumoniae ST20-K23 strain KPN945 harboring blaIMP-4 and qnrS1. The minimum inhibitory concentration of KPN945 against antimicrobials was determined by the broth microdilution method. The virulence of KPN945 was evaluated through string test, serum killing resistance, and Galleria mellonella larvae infection models. The transferability of pKPN945B was assessed using a conjugation test. The genome sequence characteristics of KPN945 were analyzed through whole genome sequencing, and a phylogenetic tree was constructed to evaluate the prevalence of imipenemase. Our findings showed that KPN945 was non-susceptible to β-lactam antibiotics, highly resistant to serum killing, and highly lethal to G. mellonella larvae. The fusion plasmid pKPN945B carried by the isolate KPN945 belonged to the IncR incompatibility group and harbored multiple drug resistance genes such as blaIMP-4, blaCTX-M-14, qnrS1, and sul2. The most important point is that the IncR plasmid is a novel plasmid that arose by the accretion of parts from different plasmids, making it transferable and with a fitness cost. Globally, blaIMP-4 is the most prevalent imipenemase subtype, with the highest isolation rates in Asia, particularly China. The spread of blaIMP-4, especially the emergence of transferable plasmids, deserves our vigilance and prevention. Additionally, we should pay attention to the formation of hypervirulent K. pneumoniae mediated by non-virulent plasmids.IMPORTANCEUp to now, IncR replicons carrying blaIMP-4 have not been reported, and the IncR plasmids described in previous studies have been found to be non-transferrable to other bacteria through conjugation. Moreover, there have been no extensive phylogenetic analyses of strains carrying blaIMP in the published papers. The lack of data in these studies is noteworthy because blaIMP appears in the novel transferable fusion plasmid IncR. Although the IncR plasmid has no tra operon, it can still be transferred to Escherichia coli EC600 or Klebsiella pneumoniae ATCC13883 (RIFR) without high fitness cost, but it only affects the MIC of imipenem. blaIMP integrates with other resistance mechanisms leading to the formation of multidrug-resistant strains. Notably, the high prevalence of blaIMP-4 in Asia and the presence of blaIMP-4 on novel transferable IncR plasmids suggest the urgent need to monitor the emergence of such plasmids and control their spread.

Cholangiocarcinoma (CCA) is a tumor that arises from the epithelium of the intrahepatic bile ducts. It is rarely diagnosed in individuals under 40 years of age and has a very aggressive nature: 95% of patients die within 5 years. We present the first detailed report of a case of perihilar CCA (pCCA) presenting during pregnancy masquerading as intrahepatic cholestasis of pregnancy (ICP). First, the patient exhibited typical pruritus, particularly in her limbs; second, a raised biomarker of total bile acid (TBA) was noted; third, the onset occurred in the second trimester, aligning with the epidemiological profile; and finally, importantly, there was no mass detected in her liver. First-line drugs were given to treat ICP, but they failed, and ultimately, the condition was identified as pCCA. Following an inadequate excision, traditional Chinese medicine was administered. After 26 months, she succumbed to cachexia. As gestational symptoms are sometimes associated with pregnancy-related disorders, pCCA in pregnant women is frequently misdiagnosed. Symptoms such as jaundice, pruritus, and dilated bile ducts in pregnant women may indicate pCCA. In addition, the appropriate treatment for pCCA in pregnant women may be surgery or chemotherapy; if surgery is not an option, chemotherapy may also help extend the gestational week. Our work is important and can educate on the diagnosis and treatment of pregnancy-related diseases, such as ICP and pCCA.

In Parkinson's disease (PD), exogenous ghrelin protects dopaminergic neurons through its receptor, growth hormone secretagogue receptor (GHSR). However, in contrast to the strikingly low levels of ghrelin, GHSR is highly expressed in the substantia nigra (SN). What role does GHSR play in dopaminergic neurons is unknown. In this study, using GHSR knockout mice (Ghsr−/− mice) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model, we found that GHSR deletion aggravated dopaminergic neurons degeneration, and the expression and activity of GHSR were significantly reduced in PD. Furthermore, we explored the potential mechanism that GHSR deficiency aggregated PD-related neurodegeneration. We showed that DEPTOR, a subunit of mTORC1, was overexpressed in Ghsr−/− mice, positively regulating autophagy and enhancing autophagy initiation. The expression of lysosomal markers was abnormal, implying lysosomal dysfunction. As a result, the damaged mitochondria could not be effectively eliminated, which ultimately exacerbated the injury of nigral dopaminergic neurons. In particular, we demonstrated that DEPTOR could be transcriptionally regulated by KLF4. Specific knockdown of KLF4 in dopaminergic neurons effectively alleviated neurodegeneration in Ghsr−/− mice. In summary, our results suggested that endogenous GHSR deletion-compromised autophagy by impairing lysosomal function, is a key contributor to PD, which provided ideas for therapeutic approaches involving the manipulation of GHSR.

Backgroud: Cellular senescence is closely related to human aging and multiple aging-related diseases, and impaired mitochondrial energy metabolism is an important mechanism of cellular senescence. Notably, microRNA-125b-1-3p (miR-125b-1-3p) is a microRNA (miR, miRNA) that may be associated with mitochondrial energy metabolism. Ubiquinol-cytochrome c reductase binding protein (UQCRB) gene, predicted by bioinformatics tools to be targeted by miR-125b-1-3p, could serve as a novel diagnostic indicator and therapeutic target for cellular senescence-associated diseases, as well as a new idea for delaying aging. Methods: First, the dual-luciferase reporter gene assay was used to identify UQCRB as a target gene of miR-125b-1-3p. Next, miRNA interference technology was conducted to verify that miR-125b-1-3p could negatively regulate the expression of UQCRB. Subsequently, the influence of miR-125b-1-3p on mitochondrial energy metabolism function was explored by observing the internal substances and ultrastructure of mitochondria. Further, an in vitro model of cellular senescence was established in rat renal tubular epithelial cells, which was characterized by detecting senescence-related proteins p16 and p21 and beta-galactosidase (β-gal) activity. Finally, the mitochondrial energy metabolism function of hydrogen peroxide (H2O2)-incubated cells was explored. Results: The experimental results revealed that miR-125b-1-3p affected the mitochondrial energy metabolism function by inhibiting the target gene UQCRB. Meanwhile, the level of mitochondrial energy metabolism function in H2O2-incubated senescent cells was lower than that in normal cells. Conclusion: In this study, we identified the target gene, UQCRB, of miR-125b-1-3p, and demonstrated its role in the pathway of mitochondrial energy metabolism, as well as its possible effect on cellular senescence through this pathway. The ameliorative effects on cellular senescence can be further explored in subsequent studies to provide additional options for delaying aging or treating aging-related diseases.

In order to reveal the aroma compositions of two varieties of Yunnan teas processed based on the Liu Bao tea craft and to explore the more suitable varieties of tea plants for making Liu Bao tea, headspace solid-phase micro extraction and gas chromatography mass spectrometry (HS-SPME-GC/MS) was used to analyze the aroma compositions of two varieties of Yunnan teas by combining the relative odor activity value (ROAV) method with the relative odor activity value (ROAV) method. Headspace solid-phase micro extraction and gas chromatography mass spectrometry (HS-SPME-GC/MS) was used to analyze the volatile constituents of the two varieties of tea from Yunnan by using the relative aroma activity value (ROAV) method. The results showed that a total of 152 volatile components were detected, with alcohols and esters as the main volatile components, and linalool, lauryl alcohol, nonanal, dihydrokiwifruit lactone, methyl linolenate and methyl palmitate as the main volatile components, and the results of ROAV showed that there were 19 main aroma-contributing volatile components during the processing of the two varieties, and the aroma compounds that were significantly (P

Abstract Background Transcatheter angiography (TA) could help to diagnose and treat refractory nonvariceal upper gastrointestinal bleeding (NVUGIB). Proton pump inhibitors (PPIs) are the key medication for reducing the rebleeding rate and mortality and are usually continued after TA. It is unknown whether high-dose PPIs after TA are more effective than the standard regimen. Methods We retrospectively collected data from patients who received TA because of refractory NVUGIB from 2010 to 2020 at West China Hospital. 244 patients were included and divided into two groups based on the first 3 days of PPIs treatment. All baseline characteristics were balanced using the inverse probability of treatment weighting method. The 30-day all-cause mortality, rebleeding rate and other outcomes were compared. The propensity score matching method was also used to verify the results. Results There were 86 patients in the high-dose group and 158 in the standard group. The average daily doses of PPI were 192.1 ± 17.9 mg and 77.8 ± 32.0 mg, respectively. Cox regression analysis showed no difference in the 30-day all-cause mortality (aHR 1.464, 95% CI 0.829 to 2.584) or rebleeding rate (aHR 1.020, 95% CI 0.693 to 1.501). There were no differences found in red blood cell transfusion, hospital stay length and further interventions, including endoscopy, repeating TA, surgery and ICU admission. The results were consistent in the subgroup analysis of patients with transcatheter arterial embolization. Conclusion In refractory NVUGIB patients who received TA, regardless of whether embolization was performed, high-dose PPI treatment did not provide additional benefits compared with the standard regimen.

Abstract Background Dysregulation of iron metabolism has been shown to have significant implications for cancer development. We aimed to investigate the prognostic and immunological significance of iron metabolism-related genes (IMRGs) in nasopharyngeal carcinoma (NPC). Methods Multiple Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets were analyzed to identify key IMRGs associated with prognosis. Additionally, the immunological significance of IMRGs was explored. Results A novel risk model was established using the LASSO regression algorithm, incorporating three genes (TFRC, SLC39A14, and ATP6V0D1).This model categorized patients into low and high-risk groups, and Kaplan–Meier analysis revealed significantly shorter progression-free survival for the high-risk group (P

Abstract It is generally recognized that tumor cells proliferate more rapidly than normal cells. Due to such an abnormally rapid proliferation rate, cancer cells constantly encounter the limits of insufficient oxygen and nutrient supplies. To satisfy their growth needs and resist adverse environmental events, tumor cells modify the metabolic pathways to produce both extra energies and substances required for rapid growth. Realizing the metabolic characters special for tumor cells will be helpful for eliminating them during therapy. Cell death is a hot topic of long-term study and targeting cell death is one of the most effective ways to repress tumor growth. Many studies have successfully demonstrated that metabolism is inextricably linked to cell death of cancer cells. Here we summarize the recently identified metabolic characters that specifically impact on different types of cell deaths and discuss their roles in tumorigenesis.

Koumiss, a traditional Mongolian beverage, is believed to possess high nutritional value and potential medical benefits. However, there is a lack of comprehensive research on its potential impact on the human body. Metabolomics, as a sensitive approach in systems biology, offers a new avenue for studying the overall effects of koumiss. In this work, metabolomics was utilized to identify potential biomarkers and pathways associated with koumiss using UPLC-MS detection, pattern recognition analysis, pathway enrichment, network pharmacology. The findings indicated that koumiss exerts a beneficial regulatory influence on lipid metabolism, neurotransmitters, hormones, phospholipids and arachidonic acid metabolism, besides up regulating the content of nutrients. It could reduce the risks of dyslipidemia and inflammatory responses. This study confirmed the benign regulatory effect of koumiss on normal organism from the perspective of endogenous metabolites, and provided objective support for the promotion and application of this ethnic food.

Intracellular bacteria can multiply inside host cells and manipulate their biology, and the efficacy of traditional antibiotic drug therapy for intracellular bacteria is limited by inadequate drug accumulation. Fighting against these stealthy bacteria has been a long-standing challenge. Here, a system of stimuli-responsive lactoferrin (Lf) nanoparticles is prepared using protein self-assembly technology to deliver broad-spectrum antibiotic rifampicin (Rif) (Rif@Lf NPs) for enhanced infection therapy through targeted elimination of intracellular bacteria. Compared to Rif@BSA NPs, the Rif@Lf NPs can specifically target macrophages infected by bacteria, thus increasing the accumulation of Rif within macrophages. Subsequently, Rif@Lf NPs with positive surface charge further displayed targeted adherence to the bacteria within macrophages and released Rif rapidly in a redox-responsive manner. Combined with the antibacterial activities of Lf and Rif, the Rif@Lf NPs showed broad-spectrum antibiotic abilities to intracellular bacteria and biofilms. As a result, the Rif@Lf NPs with high safety exhibited excellent therapeutic efficacy in the disease models of subcutaneous infection, sepsis, and bacterial keratitis. Taken together, the antibiotic-loaded Lf nanoparticles present a promising platform to combat pathogen infections through targeted elimination of intracellular bacteria.

A rapid and sensitive ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was established for the simultaneous determination of doxorubicin (DOX) in mouse plasma and tissues, including the heart, liver, spleen, lung, kidney and tumor, and to investigate the pharmacokinetics and distribution in mice. In this study, daunorubicin (DNR) was used as an internal standard, and the mobile phase consisted of ammonium formate 2 mM containing 0.1 % formic acid (A) and acetonitrile (B), the chromatographic column was ACQUITY UPLC BEHTM C18 with a gradient elution at a flow rate of 0.2 mL/min. Electrospray ionization (ESI) in positive ion pattern was utilized for the ion separation of DOX, with the ions used for quantitative analysis being DOX m/z 544.28 → 397.10 and DNR m/z 528.35 → 321.08, respectively. The results showed that a good linear relationship in the calibration curve range of 1–800 ng/mL in mouse plasma and 1–2500 ng/g in tissues (R2 > 0.99) with the limits of quantification of 1 ng/mL in plasma and tissues. The method exhibited good matrix effect and extraction recovery, with the intra-day and inter-day precision of plasma and tissue were less than 10.3 % and 15.4 %, and the relative error (RE) were both less than ±14.8 % and ±18.9 %, respectively. The stability results under different conditions were found to be accurate. It also revealed the distribution of DOX in various tissues of mice, with the concentration ranking as liver > heart > kidney > spleen > lung > tumor. This method was successfully used to the study for the pharmacokinetics in plasma and drug distribution in tissues of BALB/c mice.

PurposeNanophthalmos is a congenital ocular structural anomaly that can cause significant visual loss in children. The early diagnosis and then taking appropriate clinical and surgical treatment remains a challenge for many ophthalmologists because of genetic and phenotypic heterogeneity. The objective of this study is to identify the genetic cause of nanophthalmos in the affected families and analyze the clinical phenotype of nanophthalmos with MFRP gene variation (Microphthalmia, isolated; OMIM#611040 and Nanophthalmos 2; OMIM#609549, respectively).MethodsComprehensive ophthalmic examinations were performed on participants to confirm the phenotype. The genotype was identified using whole exome sequencing, and further verified the results among other family members by Sanger sequencing. The normal protein structure was constructed using Alphafold. Mutant proteins were visualized using pymol software. Pathogenicity of identified variant was determined by in silico analysis and the guidelines of American College of Medical Genetics and Genomics (ACMG). The relationship between genetic variants and clinical features was analyzed.ResultsFive nanophthalmos families were autosomal recessive, of which four families carried homozygous variants and one family had compound heterozygous variants in the MFRP gene. Both family one and family three carried the homozygous missense variant c.1486G>A (p.Glu496Lys) in the MFRP gene (Clinvar:SCV005060845), which is a novel variant and evaluated as likely pathogenic according to the ACMG guidelines and in silico analysis. The proband of family one presented papilloedema in both eyes, irregular borders, thickened retinas at the posterior pole, tortuous and dilated retinal vessels, and indistinguishable arteries and veins, while the proband of family three presented uveal effusion syndrome-like changes in the right eye. In families one and 3, despite carrying the same gene variant, the probands had completely different clinical phenotypes. The homozygous nonsense variant c.271C>T (p.Gln91Ter) (Clinvar:SCV005060846) of the MFRP gene was detected in family 2, presenting shallow anterior chamber in both eyes, pigmentation of peripheral retina 360° from the equator to the serrated rim showing a clear demarcation from the normal retina in the form of strips. Family four proband carried the homozygous missense variant c.1411G>A (p.Val471Met) in the MFRP gene (Clinvar:SCV005060847), family five proband carried compound heterozygous missense variants c.1486G>A (p.Glu496Lys) and c.602G>T (p.Arg201Leu) in the MFRP gene (Clinvar:SCV005060848), which is a novel variant and evaluated as likely pathogenic according to the ACMG guidelines and in silico analysis, and they all presented clinically with binocular angle-closure glaucoma, family four also had retinal vein occlusion in the right eye during the follow-up.ConclusionIn this study, pathogenic variants of the MFRP gene were detected in five nanophthalmos families, including two novel variants. It also revealed a distinct phenotypic diversity among five probands harboring variants in the MFRP gene. Our findings extend the phenotype associated with MFRP variants and is helpful for ophthalmologists in early diagnosis and making effective treatment and rehabilitation strategies.

Abstract Background According to prenatal ultrasonographic studies, single umbilical artery may be present alone or in association with other fetal abnormalities. So far, the exact pathogenesis of bladder exstrophy is unclear. Some scholars believe that bladder exstrophy and cloacal exstrophy should be regarded as a disease spectrum to explore their pathogenesis. If bladder exstrophy and cloacal exstrophy are regarded as the same disease spectrum, then we can speculate that the single umbilical artery should have the probability of being accompanied by bladder exstrophy at the same time. Case presentation For the first time, we report a rare case of fetal bladder exstrophy with single umbilical artery in single pregnancy. This patient underwent targeted color Doppler ultrasound at 26 weeks of pregnancy which first suspected bladder exstrophy with single umbilical artery and fetal MRI for diagnosis at 38 + 3 weeks of pregnancy which confirmed the suspicion. After the diagnosis was confirmed, the patient was scheduled for a multidisciplinary discussion. Ultimately the patient opted for induced fetal demise at 38 + 5 weeks of pregnancy and the physical appearance of the fetal demise affirmed previous ultrasound and MRI examination results. Conclusions Our report is the first finding of single umbilical artery combined with bladder exstrophy in a singleton pregnancy. Accordingly, our case enhances the evidence that cloacal exstrophy and bladder exstrophy should be treated as the same disease spectrum. In addition, we conducted a literature review on the diagnostic progress of single umbilical artery combined with bladder exstrophy, hoping to provide useful references for the diagnosis of this disease.

Abstract Frequent relapse and chemoresistance cause poor outcome in ovarian cancer (OC) and cancer stem cells (CSCs) are important contributors. While most studies focus exclusively on CSCs, the role of the microenvironment in providing optimal conditions to maintain their tumor-initiating potential remains poorly understood. Cancer associated fibroblasts (CAFs) are a major constituent of the OC tumor microenvironment and we show that CAFs and CSCs are enriched following chemotherapy in patient tumors. CAFs significantly increase OC cell resistance to carboplatin. Using heterotypic CAF-OC cocultures and in vivo limiting dilution assay, we confirm that the CAFs act by enriching the CSC population. CAFs increase the symmetric division of CSCs as well as the dedifferentiation of bulk OC cells into CSCs. The effect of CAFs is limited to OC cells in their immediate neighborhood, which can be prevented by inhibiting Wnt. Analysis of single cell RNA-seq data from OC patients reveal Wnt5a as the highest expressed Wnt in CAFs and that certain subpopulations of CAFs express higher levels of Wnt5a. Our findings demonstrate that Wnt5a from CAFs activate a noncanonical Wnt signaling pathway involving the ROR2/PKC/CREB1 axis in the neighboring CSCs. While canonical Wnt signaling is found to be predominant in interactions between cancer cells in patients, non-canonical Wnt pathway is activated by the CAF-OC crosstalk. Treatment with a Wnt5a inhibitor sensitizes tumors to carboplatin in vivo. Together, our results demonstrate a novel mechanism of CSC maintenance by signals from the microenvironmental CAFs, which can be targeted to treat OC chemoresistance and relapse.

Proton pump inhibitors (PPIs) are some of the most commonly prescribed drugs worldwide, but there are increasing concerns about digestive complications linked to PPIs. Next-generation sequencing studies have suggested that PPIs can significantly affect the composition of the gut microbiota, which in turn may substantially contribute to the development of these complications. Recently, emerging evidence has suggested that the translocation of oral microbes into the gut may be the primary mechanism underlying the alterations in the gut microbiota induced by PPIs in the presence of gastric acid suppression and impaired oral–gut barrier function. Moreover, the significance of oral–gut microbial translocation in health and disease conditions has gained increasing recognition. Consequently, it is imperative to enhance our understanding of the functions of the oral–gut microbiota axis in digestive disorders associated with PPI therapies. This review aims to summarize current research findings and further elucidate the contribution of the oral–gut microbiota to the pathogenesis of PPI-related digestive diseases. We aim to provide a theoretical foundation for future therapeutic and preventive strategies targeting PPI-related digestive complications through modulation of the oral–gut microbiota.

Objectives This study aimed to analyse the current status, trends and risk factors of disease burden from 1990 to 2019 among Chinese children.Design and participants It was a retrospective study on data from the Global Burden of Disease Study 2019 (GBD 2019). Data of disease burden and risk factors were extracted from the GBD 2019. Children were divided into two groups of

Abstract Drought has a significant impact on plant–insect interactions by altering plant survival, growth, leaf quality, and defense traits. Tropical plants are particularly vulnerable to water depression because of shallow root depth. In the context of climate change, drought events are expected to increase in frequency and intensity; however, their impact on tropical ecosystems remains poorly known. Insect herbivores represent the largest feeding guild of arthropods, and they devour four to five times more plant material than vertebrates do. Understanding how drought affects plant traits and leaf palatability in a keystone and ecologically diverse plant genus, such as Ficus (Moraceae), is crucial for predicting how climate change might alter tropical plant–insect interactions. We examined the impact of drought intensity and duration on the leaf nutritional quality, defensive traits, and herbivory damage by caterpillars in three tropical and one Mediterranean Ficus species in a greenhouse. We also conducted food choice trials with generalist caterpillars to evaluate the impact of drought on herbivores. Drought intensity and duration had no direct effect on leaf palatability across the Ficus species. However, drought indirectly affected leaf palatability via drought‐induced leaf traits in a species‐specific manner. Drought intensity and duration decreased leaf water content, resulting in decreased leaf palatability in F. benjamina and F. lyrata. Leaf defensive traits such as flavonoid concentration were affected by drought intensity and decreased leaf palatability in F. carica. Drought influenced the leaf traits of F. elastica, but none of them affected leaf palatability. Overall, this study establishes the link between drought and insect feeding on plants via leaf traits. The species‐specific responses to drought highlight the significance of climate‐related plant life histories in relation to climate change, underscoring the need for further investigations.

ObjectiveThis study aimed to establish an effective prognostic model based on triglyceride and inflammatory markers, including neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR), to predict overall survival (OS) in patients with nasopharyngeal carcinoma (NPC). Additionally, we aimed to explore the interaction and mediation between these biomarkers in their association with OS.MethodsA retrospective review was conducted on 259 NPC patients who had blood lipid markers, including triglyceride and total cholesterol, as well as parameters of peripheral blood cells measured before treatment. These patients were followed up for over 5 years, and randomly divided into a training set (n=155) and a validation set (n=104). The triglyceride-inflammation (TI) score was developed using the random survival forest (RSF) algorithm. Subsequently, a nomogram was created. The performance of the prognostic model was measured by the concordance index (C-index), time-dependent receiver operating characteristic (ROC) curve, and decision curve analysis (DCA). The interaction and mediation between the biomarkers were further analyzed. Bioinformatics analysis based on the GEO dataset was used to investigate the association between triglyceride metabolism and immune cell infiltration.ResultsThe C-index of the TI score was 0.806 in the training set, 0.759 in the validation set, and 0.808 in the entire set. The area under the curve of time-dependent ROC of TI score in predicting survival at 1, 3, and 5 years were 0.741, 0.847, and 0.871 respectively in the training set, and 0.811, 0.837, and 0.758 in the validation set, then 0.771, 0.848, and 0.862 in the entire set, suggesting that TI score had excellent performance in predicting OS in NPC patients. Patients with stage T1-T2 or M0 had significantly lower TI scores, NLR, and PLR, and higher LMR compared to those with stage T3-T3 or M1, respectively. The nomogram, which integrated age, sex, clinical stage, and TI score, demonstrated good clinical usefulness and predictive ability, as evaluated by the DCA. Significant interactions were found between triglyceride and NLR and platelet, but triglyceride did not exhibit any medicating effects in the inflammatory markers. Additionally, NPC tissues with active triglyceride synthesis exhibited high immune cell infiltration.ConclusionThe TI score based on RSF represents a potential prognostic factor for NPC patients, offering convenience and economic advantages. The interaction between triglyceride and NLR may be attributed to the effect of triglyceride metabolism on immune response.

Compound pollution with cadmium (Cd) and zinc (Zn) is common in nature. The effects of compounded Cd and Zn on the growth and development of Iris pseudacorus in the environment and the plant’s potential to remediate heavy metals in the environment remain unclear. In this study, the effects of single and combined Cd and Zn stress on I. pseudacorus growth and the enrichment of heavy metals in I. pseudacorus seedlings were investigated. The results showed that under Cd (160 μM) and Zn (800 μM) stress, plant growth was significantly inhibited and photosynthetic performance was affected. Cd+Zn200 (160 μM + 200 μM) reduced the levels of malondialdehyde, hydrogen peroxide, and non-protein thiols by 31.29%, 53.20%, and 13.29%, respectively, in the aboveground tissues compared with levels in the single Cd treatment. However, Cd+Zn800 (160 μM + 800 μM) had no effect. Cd and Zn800 inhibited the absorption of mineral elements, while Zn200 had little effect on plants. Compared with that for Cd treatment alone, Cd + Zn200 and Cd+Zn800 reduced the Cd content in aboveground tissues by 54.15% and 49.92%, respectively, but had no significant effect on Cd in the root system. Zn significantly reduced the Cd content in subcellular components and limited the content and proportion of Cd extracted using water and ethanol. These results suggest that a low supply of Zn reduces Cd accumulation in aboveground tissues by promoting antioxidant substances and heavy metal chelating agents, thus protecting the photosynthetic systems. The addition of Zn also reduced the mobility and bioavailability of Cd to alleviate its toxicity in I. pseudacorus.

Abstract Background Appendiceal bleeding is a rare cause of lower gastrointestinal bleeding, could be overlooked and diagnosed as obscure gastrointestinal bleeding. Due to limited real-world cases, the optimized management of appendiceal bleeding is unclear. We here shared our experiences in the past 20 years. Methods A retrospective study was conducted at West China Hospital of Sichuan University. We reviewed data of 28,175 colonoscopies from 43,095 gastrointestinal bleeding patients between June 2003 and June 2023. Six patients diagnosed as appendiceal bleeding were included. Data including symptoms, laboratory tests, imaging results, endoscopic findings, treatment and prognosis were collected and analyzed. Results Appendiceal bleeding accounts for 0.014% in gastrointestinal bleeding patients. Of the six patients, five were male, with a mean age of 48.5 years. Hematochezia was the most common symptom. The etiology included appendiceal angiodysplasia, appendicitis and appendectomy associated bleeding. Hemostasis was achieved by appendectomy, endoscopic therapy or medication according to different cases. One patient did not receive any treatment because of self-limiting bleeding. Conclusions The diagnosis of appendiceal bleeding is challenging, repeated flushing during endoscopy is helpful. Appendectomy is the priority option for treatment as well as the etiology clarification, therapeutic endoscopy and medication could be considered case by case.

Abstract Self-renewal and differentiation of skeletal stem and progenitor cells (SSPCs) are tightly regulated processes, with SSPC dysregulation leading to progressive bone disease. While the application of single-cell RNA sequencing (scRNAseq) to the bone field has led to major advancements in our understanding of SSPC heterogeneity, stem cells are tightly regulated by their neighboring cells which comprise the bone marrow niche. However, unbiased interrogation of these cells at the transcriptional level within their native niche environment has been challenging. Here, we combined spatial transcriptomics and scRNAseq using a predictive modeling pipeline derived from multiple deconvolution packages in adult mouse femurs to provide an endogenous, in vivo context of SSPCs within the niche. This combined approach localized SSPC subtypes to specific regions of the bone and identified cellular components and signaling networks utilized within the niche. Furthermore, the use of spatial transcriptomics allowed us to identify spatially restricted activation of metabolic and major morphogenetic signaling gradients derived from the vasculature and bone surfaces that establish microdomains within the marrow cavity. Overall, we demonstrate, for the first time, the feasibility of applying spatial transcriptomics to fully mineralized tissue and present a combined spatial and single-cell transcriptomic approach to define the cellular components of the stem cell niche, identify cell‒cell communication, and ultimately gain a comprehensive understanding of local and global SSPC regulatory networks within calcified tissue.

The high efficiency and low cost repair of perforation damage of aluminum honeycomb sandwich structure is of great significance to ensure the integrity of aviation equipment. A composite carbon fiber wet patch bonding repair process is proposed for metal panels with perforated damage in aluminum honeycomb sandwich structures. Combined with typical aluminum honeycomb sandwich structures in aircraft, intact and perforated damage samples are prepared, and composite bonding repair is carried out on perforated damage samples. A finite element simulation analysis model for four point bending strength analysis of aluminum honeycomb sandwich structure after patching and bonding repair is established, and the influence of perforation damage size on the four point bending strength of aluminum honeycomb sandwich structure and the strength recovery after repair are analyzed through simulation calculation. The results show that the bending strength of aluminum honeycomb sandwich structure can be effectively restored by using composite materials bonding method. The results of finite element simulation are in good agreement with the experimental results. The simulation model can accurately calculate the ultimate load and failure mode of all kinds of samples. The simulation results show that when the damage range is ≤φ30 mm (diameter to width ratio is less than 40%),the adhesive repair technology of composite materials can be applied to the damage repair of aluminum honeycomb sandwich structures of aircraft.

Abstract Mechanotransduction in endothelial cells is critical to maintain vascular homeostasis and can contribute to disease development, yet the molecules responsible for sensing flow remain largely unknown. Here, we demonstrate that the discoidin domain receptor 1 (DDR1) tyrosine kinase is a direct mechanosensor and is essential for connecting the force imposed by shear to the endothelial responses. We identify the flow-induced activation of endothelial DDR1 to be atherogenic. Shear force likely causes conformational changes of DDR1 ectodomain by unfolding its DS-like domain to expose the buried cysteine-287, whose exposure facilitates force-induced receptor oligomerization and phase separation. Upon shearing, DDR1 forms liquid-like biomolecular condensates and co-condenses with YWHAE, leading to nuclear translocation of YAP. Our findings establish a previously uncharacterized role of DDR1 in directly sensing flow, propose a conceptual framework for understanding upstream regulation of the YAP signaling, and offer a mechanism by which endothelial activation of DDR1 promotes atherosclerosis.

This research explores edge computing for construction site monitoring using computer vision (CV)-based worker detection methods. The feasibility of using edge computing is validated by testing worker detection models (yolov5 and yolov8) on local computers and three edge computing devices (Jetson Nano, Raspberry Pi 4B, and Jetson Xavier NX). The results show comparable mAP values for all devices, with the local computer processing frames six times faster than the Jetson Xavier NX. This study contributes by proposing an edge computing solution to address data security, installation complexity, and time delay issues in CV-based construction site monitoring. This approach also enhances data sustainability by mitigating potential risks associated with data loss, privacy breaches, and network connectivity issues. Additionally, it illustrates the practicality of employing edge computing devices for automated visual monitoring and provides valuable information for construction managers to select the appropriate device.

Objective In recent years, new discoveries have been made in the He 1 Member of the Hangjinqi Gas Field. And the initial gas production of some wells by fracturing can reach 10×104 m3/d, which shows that the He 1 Member has great exploration potential. However, due to the strong heterogeneity of the He 1 Member, the gas production mechanism of the He 1 Member is not clear at present, which restricts its efficient development. To accurately and quantitatively characterize the microscopic pore structure and movable fluid characteristics of tight gas sandstone reservoirs. Methods In this paper, taking the tight sandstone reservoir in the He 1 Member of the Shangshihezi Formation in the Hangjinqi Gas Field as an example, NMR and CT tests were used to study the response characteristics and fluid identification ability of different types of pores in tight sandstone. Results The research shows that the porosity of the test samples is mainly distributed in 1.7%-10%, and the gas permeability is mainly distributed in 0.1×10-3-1.4×10-3 μm2, which belongs to the typical low-porosity and low-permeability porous tight sandstone reservoir. According to the T2 relaxation time curve of the saturation component before centrifugation, the pore type of the reservoir in the He 1 Member is bimodal (mainly the left peak, the right peak is not obvious), including 3 subtypes: micropore-small pore type, small pore-mesopore type, micropore-small pore-mesopore type. The T2 relaxation time intervals corresponding to the above three subtypes of pore types are 0.1-10 ms, 1-100 ms, and 0.1-100 ms, respectively. The results of 3D CT scans show that the micropore-mesopore reservoir has the best physical properties, followed by the micropore-small pore-mesopore type, and the micropore-small pore type reservoirs have relatively poor physical properties. The T2 cut-off values of the tested samples were mainly distributed between 1 and 14 ms, with an average value of 6.11 ms. There is a certain negative correlation between the T2 cut-off value and the movable fluid percentage of the rock samples. The movable fluid porosity and permeability have a very good positive correlation, reflecting that the amount of movable fluid is significantly affected by the reservoir permeability and the number of throats. The movable water saturation in the tight sandstone reservoirs of He 1 Member in the study area is mainly distributed at 4%-9%, with an average value of 5.8%. Conclusion Overall, the original movable water saturation of the He 1 Member is low and has great development potential.

Abstract Objectives The main objective of this study is to evaluate the methodological quality and reporting quality of living systematic reviews (LSRs) on Coronavirus disease 2019 (COVID-19), while the secondary objective is to investigate potential factors that may influence the overall quality of COVID-19 LSRs. Methods Six representative databases, including Medline, Excerpta Medica Database (Embase), Cochrane Library, China national knowledge infrastructure (CNKI), Wanfang Database, and China Science, Technology Journal Database (VIP) were systematically searched for COVID-19 LSRs. Two authors independently screened articles, extracted data, and then assessed the methodological and reporting quality of COVID-19 LSRs using the "A Measurement Tool to Assess systematic Reviews-2" (AMSTAR-2) tool and "Preferred Reporting Items for Systematic reviews and Meta-Analyses" (PRISMA) 2020 statement, respectively. Univariate linear regression and multivariate linear regression were used to explore eight potential factors that might affect the methodological quality and reporting quality of COVID-19 LSRs. Results A total of 64 COVID-19 LSRs were included. The AMSTAR-2 evaluation results revealed that the number of "yes" responses for each COVID-19 LSR was 13 ± 2.68 (mean ± standard deviation). Among them, 21.9% COVID-19 LSRs were rated as "high", 4.7% as "moderate", 23.4% as "low", and 50% as "critically low". The evaluation results of the PRISMA 2020 statement showed that the sections with poor adherence were methods, results and other information. The number of "yes" responses for each COVID-19 LSR was 21 ± 4.18 (mean ± standard deviation). The number of included studies and registration are associated with better methodological quality; the number of included studies and funding are associated with better reporting quality. Conclusions Improvement is needed in the methodological and reporting quality of COVID-19 LSRs. Researchers conducting COVID-19 LSRs should take note of the quality-related factors identified in this study to generate evidence-based evidence of higher quality.

Angiotensin converting enzyme 2 (ACE2) is a new identified member of the renin-angiotensin-aldosterone system (RAAS) that cleaves angiotensin II (Ang II) to Ang (1–7), which exerts anti-inflammatory and antioxidative activities via binding with Mas receptor (MasR). However, the functional role of ACE2 in sepsis-related hypotension remains unknown. Our results indicated that sepsis significantly reduced blood pressure and led to disruption between ACE-Ang II and ACE2-Ang (1–7) balance. ACE2 knock-in mice exhibited improved sepsis-induced mortality, hypotension and vascular dysfunction, while ACE2 knockout mice exhibited the opposite effects. Bone marrow transplantation and in vitro experiments confirmed that myeloid ACE2 exerted a protective role by suppressing oxidative stress, NO production and macrophage polarization via the Ang (1–7)-MasR–NF–κB and STAT1 pathways. Thus, ACE2 on myeloid cells could protect against sepsis-mediated hypotension and vascular dysfunction, and upregulating ACE2 may represent a promising therapeutic option for septic patients with hypotension.

The precise and prompt determination of quality control indicators such as moisture, stilbene glycosides, and anthraquinone glycosides is crucial in assessing the quality of Polygoni Multiflori Radix. Near-infrared spectroscopy is a nondestructive analytical technique that offers a more desirable approach than traditional methods for assessing content levels. In this study, various spectral preprocessing techniques were used to preprocess the raw spectral data. The spectral data were correlated with the determination of three-component contents using the partial least squares regression (PLSR) method. Then different algorithms, such as competitive adaptive weighted sampling (CARS), Monte Carlo uninformative variable elimination (MCUVE), and random frog hopping (RF), were used for model simplification and feature selection. The data suggest that the first-order deconvolution derivative (1st Dev.) processing of the spectral data is superior to other methods in all three model evaluation metrics. The PLSR model for moisture, stilbene glycosides, and anthraquinone glycosides produced the calibration coefficient of determination (R2C) of 0.82, 0.52, and 0.58, the root mean square error of cross validation (RMSECV) of 0.91%, 0.77%, and 0.69%, the prediction coefficient of determination (R2P) of 0.72, 0.28, and 0.54, the root mean square error of prediction (RMSEP) of 0.65%, 0.81%, and 0.75%, and relative percentage differences (RPDs) of 1.7, 1.0, and 0.8. After optimizing the model using CARS, R2C increased by 0.15%, 0.41%, and 0.34%, RMSECV decreased by 0.53%, 0.32%, and 0.24%, R2P increased by 0.21%, 0.63%, and 0.35%, RMSEP decreased by 0.36%, 0.41%, and 0.31%, and RPD increased by 1.1, 0.9, and 0.6, significantly improving the predictive capacity of the model. This research provides a feasible method for rapid compliance testing of Polygoni Multiflori Radix. To further improve the model’s performance and applicability, it is necessary to continuously expand the sample set with different varieties and locations for wide variation.

Objective: We aimed to determine the safety of Vaginal natural orifice transluminal endoscopic surgery (vNOTES) in terms of the Enhanced Recovery after Surgery (ERAS) concept for tubal pregnancy surgery and provide a detailed process of vNOTES for tubal pregnancy surgery, including experience and key points for surgeons performing this procedure. Methods: The Longitudinal Vaginal Natural Orifice Transluminal Endoscopic Surgery Study (LovNOTESS), which was conducted in Chengdu, China. A total of 219 patients who underwent tubal ectopic pregnancy surgery between September 2021 and March 2022. The patients underwent salpingectomy or salpingostomy using transumbilical laparoendoscopic single-site surgery (LESS) or vNOTES, according to their preferences. This study prospectively collected perioperative and one-year follow-up data on tubal pregnancy outcomes after vNOTES and compared them with those after LESS. Results: The vNOTES group showed a shorter surgical duration, hospitalization duration, and postoperative exhaust time and a lower analgesic medication usage rate, but it showed a higher surgical conversion rate. The vNOTES approach reduced the postoperative exhaust time by approximately 9 h (95% confidence interval [CI]: −11.93, −5.57 h, p

Summary: The differentiation of embryonic stem cells (ESCs) begins with the transition from the naive to the primed state. The formative state was recently established as a critical intermediate between the two states. Here, we demonstrate the role of the histone chaperone FACT in regulating the naive-to-formative transition. We found that the Q265K mutation in the FACT subunit SSRP1 increased the binding of FACT to histone H3-H4, impaired nucleosome disassembly in vitro, and reduced the turnover of FACT on chromatin in vivo. Strikingly, mouse ESCs harboring this mutation showed elevated naive-to-formative transition. Mechanistically, the SSRP1-Q265K mutation enriched FACT at the enhancers of formative-specific genes to increase targeted gene expression. Together, these findings suggest that the turnover of FACT on chromatin is crucial for regulating the enhancers of formative-specific genes, thereby mediating the naive-to-formative transition. This study highlights the significance of FACT in fine-tuning cell fate transition during early development.

Abstract Background Detection of lung cancer at earlier stage can greatly improve patient survival. We aim to develop, validate, and implement a cost-effective ctDNA-methylation-based plasma test to aid lung cancer early detection. Methods Case-control studies were designed to select the most relevant markers to lung cancer. Patients with lung cancer or benign lung disease and healthy individuals were recruited from different clinical centers. A multi-locus qPCR assay, LunaCAM, was developed for lung cancer alertness by ctDNA methylation. Two LunaCAM models were built for screening (-S) or diagnostic aid (-D) to favor sensitivity or specificity, respectively. The performance of the models was validated for different intended uses in clinics. Results Profiling DNA methylation on 429 plasma samples including 209 lung cancer, 123 benign diseases and 97 healthy participants identified the top markers that detected lung cancer from benign diseases and healthy with an AUC of 0.85 and 0.95, respectively. The most effective methylation markers were verified individually in 40 tissues and 169 plasma samples to develop LunaCAM assay. Two models corresponding to different intended uses were trained with 513 plasma samples, and validated with an independent collection of 172 plasma samples. In validation, LunaCAM-S model achieved an AUC of 0.90 (95% CI: 0.88–0.94) between lung cancer and healthy individuals, whereas LunaCAM-D model stratified lung cancer from benign pulmonary diseases with an AUC of 0.81 (95% CI: 0.78–0.86). When implemented sequentially in the validation set, LunaCAM-S enables to identify 58 patients of lung cancer (90.6% sensitivity), followed by LunaCAM-D to remove 20 patients with no evidence of cancer (83.3% specificity). LunaCAM-D significantly outperformed the blood test of carcinoembryonic antigen (CEA), and the combined model can further improve the predictive power for lung cancer to an overall AUC of 0.86. Conclusions We developed two different models by ctDNA methylation assay to sensitively detect early-stage lung cancer or specifically classify lung benign diseases. Implemented at different clinical settings, LunaCAM models has a potential to provide a facile and inexpensive avenue for early screening and diagnostic aids for lung cancer.

Abstract Background Decreased bioavailability of nitric oxide (NO) under hypoxic conditions can lead to endothelial dysfunction. NO supplementation may protect endothelial function in ischemia-reperfusion (IR) injury. Therefore, a meta-analysis of randomized controlled trials (RCTs) was performed to verify the protective effect of NO donors on endothelium in IR injury. Methods Medline, Embase, Cochrane Library, and Web of Science databases were searched from inception to April 1, 2023. The specific inclusion criteria were as follows: (1) RCTs; (2) trials comparing NO donors with placebo control groups; and (3) trials reporting the effects of these interventions on vascular endothelial functional outcomes in IR injury. Random-effects models were used to assess pooled effect sizes, which were expressed as standardized mean differences (SMD). Results Seven studies satisfied the inclusion criteria and consisted of a total of 149 participants. NO donors were protective of endothelial function in IR injury (SMD: − 1.60; 95% confidence interval [CI]: − 2.33, − 0.88, P

Abstract Background Removal of tonsils and adenoids is among the most common surgical procedures worldwide. Evidence of increased risk of cancer following such surgery is, however, inconclusive. Methods We conducted a population-based, sibling-controlled cohort study of 4,953,583 individuals in Sweden with a follow-up during 1980–2016. History of tonsillectomy, adenotonsillectomy, and adenoidectomy was identified from the Swedish Patient Register whereas incident cases of cancer during follow-up were identified from the Swedish Cancer Register. We used Cox models to calculate hazard ratios (HR) with 95% confidence intervals (CI) of cancer in both a population and a sibling comparison. The sibling comparison was used to assess the potential impact of familial confounding, due to shared genetic or non-genetic factors within a family. Results We found a modestly increased risk for any cancer following tonsillectomy, adenoidectomy, or adenotonsillectomy in both the population (HR 1.10; 95%CI 1.07–1.12) and sibling (HR 1.15; 95%CI 1.10–1.20) comparisons. The association did not differ greatly by type of surgery, age at surgery, or potential indication for surgery, and persisted more than two decades after surgery. An excess risk was consistently observed for cancer of the breast, prostate, thyroid, and for lymphoma in both population and sibling comparisons. A positive association was observed for pancreatic cancer, kidney cancer, and leukemia in the population comparison whereas a positive association was observed for esophageal cancer in the sibling comparison. Conclusions Surgical removal of tonsils and adenoids is associated with a modestly increased risk of cancer during the decades following the surgery. The association is unlikely attributed to confounding due to shared genetic or non-genetic factors with a family.

Abstract Germ cell tumors (GCTs) are neoplasms of the testis, ovary and extragonadal sites that occur in infants, children, adolescents and adults. Post-pubertal (type II) malignant GCTs may present as seminoma, non-seminoma or mixed histologies. In contrast, pre-pubertal (type I) GCTs are limited to (benign) teratoma and (malignant) yolk sac tumor (YST). Epidemiologic and molecular data have shown that pre- and post-pubertal GCTs arise by distinct mechanisms. Dedicated studies of the genomic landscape of type I and II GCT in children and adolescents are lacking. Here we present an integrated genomic analysis of extracranial GCTs across the age spectrum from 0–24 years. Activation of the WNT pathway by somatic mutation, copy-number alteration, and differential promoter methylation is a prominent feature of GCTs in children, adolescents and young adults, and is associated with poor clinical outcomes. Significantly, we find that small molecule WNT inhibitors can suppress GCT cells both in vitro and in vivo. These results highlight the importance of WNT pathway signaling in GCTs across all ages and provide a foundation for future efforts to develop targeted therapies for these cancers.

Abstract Severe COVID-19 is characterized by an increase in the number and changes in the function of innate immune cells including neutrophils. However, it is not known how the metabolome of immune cells changes in patients with COVID-19. To address these questions, we analyzed the metabolome of neutrophils from patients with severe or mild COVID-19 and healthy controls. We identified widespread dysregulation of neutrophil metabolism with disease progression including in amino acid, redox, and central carbon metabolism. Metabolic changes in neutrophils from patients with severe COVID-19 were consistent with reduced activity of the glycolytic enzyme GAPDH. Inhibition of GAPDH blocked glycolysis and promoted pentose phosphate pathway activity but blunted the neutrophil respiratory burst. Inhibition of GAPDH was sufficient to cause neutrophil extracellular trap (NET) formation which required neutrophil elastase activity. GAPDH inhibition increased neutrophil pH, and blocking this increase prevented cell death and NET formation. These findings indicate that neutrophils in severe COVID-19 have an aberrant metabolism which can contribute to their dysfunction. Our work also shows that NET formation, a pathogenic feature of many inflammatory diseases, is actively suppressed in neutrophils by a cell-intrinsic mechanism controlled by GAPDH.

Ovarian cancer is one of the female reproductive system tumors. Chemotherapy is used for advanced ovarian cancer patients; however, drug resistance is a pivotal cause of chemotherapeutic failure. Hence, it is critical to explore the molecular mechanisms of drug resistance of ovarian cancer cells and to ameliorate chemoresistance. Noncoding RNAs (ncRNAs) have been identified to critically participate in drug sensitivity in a variety of human cancers, including ovarian cancer. Among ncRNAs, circRNAs sponge miRNAs and prevent miRNAs from regulation of their target mRNAs. CircRNAs can interact with DNA or proteins to modulate gene expression. In this review, we briefly describe the biological functions of circRNAs in the development and progression of ovarian cancer. Moreover, we discuss the underneath regulatory molecular mechanisms of circRNAs on governing drug resistance in ovarian cancer. Furthermore, we mention the novel strategies to overcome drug resistance via targeting circRNAs in ovarian cancer. Due to that circRNAs play a key role in modulation of drug resistance in ovarian cancer, targeting circRNAs could be a novel approach for attenuation of chemoresistance in ovarian cancer.

Buckwheat is considered as a healthy cereal food, and it is essential to cultivate new buckwheat lines with good starch physicochemical properties for both consumers and food producers. Six novel buckwheat (Duoku, Dk) were generated by crossing of Golden buckwheat and Tatary buckwheat, and their kernel appearance properties and starch physicochemical properties were analyzed together with one domestic line (Cimiqiao) and one wild line (Yeku). The results showed that Dk samples had better appearance properties than two control samples. The Dk samples showed lower amylose content, similar amylopectin molecular structure and chain length distributions, and larger starch granules compared with Cimiqiao. The digestion results showed that two Dk samples: Dk6 & Dk9 had high resistant starch content; while the other two Dk samples: Dk37 & Dk38 had a steady glucose releasing rate. The Dk samples also showed high gelatinization temperature, indicating they were good raw materials for producing glass noodle. This study proved that Dk buckwheat had unique starch physicochemical properties, and could be used as new food materials in the future.

Objective: Sialic acid is a terminal monosaccharide of glycans in glycoproteins and glycolipids, and its derivation from glucose is regulated by the rate-limiting enzyme UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE). Although the glycans on key endogenous hepatic proteins governing glucose metabolism are sialylated, how sialic acid synthesis and sialylation in the liver influence glucose homeostasis is unknown. Studies were designed to fill this knowledge gap. Methods: To decrease the production of sialic acid and sialylation in hepatocytes, a hepatocyte-specific GNE knockdown mouse model was generated, and systemic glucose metabolism, hepatic insulin signaling and glucagon signaling were evaluated in vivo or in primary hepatocytes. Peripheral insulin sensitivity was also assessed. Furthermore, the mechanisms by which sialylation in the liver influences hepatic insulin signaling and glucagon signaling and peripheral insulin sensitivity were identified. Results: Liver GNE deletion in mice caused an impairment of insulin suppression of hepatic glucose production. This was due to a decrease in the sialylation of hepatic insulin receptors (IR) and a decline in IR abundance due to exaggerated degradation through the Eph receptor B4. Hepatic GNE deficiency also caused a blunting of hepatic glucagon receptor (GCGR) function which was related to a decline in its sialylation and affinity for glucagon. An accompanying upregulation of hepatic FGF21 production caused an enhancement of skeletal muscle glucose disposal that led to an overall increase in glucose tolerance and insulin sensitivity. Conclusion: These collective observations reveal that hepatic sialic acid synthesis and sialylation modulate glucose homeostasis in both the liver and skeletal muscle. By interrogating how hepatic sialic acid synthesis influences glucose control mechanisms in the liver, a new metabolic cycle has been identified in which a key constituent of glycans generated from glucose modulates the systemic control of its precursor.

IntroductionSeveral small sample-sized clinical trials have demonstrated a beneficial effect of statin on depressive mood among major depressive disorder (MDD) patients. However, observational studies have showed the increased risk of anxiety/depression with statin treatment. Therefore, we aimed to evaluate the effects of statin on depressive mood and inflammation status among MDD patients.MethodsWe performed an updated meta-analysis RCTs identified in systematic searches of PubMed, Cochrane library, Embase, ClinicalTrials.gov, CNKI, Wan fang, VIP, and SinoMed database (up to August 2023). The primary endpoint was the Hamilton depression rating scale (HDRS). The secondary endpoints were rate of response to treatment, remission rate, levels of C-reactive protein (CRP), cognition and blood lipid. We evaluated the certainty of the evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach.ResultsThe search identified seven RCTs involving 448 patients with a median follow-up of 10.4 weeks (range, 6–12 weeks). Compared with selective serotonin reuptake inhibitors (SSRIs) alone, treatment with statin plus SSRIs was associated with a significantly decreased HDRS [mean difference (MD) = −2.79; 95% confidence interval (CI): −3.83 to −1.76] and C-reactive protein (MD = −0.42 mg/L; 95% CI: −0.53 to −0.12 mg/L), and decreased levels of lipid profiles (P < 0.05). Moreover, statin plus SSRIs was associated with a comparable rate of treatment response [relative risk (RR) = 1.26; 95% CI: 0.98 to 1.62], remission rate (RR = 1.33; 95% CI: 0.89 to 1.99). Meta-regression indicated that the follow-up period was a source of heterogeneity regarding the HDRS (r = 0.302, P = 0.041). The quality of evidence was rated as moderate for HDRS and response rate according to the GRADE.ConclusionStatin could safely and effectively improve the symptoms of depression and inflammation status among MDD patients.Systematic review registrationhttps://inplasy.com/inplasy-2022-3-0016/, identifier INPLASY2022230016.

Summary: Patient-derived xenografts (PDX) remain valuable models for understanding the biology and for developing novel therapeutics. To expand current PDX models of childhood leukemia, we have developed new PDX models from Hispanic patients, a subgroup with a poorer overall outcome. Of 117 primary leukemia samples obtained, successful engraftment and serial passage in mice were achieved in 82 samples (70%). Hispanic patient samples engrafted at a rate (51/73, 70%) that was similar to non-Hispanic patient samples (31/45, 70%). With a new algorithm to remove mouse contamination in multi-omics datasets including methylation data, we found PDX models faithfully reflected somatic mutations, copy-number alterations, RNA expression, gene fusions, whole-genome methylation patterns, and immunophenotypes found in primary tumor (PT) samples in the first 50 reported here. This cohort of characterized PDX childhood leukemias represents a valuable resource in that germline DNA sequencing has allowed the unambiguous determination of somatic mutations in both PT and PDX.