Identification of crosstalk genes relating to ECM-receptor interaction genes in MASH and DN using bioinformatics and machine learning.

This study aimed to identify genes shared by metabolic dysfunction-associated fatty liver disease (MASH) and diabetic nephropathy (DN) and the effect of extracellular matrix (ECM) receptor interaction genes on them. Datasets with MASH and DN were downloaded from the Gene Expression Omnibus (GEO) database. Pearson's coefficients assessed the correlation between ECM-receptor interaction genes and cross talk genes. The coexpression network of co-expression pairs (CP) genes was integrated with its protein-protein interaction (PPI) network, and machine learning was employed to identify essential disease-representing genes. Finally, immuno-penetration analysis was performed on the MASH and DN gene datasets using the CIBERSORT algorithm to evaluate the plausibility of these genes in diseases. We found 19 key CP genes. Fos proto-oncogene (FOS), belonging to the IL-17 signalling pathway, showed greater centrality PPI network; Hyaluronan Mediated Motility Receptor (HMMR), belonging to ECM-receptor interaction genes, showed most critical in the co-expression network map of 19 CP genes; Forkhead Box C1 (FOXC1), like FOS, showed a high ability to predict disease in XGBoost analysis. Further immune infiltration showed a clear positive correlation between FOS/FOXC1 and mast cells that secrete IL-17 during inflammation. Combining the results of previous studies, we suggest a FOS/FOXC1/HMMR regulatory axis in MASH and DN may be associated with mast cells in the acting IL-17 signalling pathway. Extracellular HMMR may regulate the IL-17 pathway represented by FOS through the Mitogen-Activated Protein Kinase 1 (ERK) or PI3K-Akt-mTOR pathway. HMMR may serve as a signalling carrier between MASH and DN and could be targeted for therapeutic development.

Primerdiffer: a python command-line module for large-scale primer design in haplotype genotyping.

MOTIVATION: Primer design is a routine practice for modern molecular biology labs. Bioinformatics tools like primer3 and primer-blast have standardized the primer design for a specific region. However, large-scale primer design, especially for genome-wide screening, is still a labor-intensive job for most wet-lab researchers using these pipelines. RESULTS: Here, we present the primerdiffer pipeline, which can be used to batch design primers that differentiate haplotypes on a large scale with precise false priming checking. This command-line interface (CLI) pipeline includes greedy primer search, local and global in silico PCR-based false priming checking, and automated best primer selection. The local CLI application provides flexibility to design primers with the user's own genome sequences and specific parameters. Some species-specific primers designed to genotype the hybrid introgression strains from Caenorhabditis briggsae and Caenorhabditis nigoni have been validated using single-worm PCR. This pipeline provides the first CLI-based large-scale primer design tool to differentiate haplotypes in any targeted region. AVAILABILITY AND IMPLEMENTATION: The open-source python modules are available at github (https://github.com/runsheng/primerdiffer, https://github.com/runsheng/primervcf) and Python package index (https://pypi.org/project/primerdiffer/, https://pypi.org/project/primervcf/).

Germline cancer susceptibility in individuals with melanoma.

BACKGROUND: Prior studies have estimated a small number of individuals with melanoma (2%-2.5%) have germline cancer predisposition, yet a recent twin study suggested melanoma has the highest hereditability among cancers. OBJECTIVE: To determine the incidence of hereditary melanoma and characterize the spectrum of cancer predisposition genes that may increase the risk of melanoma. METHODS: Four hundred individuals with melanoma and personal or family history of cancers underwent germline testing of >80 cancer predisposition genes. Comparative analysis of germline data was performed on 3 additional oncologic and dermatologic data sets. RESULTS: Germline pathogenic/likely pathogenic (P/LP) variants were identified in 15.3% (61) individuals with melanoma. Most variants (41, 67%) involved genes considered unrelated to melanoma (BLM, BRIP1, CHEK2, MLH1, MSH2, PMS2, RAD51C). A third (20, 33%) were in genes previously associated with familial melanoma (BAP1, BRCA2, CDKN2A, MITF, TP53). Nearly half (30, 46.9%) of P/LP variants were in homologous repair deficiency genes. Validation cohorts demonstrated P/LP rates of 10.6% from an unselected oncologic cohort, 15.8% from a selected commercial testing cohort, and 14.5% from a highly selected dermatologic study. LIMITATIONS: Cohorts with varying degrees of selection, some retrospective. CONCLUSION: Germline predisposition in individuals with melanoma is common, with clinically actionable findings diagnosed in 10.6% to 15.8%.

Application of root cause analysis and TEAMSTEPPS post intravesical gas explosion during transurethral resection of the prostate: a rare case report.

BACKGROUND: An intravesical gas explosion is a rare complication of transurethral resection of the prostate (TURP). It was first reported in English literature in 1926, and up to 2022 were only forty-one cases. Injury from an intravesical gas explosion, in the most severe cases appearing as extraperitoneal or intraperitoneal bladder rupture needed emergent repair surgery. CASE PRESENTATION: We present a case of a 75-year-old man who suffered an intravesical gas explosion during TURP. The patient underwent an emergent exploratory laparotomy for bladder repair and was transferred to the intensive care unit for further observation and treatment. Under the medical team's care for up to sixty days, the patient recovered smoothly without clinical sequelae. CONCLUSIONS: This case report presents an example of a rare complication of intravesical gas explosion during TURP, utilizing root cause analysis (RCA) to comprehend causal relationships and team strategies and tools to improve performance and patient safety (TeamSTEPPS) method delivers four teamwork skills that can be utilized during surgery and five recommendations to avoid gas explosions during TURP to prevent the recurrence of medical errors. In modern healthcare systems, promoting patient safety is crucial. Once complications appear, RCA and TeamSTEPPS are helpful means to support the healthcare team reflect and improve as a team.

Lag effect of ambient temperature on respiratory emergency department visits in Beijing: a time series and pooled analysis.

BACKGROUND: Although the association between ambient temperature and mortality of respiratory diseases was numerously documented, the association between various ambient temperature levels and respiratory emergency department (ED) visits has not been well studied. A recent investigation of the association between respiratory ED visits and various levels of ambient temperature was conducted in Beijing, China. METHODS: Daily meteorological data, air pollution data, and respiratory ED visits data from 2017 to 2018 were collected in Beijing. The relationship between ambient temperature and respiratory ED visits was explored using a distributed lagged nonlinear model (DLNM). Then we performed subgroup analysis based on age and gender. Finally, meta-analysis was utilized to aggregate the total influence of ambient temperature on respiratory ED visits across China. RESULTS: The single-day lag risk for extreme cold peaked at a relative risk (RR) of 1.048 [95% confidence interval (CI): 1.009, 1.088] at a lag of 21 days, with a long lag effect. As for the single-day lag risk for extreme hot, a short lag effect was shown at a lag of 7 days with an RR of 1.076 (95% CI: 1.038, 1.114). The cumulative lagged effects of both hot and cold effects peaked at lag 0-21 days, with a cumulative risk of the onset of 3.690 (95% CI: 2.133, 6.382) and 1.641 (95% CI: 1.284, 2.098), respectively, with stronger impact on the hot. Additionally, the elderly were more sensitive to ambient temperature. The males were more susceptible to hot weather than the females. A longer cold temperature lag effect was found in females. Compared with the meta-analysis, a pooled effect of ambient temperature was consistent in general. In the subgroup analysis, a significant difference was found by gender. CONCLUSIONS: Temperature level, age-specific, and gender-specific effects between ambient temperature and the number of ED visits provide information on early warning measures for the prevention and control of respiratory diseases.

Aquaporin ZmTIP2;3 Promotes Drought Resistance of Maize through Symbiosis with Arbuscular Mycorrhizal Fungi.

Arbuscular mycorrhizal fungi symbiosis plays important roles in enhancing plant tolerance to biotic and abiotic stresses. Aquaporins have also been linked to improved drought tolerance in plants and the regulation of water transport. However, the mechanisms that underlie this association remain to be further explored. In this study, we found that arbuscular mycorrhiza fungi symbiosis could induce the gene expression of the aquaporin ZmTIP2;3 in maize roots. Moreover, compared with the wild-type plants, the maize zmtip2;3 mutant also showed a lower total biomass, colonization rate, relative water content, and POD and SOD activities after arbuscular mycorrhiza fungi symbiosis under drought stress. qRT-PCR assays revealed reduced expression levels of stress genes including LEA3, P5CS4, and NECD1 in the maize zmtip2;3 mutant. Taken together, these data suggest that ZmTIP2;3 plays an important role in promoting maize tolerance to drought stress during arbuscular mycorrhiza fungi symbiosis.

Germline EGFR variants are over-represented in adolescents and young adults (AYA) with adrenocortical carcinoma.

Adrenocortical Carcinoma (ACC) is a rare endocrine tumor with poor overall prognosis and 1.5-fold overrepresentation in females. In children, ACC is associated with inherited cancer syndromes with 50-80% of childhood-ACC associated with TP53 germline variants. ACC in adolescents and young adults (AYA) is rarely due to germline TP53, IGF2, PRKAR1A and MEN1 variants. We analyzed exome sequencing data from 21 children (<15y), 32 AYA (15-39y), and 60 adults (>39y) with ACC, and retained all pathogenic, likely pathogenic, and highly prioritized variants of uncertain significance. We engineered a stable lentiviral-mutant ACC cell line, harboring an EGFR variant (p.Asp1080Asn) from a 21-year-old female without germline-TP53-variant and with aggressive ACC. We found that 4.8% of the children (P = 0.004) and 6.2% of AYA (P < 0.0001), all-female participants, harbored germline EGFR variants, compared to only 0.3% of the control group. Expanding our analysis to the RTK-RAS-MAPK pathway, we found that the RTK genes have the highest number of highly prioritized germline variants in these individuals amongst all three arms of this pathway. We showed EGFR mutant cells migrate faster and are characterized by a stem-like phenotype compared to wild type cells. While EGFR inhibitors did not affect the stemness of mutant cells, Sunitinib, a multireceptor tyrosine kinase inhibitor, significantly reduced their stem-like behavior. Our data suggest that EGFR could be a novel underlying germline predisposition factor for ACC, especially in the Childhood-AYA (C-AYA) population. Further clinical validation can improve precision oncology management of this disease, which is known to have limited therapeutic options.

WWP1 Gain-of-Function Inactivation of PTEN in Cancer Predisposition.

BACKGROUND: Patients with PTEN hamartoma tumor syndrome (PHTS) have germline mutations in the tumor-suppressor gene encoding phosphatase and tensin homologue (PTEN). Such mutations have been associated with a hereditary predisposition to multiple types of cancer, including the Cowden syndrome. However, a majority of patients who have PHTS-related phenotypes have tested negative for PTEN mutations. In a previous study, we found that the E3 ubiquitin ligase WWP1 negatively regulates the function of PTEN. METHODS: In a prospective cohort study conducted from 2005 through 2015, we enrolled 431 patients with wild-type PTEN who met at least the relaxed diagnostic criteria of the International Cowden Consortium. Patients were scanned for WWP1 germline variants. We used the Cancer Genome Atlas (TCGA) data set as representative of apparently sporadic cancers and the Exome Aggregation Consortium data set excluding TCGA (non-TCGA ExAC) and the noncancer Genome Aggregation Database (gnomAD) as representative of population controls without a reported cancer diagnosis. We established both in vitro and murine in vivo models to functionally characterize representative WWP1 variants. RESULTS: The existence of germline WWP1 variants was first established in a family with wild-type PTEN who had oligopolyposis and early-onset colon cancers. A validation series indicated that WWP1 germline variants occurred in 5 of 126 unrelated patients (4%) with oligopolyposis as a predominant phenotype. Germline WWP1 variants, particularly the WWP1 K740N and N745S alleles, were enriched in patients who did not have PHTS but had prevalent sporadic cancers, including PTEN-related cancer types in TCGA (odds ratio, 1.5; 95% confidence interval, 1.1 to 2.1; P = 0.01). The prioritized WWP1 variants resulted in gain-of-function effects, which led to aberrant enzymatic activation with consequent PTEN inactivation, thereby triggering hyperactive growth-promoting PI3K signaling in cellular and murine models. CONCLUSIONS: In this study involving patients with disorders resulting in a predisposition to the development of multiple malignant neoplasms without PTEN germline mutations, we confirmed the function of WWP1 as a cancer-susceptibility gene through direct aberrant regulation of the PTEN-PI3K signaling axis. (Funded by the National Institutes of Health and others.).

Genomic Predictors Associated With Exceptional Response to Systemic Therapy in Advanced Pancreatic Cancer.

INTRODUCTION: Exceptional response to therapy is rare in patients with advanced pancreatic cancer. This study explored potential genomic differences between typical and exceptional responses that could confer more favorable biology. METHODS: We included exceptional responders and controls with advanced pancreatic cancer from Cleveland Clinic from April 2013 to August 2017. Exceptional responders were defined as patients with an overall survival of more than 18 months for metastatic disease and more than 24 months for locally advanced disease. Clinical data were obtained, and next-generation sequencing was performed. Statistical analyses comparing the 2 groups were performed using descriptive statistics, the Kaplan-Meier method, and the log-rank test. RESULTS: The study comprised 4 exceptional responders and 6 controls. Both groups were well balanced in age, sex, race, and treatment regimens. Exceptional responders had significantly fewer nonsynonymous mutations than controls (2.25 vs 5.17; P = .014). A mutation count of less than 3 was associated with significantly better progression-free survival (17.2 vs 2.3 months; P = .002) and overall survival (29.4 vs 4.6 months; P = .013). Tumor mutational burden did not differ between exceptional responders and controls (4.88 vs 5.70 mut/Mb; P = .39). CONCLUSION: A lower number of nonsynonymous mutations may correlate with exceptional outcomes in patients with pancreatic cancer. These findings should encourage future studies into genomic signatures of exceptional response.

Hair embedding after transperineal prostate biopsy: two case reports.

BACKGROUND: Transperineal prostate biopsy is gradually becoming the standard methodology for diagnosing prostate cancer because of its high accuracy and low risk of infection, but careful preparation is not always highlighted before a transperineal biopsy. we reported two cases of hair embedding during transurethral resection of the prostate following transperineal puncture biopsy with a Bard MC1820 disposable biopsy needle. Histological examination did not find the hair follicle structure required for hair growth. The hair source was suspected to be percutaneously brought in by needle during the biopsya simulated experiment was used to analyze and reconstruct the process of hair embedding in prostate tissue. CONCLUSION: Hair embedding caused by perineal prostate biopsy is a consumable-related adverse event, and skin preparation before a transperineal prostate biopsy is recommended.

Genome-Wide Identification of BES1 Gene Family in Six Cucurbitaceae Species and Its Expression Analysis in Cucurbita moschata.

The BES1 (BRI1-EMSSUPPRESSOR1) gene family play a vital role in the BR (brassinosteroid) signaling pathway, which is involved in the growth and development, biotic, abiotic, and hormone stress response in many plants. However, there are few reports of BES1 in Cucurbita moschata. In this study, 50 BES1 genes were identified in six Cucurbitaceae species by genome-wide analysis, which could be classified into 3 groups according to their gene structural features and motif compositions, and 13 CmoBES1 genes in Cucurbita moschata were mapped on 10 chromosomes. Quantitative real-time PCR analysis showed that the CmoBES1 genes displayed differential expression under different abiotic stress and hormone treatments. Subcellular localization showed that the most of CmoBES1 proteins localized in nucleus and cytoplasm, and transactivation assay indicated 9 CmoBES1 proteins played roles as transcription factors. Our analysis of BES1s diversity, localization, and expression in Curcubitaceae contributes to the better understanding of the essential roles of these transcription factors in plants.

TMT-Based Comparative Peptidomics Analysis of Rice Seedlings under Salt Stress: An Accessible Method to Explore Plant Stress-Tolerance Processing.

Rice (Oryza sativa L.) is an important staple crop, particularly in Asia, and abiotic stress conditions easily reduce its yields. Salt stress is one of the critical factors affecting rice growth and yield. In this study, a tandem mass tag (TMT)-based comparative peptidomics analysis of rice seedlings under salt stress was conducted. Rice seedlings were exposed to 50 and 150 mM NaCl for 24 and 72 h, respectively, and the root and shoot tissues of different treatment groups were collected separately for peptidomics analysis. A total of 911 and 1263 nonredundant peptides were identified in two pooled shoot tissue samples, while there were 770 and 672 nonredundant peptides in two pooled root tissue samples, respectively. Compared with the control groups, dozens to hundreds of differentially expressed peptides (DEPs) were characterized in all treatment groups. To explore the potential functions of these DEPs, we analyzed the basic characteristics of DEPs and further analyzed the annotated Gene Ontology terms according to their precursor proteins. Several DEP precursor proteins were closely related to the response to salt stress, and some were derived from the functional domains of their corresponding precursors. The germination rate and cotyledon greening rate of transgenic Arabidopsis expressing two DEPs, OsSTPE2 and OsSTPE3, were significantly enhanced under salt stress. The described workflow enables the discovery of a functional pipeline for the characterization of the plant peptidome and reveals two new plant peptides that confer salinity tolerance to plants. Data are available via ProteomeXchange with identifier PXD037574.

Distinct Alterations in Tricarboxylic Acid Cycle Metabolites Associate with Cancer and Autism Phenotypes in Cowden Syndrome and Bannayan-Riley-Ruvalcaba Syndrome.

Germline heterozygous PTEN mutations cause subsets of Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRRS); these subsets are characterized by high risks of breast, thyroid, and other cancers and, in one subset, autism spectrum disorder (ASD). Up to 10% of individuals with PTENMUT CS, CS-like syndrome, or BRRS have germline SDHx (succinate dehydrogenase, mitochondrial complex II) variants, which modify cancer risk. PTEN contributes to metabolic reprogramming; this is a well-established role in a cancer context. Relatedly, SDH sits at the crossroad of the electron transport chain and tricarboxylic acid (TCA) cycle, two central bioenergetic pathways. Intriguingly, PTENMUT and SDHMUT individuals have reduced SDH catalytic activity, resulting in succinate accumulation; this indicates a common genotype-independent biochemical alteration. Here, we conducted a TCA targeted metabolomics study on 511 individuals with CS, CS-like syndrome, or BRRS with various genotypes (PTEN or SDHx, mutant or wild type [WT]) and phenotypes (cancer or ASD) and a series of 187 population controls. We found consistent TCA cycle metabolite alterations in cases with various genotypes and phenotypes compared to controls, and we found unique correlations of individual metabolites with particular genotype-phenotype combinations. Notably, increased isocitrate (p = 1.2 × 10-3), but reduced citrate (p = 5.0 × 10-4), were found to be associated with breast cancer in individuals with PTENMUT/SDHxWT. Conversely, increased lactate was associated with neurodevelopmental disorders regardless of genotype (p = 9.7 × 10-3); this finding was replicated in an independent validation series (n = 171) enriched for idiopathic ASD (PTENWT, p = 5.6 × 10-4). Importantly, we identified fumarate (p = 1.9 × 10-2) as a pertinent metabolite, distinguishing individuals who develop ASD from those who develop cancer. Our observations suggest that TCA cycle metabolite alterations are germane to the pathobiology of PTEN-related CS and BRRS, as well as genotype-independent ASD, with implications for potential biomarker and/or therapeutic value.

The analysis of fertility quality of life and the influencing factors of patients with repeated implantation failure.

BACKGROUND: The objective of this study was to investigate the current status of fertility quality of life (QoL) and explore the influencing factors for infertile women with repeated implantation failure (RIF). METHODS: The sample consisted of 137 infertile women with RIF who were under treatment from January 2019 to December 2019 in the Reproductive Medical Center of Ruijin Hospital, affiliated with Shanghai Jiaotong University School of Medicine in China. A general information questionnaire, FertiQoL scale, perceived social support scale (PSSS), self-rating anxiety scale (SAS), and self-rating depression scale (SDS) were used to analyse the fertility QoL and related factors of RIF patients. RESULTS: The total fertility QoL score of RIF patients was 60.44 ± 11.60. The results of multivariate regression analysis showed that residence, financial difficulties, male infertility, BMI index, depression, and family social support were the main factors that influenced the fertility QoL of RIF patients (adjusted R2 = 0.762). CONCLUSION: Based on the results of this study, RIF patients' psychological status must be addressed. Corresponding interventions such as building a sound family and social support system, creating a good medical environment and offering diverse health education should be provided to improve the fertility QoL of RIF patients.

Unexpected cancer-predisposition gene variants in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome patients without underlying germline PTEN mutations.

Patients with heritable cancer syndromes characterized by germline PTEN mutations (termed PTEN hamartoma tumor syndrome, PHTS) benefit from PTEN-enabled cancer risk assessment and clinical management. PTEN-wildtype patients (~50%) remain at increased risk of developing certain cancers. Existence of germline mutations in other known cancer susceptibility genes has not been explored in these patients, with implications for different medical management. We conducted a 4-year multicenter prospective study of incident patients with features of Cowden/Cowden-like (CS/CS-like) and Bannayan-Riley-Ruvalcaba syndromes (BRRS) without PTEN mutations. Exome sequencing and targeted analysis were performed including 59 clinically actionable genes from the American College of Medical Genetics and Genomics (ACMG) and 24 additional genes associated with inherited cancer syndromes. Pathogenic or likely pathogenic cancer susceptibility gene alterations were found in 7 of the 87 (8%) CS/CS-like and BRRS patients and included MUTYH, RET, TSC2, BRCA1, BRCA2, ERCC2 and HRAS. We found classic phenotypes associated with the identified genes in 5 of the 7 (71.4%) patients. Variant positive patients were enriched for the presence of second malignant neoplasms compared to patients without identified variants (OR = 6.101, 95% CI 1.143-35.98, p = 0.035). Germline variant spectrum and frequencies were compared to The Cancer Genome Atlas (TCGA), including 6 apparently sporadic cancers associated with PHTS. With comparable overall prevalence of germline variants, the spectrum of mutated genes was different in our patients compared to TCGA. Intriguingly, we also found notable enrichment of variants of uncertain significance (VUS) in our patients (OR = 2.3, 95% CI 1.5-3.5, p = 0.0002). Our data suggest that only a small subset of PTEN-wildtype CS/CS-like and BRRS patients could be accounted for by germline variants in some of the known cancer-related genes. Thus, the existence of alterations in other and more likely non-classic cancer-associated genes is plausible, reflecting the complexity of these heterogeneous hereditary cancer syndromes.

Analysis of the levels of hope and influencing factors in infertile women with first-time and repeated IVF-ET cycles.

PURPOSE: To explore the hope levels and influencing factors in infertile women undergoing first-time and repeated in vitro fertilization-embryo transfer (IVF-ET) cycles. METHODS: This study was a cross-sectional and convenient sampling study conducted among patients undergoing IVF-ET from January to June 2019. Patients were divided into first-time and repeated groups by the number of IVF-ET cycles, and then a questionnaire survey was administered. The questionnaire included demographic information, Herth hope index (HHI) scale, Locke-Wallace short marital-adjustment test scale and social support rating scale. Multiple linear regression was used to analyse the influencing factors associated with hope levels. RESULTS: A total of 298 IVF-ET patients were recruited for the study, including 150 (50.3%) in the first-time cycle group and 148 (49.7%) in the repeated cycle group. The HHI score of the repeated cycle group was significantly lower than that of the first-time cycle group (34.4 ± 3.5 vs. 37.5 ± 3.7, P < 0.001). Multiple linear regression analysis indicated that repeated IVF-ET and age were independently negatively correlated with HHI, with standardized coefficient ß values of - 0.895 and - 0.223, respectively (both P < 0.001). High education level (P = 0.002), high monthly income (P = 0.020), high degree of short marital-adjustment test (P < 0.001) and social support rating (P < 0.001) were independently positively correlated with HHI. CONCLUSION: Infertile women undergoing repeated IVF-ET have low hope levels. Maintaining a good marriage adjustment and establishing a good social support and relationship network could effectively improve their hope levels.

Hope level is closely related to patients' mental health and emotional state. Therefore, improving the hope level of infertile women with IVF-ET could contribute to relieving the psychological pressure of patients and improving the success rate of pregnancy. This study aimed to evaluate the hope level of infertile women with different IVF-ET cycles and analyse its influencing factors to provide guidance for clinical nurses to clarify the intervention objects, select reasonable intervention measures and improve the hope levels of patients. A total of 298 IVF-ET patients were recruited in the study, including 150 in the first-time cycle group and 148 in the repeated cycle group. The results showed that the hope level of patients with repeated IVF-ET cycles was significantly lower than that of patients undergoing first-time treatment. We also analysed its influencing factors and found that repeated IVF-ET cycles and age were independent negative correlation factors in hope levels. High monthly income, living in the city, high marital adjustment and social support score were independent positive correlation factors in hope levels. Therefore, maintaining a good marriage adjustment and establishing a good social support and relationship network could effectively improve their hope levels.

Multifunctional osthole liposomes and brain targeting functionality with potential applications in a mouse model of Alzheimer's disease.

Osthole (Ost) is a coumarin compound and a potential drug for Alzheimer's disease (AD). However, the effectiveness of Ost is limited by solubility, bioavailability, and low permeability of the blood-brain barrier. In this study, we constructed Ost liposomes with modified CXCR4 on the surface (CXCR4-Ost-Lips), and investigated the intracellular distribution of liposomes in APP-SH-SY5Y cells. In addition, the neuroprotective effect of CXCR4-Ost-Lips was examined in vitro and in vivo. The results showed that CXCR4-Ost-Lips increased intracellular uptake by APP-SH-SY5Y cells and exerted a cytoprotective effect in vitro. The results of Ost brain distribution showed that CXCR4-Ost-Lips prolonged the cycle time of mice and increased the accumulation of Ost in the brain. In addition, CXCR4-Ost-Lips enhanced the effect of Ost in relieving AD-related pathologies. These results indicate that CXCR4-modified liposomes are a potential Ost carrier to treat AD.

In vivo and in vitro studies of Danzhi Jiangtang capsules against diabetic cardiomyopathy via TLR4/MyD88/NF-κB signaling pathway.

OBJECTIVES: Danzhi Jiangtang capsule (DJC) is widely used for preventing and treating diabetic cardiomyopathy (DCM). However, the underlying mechanisms of the anti-inflammatory and antiapoptotic activities are unclear. METHODS: In the in vivo diabetic cardiomyopathy rat model, cardiac function was measured through echocardiography, histological changes in the myocardium were visualized using HE staining, and cardiomyocyte apoptosis was detected using TUNEL. The serum levels of anti-inflammatory cytokines were detected using ELISA. Finally, TLR4, MyD88, and NF-κB mRNA expressions were analyzed using RT-qPCR. In the in vitro experiments, the apoptosis rate of the H9c2 cells was detected using FCM; moreover, TLR4, MyD88 and NF-κB mRNA expressions were measured using RT-qPCR and related protein levels were investigated using Western blotting. RESULTS: In vivo, DJC effectively improved cardiac function, alleviated the pathological changes, and reduced the apoptosis rate. Moreover, DJC reduced TNF-α, IL-1ß, and IL-6 activities, with significant inhibition of the TLR4, MyD88 and NF-κB p65 mRNA expression. Moreover, in vitro, DJC effectively inhibited high-glucose-induced H9c2 apoptosis-an effect similar to that for TAK242. Finally, both the DJC and TAK242 considerably reduced TLR4, MyD88, NF-κB, Bax, and caspase-3 protein expression but increased that of BCL-2. CONCLUSIONS: DJC prevented the overactivation of the TLR4/MyD88/NF-κB signaling pathway and regulate cardiomyocyte apoptosis against DCM.

[Clinical effect of multi-oil fat emulsion for parenteral nutrition support in extremely low birth weight infants].

OBJECTIVE: To study the clinical effect of multi-oil fat emulsion for parenteral nutrition support in extremely low birth weight (ELBW) infants. METHODS: A retrospective analysis was performed for 49 ELBW infants who were admitted from January 1, 2018 to July 30, 2020, with an age of ≤14 days on admission and a duration of parenteral nutrition of > 14 days. According to the type of lipid emulsion received, the ELBW infants were divided into two groups: soybean oil, medium-chain triglycerides, olive oil, and fish oil (SMOF) (n=26) and medium-chain triglycerides/long-chain triglycerides (MCT/LCT) (n=23). The two groups were compared in terms of clinical features, complications, nutrition support therapy, and outcome. RESULTS: The 49 ELBW infants had a mean birth weight of (892±83) g and a mean gestational age of (28.2±2.3) weeks. There was no significant difference between the two groups in the incidence rates of hemodynamically significant patent ductus arteriosus, intraventricular hemorrhage, neonatal necrotizing enterocolitis, retinopathy of prematurity, bronchopulmonary dysplasia (BPD), grade Ⅲ BPD, sepsis, and pneumonia (P > 0.05). There was also no significant difference in the duration of parenteral nutrition, the age of total enteral nutrition, and head circumference/body length/body weight at discharge between the two groups (P > 0.05). Of all the infants, 22 (45%) had parenteral nutrition-associated cholestasis (PNAC), with 13 (50%) in the SMOF group and 9 (39%) in the MCT/LCT group but there was no significant difference in the incidence of PNAC between the two groups (P > 0.05); however, the infants with PNAC in the SMOF group had significantly lower peak values of direct bilirubin and alanine aminotransferase than those in the MCT/LCT group (P < 0.05). CONCLUSIONS: The application of multi-oil fat emulsion in ELBW infants does not reduce the incidence rate of complications, but compared with MCT/LCT emulsion, SMOF can reduce the severity of PNAC in ELBW infants.

Global analysis of histone modifications and long-range chromatin interactions revealed the differential cistrome changes and novel transcriptional players in human dilated cardiomyopathy.

BACKGROUND: Acetylation and methylation of histones alter the chromatin structure and accessibility that affect transcriptional regulators binding to enhancers and promoters. The binding of transcriptional regulators enables the interaction between enhancers and promoters, thus affecting gene expression. However, our knowledge of these epigenetic alternations in patients with heart failure remains limited. METHODS AND RESULTS: From the comprehensive analysis of major histone modifications, 3-dimensional chromatin interactions, and transcriptome in left ventricular (LV) tissues from dilated cardiomyopathy (DCM) patients and non-heart failure (NF) donors, differential active enhancer and promoter regions were identified between NF and DCM. Moreover, the genome-wide average promoter signal is significantly lower in DCM than in NF. Super-enhancer (SE) analysis revealed that fewer SEs were found in DCM LVs than in NF ones, and three unique SE-associated genes between NF and DCM were identified. Moreover, SEs are enriched within the genomic region associated with long-range chromatin interactions. The differential enhancer-promoter interactions were observed in the known heart failure gene loci and are correlated with the gene expression levels. Motif analysis identified known cardiac factors and possible novel players for DCM. CONCLUSIONS: We have established the cistrome of four histone modifications and chromatin interactome for enhancers and promoters in NF and DCM tissues. Differential histone modifications and enhancer-promoter interactions were found in DCM, which were associated with gene expression levels of a subset of disease-associated genes in human heart failure.