Structure-based design of non-hypertrophic apelin receptor modulator.

Apelin is a key hormone in cardiovascular homeostasis that activates the apelin receptor (APLNR), which is regarded as a promising therapeutic target for cardiovascular disease. However, adverse effects through the ß-arrestin pathway limit its pharmacological use. Here, we report cryoelectron microscopy (cryo-EM) structures of APLNR-Gi1 complexes bound to three agonists with divergent signaling profiles. Combined with functional assays, we have identified "twin hotspots" in APLNR as key determinants for signaling bias, guiding the rational design of two exclusive G-protein-biased agonists WN353 and WN561. Cryo-EM structures of WN353- and WN561-stimulated APLNR-G protein complexes further confirm that the designed ligands adopt the desired poses. Pathophysiological experiments have provided evidence that WN561 demonstrates superior therapeutic effects against cardiac hypertrophy and reduced adverse effects compared with the established APLNR agonists. In summary, our designed APLNR modulator may facilitate the development of next-generation cardiovascular medications.

Snapshot of the cannabinoid receptor 1-arrestin complex unravels the biased signaling mechanism.

Cannabis activates the cannabinoid receptor 1 (CB1), which elicits analgesic and emotion regulation benefits, along with adverse effects, via Gi and ß-arrestin signaling pathways. However, the lack of understanding of the mechanism of ß-arrestin-1 (ßarr1) coupling and signaling bias has hindered drug development targeting CB1. Here, we present the high-resolution cryo-electron microscopy structure of CB1-ßarr1 complex bound to the synthetic cannabinoid MDMB-Fubinaca (FUB), revealing notable differences in the transducer pocket and ligand-binding site compared with the Gi protein complex. ßarr1 occupies a wider transducer pocket promoting substantial outward movement of the TM6 and distinctive twin toggle switch rearrangements, whereas FUB adopts a different pose, inserting more deeply than the Gi-coupled state, suggesting the allosteric correlation between the orthosteric binding pocket and the partner protein site. Taken together, our findings unravel the molecular mechanism of signaling bias toward CB1, facilitating the development of CB1 agonists.

Forte: A suite of advanced multireference quantum chemistry methods.

Forte is an open-source library specialized in multireference electronic structure theories for molecular systems and the rapid prototyping of new methods. This paper gives an overview of the capabilities of Forte, its software architecture, and examples of applications enabled by the methods it implements.

Mutagenesis of Odorant Receptor Coreceptor Orco Reveals the Odorant-Detected Behavior of the Predator Eupeodes corollae.

The successful mating of the hoverfly and the search for prey aphids are of great significance for biological control and are usually mediated by chemical cues. The odorant receptor co-receptor (Orco) genes play a crucial role in the process of insect odor perception. However, the function of Orco in the mating and prey-seeking behaviors of the hoverfly remains relatively unexplored. In this study, we characterized the Orco gene from the hoverfly, Eupeodes corollae, a natural enemy insect. We used the CRISPR/Cas9 technique to knock out the Orco gene of E. corollae, and the EcorOrco-/- homozygous mutant was verified by the genotype analysis. Fluorescence in situ hybridization showed that the antennal ORN of EcorOrco-/- mutant lack Orco staining. Electroantennogram (EAG) results showed that the adult mutant almost lost the electrophysiological response to 15 odorants from three types. The two-way choice assay and the glass Y-tube olfactometer indicated that both the larvae and adults of hoverflies lost their behavioral preference to the aphid alarm pheromone (E)-ß-farnesene (EBF). In addition, the mating assay results showed a significant decrease in the mating rate of males following the knock out of the EcorOrco gene. Although the mating of females was not affected, the amount of eggs being laid and the hatching rate of the eggs were significantly reduced. These results indicated that the EcorOrco gene was not only involved in the detection of semiochemicals in hoverflies but also plays a pivotal role in the development of eggs. In conclusion, our results expand the comprehension of the chemoreceptive mechanisms in the hoverflies and offers valuable insights for the advancement of more sophisticated pest management strategies.

Effects of prenatal artificial sweeteners consumption on birth outcomes: a systematic review and meta-analysis.

OBJECTIVE: To examine the influence of prenatal artificial sweetener (AS) consumption on birth outcomes. DESIGN: Systematic review and meta-analysis. SETTING: Online databases (Medline, CINAHL, Embase, Cochrane Library, Scopus, Web of Science, FSTA - the food resource database, and ClinicalTrials.gov) were searched up to 9 April 2020. Studies of all designs (except case studies and reviews) were eligible, which contained information on the relevant population (pregnant women), intervention/exposure (any AS consumption), comparator (no AS consumption) and birth outcomes (preterm delivery, gestational age, birth weight). RESULTS: From 677 citations, ten cohort studies and one randomised controlled trial (n 138 007 women) were included. 'Low' to 'very low' certainty evidence revealed that daily consumption of AS was associated with an increased risk of preterm delivery (three studies, n 129 009; risk ratio = 1·18, 95 % CI 1·09, 1·28, I2 = 9 %), a 24 g increase in birth weight (three studies, n 64 417; mean difference (MD): 23·74 g, 95 % CI 0·89, 45·58, I2 = 0 %) and a 0·11 week decrease in gestational age (three studies, n 64 417; MD: -0·11 weeks, 95 % CI -0·19, -0·03, I2 = 0 %). CONCLUSIONS: 'Low' to 'very low' certainty evidence suggests daily AS consumption during pregnancy is associated with an increased risk of preterm delivery, increased birth weight and decreased gestational age. Additional 'high'-quality research is urgently needed to further assess these relationships.PROSPERO registration number: CRD42019136728.

The impact of occupational activities during pregnancy on pregnancy outcomes: a systematic review and metaanalysis.

OBJECTIVE: Data: An increasing number of studies suggest that exposure to physically demanding work during pregnancy could be associated with increased risks of adverse pregnancy outcomes, but the results remain conflicted and inconclusive. The purpose of this study was to examine the influence of occupational activities during pregnancy on maternal and fetal health outcomes. STUDY: Studies of all designs (except case studies and reviews) that contained information on the relevant population (women who engaged in paid work during pregnancy), occupational exposures (heavy lifting, prolonged standing, prolonged walking, prolonged bending, and heavy physical workload), comparator (no exposure to the listed physical work demands), and outcomes (preterm birth, low birthweight, small for gestational age, miscarriage, gestational hypertension, preeclampsia, gestational diabetes mellitus, stillbirth, and intrauterine growth restriction) were included. STUDY APPRAISAL AND SYNTHESIS METHODS: Five electronic databases and 3 gray literature sources were searched up to March 15, 2019. RESULTS: Eighty observational studies (N=853,149) were included. Low-to-very low certainty evidence revealed that lifting objects ≥11 kg was associated with an increased odds ratio of miscarriage (odds ratio, 1.31; 95% confidence interval, 1.08-1.58; I2=79%), and preeclampsia (odds ratio, 1.35; 95% confidence interval, 1.07-1.71; I2=0%). Lifting objects for a combined weight of ≥100 kg per day was associated with an increased odds of preterm delivery (odds ratio, 1.31; 95% confidence interval, 1.11-1.56; I2=0%) and having a low birthweight neonate (odds ratio, 2.08; 95% confidence interval, 1.06-4.11; I2=73%). Prolonged standing was associated with increased odds of preterm delivery (odds ratio, 1.11; 95% confidence interval, 1.02-1.22; I2=30%) and having a small-for-gestational-age neonate (odds ratio, 1.17; 95% confidence interval, 1.01-1.35; I2=41%). A heavy physical workload was associated with increased odds of preterm delivery (odds ratio, 1.23; 95% confidence interval, 1.07-1.41; I2=32%) and having a low birthweight neonate (odds ratio, 1.79; 95% confidence interval, 1.11-2.87; I2=87%). All other associations were not statistically significant. Dose-response analysis showed women stand for >2.5 hours per day (vs no standing) had a 10% increase in the odds of having a preterm delivery. CONCLUSION: Physically demanding work during pregnancy is associated with an increased risk of adverse pregnancy outcomes.

The impact of occupational shift work and working hours during pregnancy on health outcomes: a systematic review and meta-analysis.

BACKGROUD: An increasing number of original studies suggest that exposure to shift work and long working hours during pregnancy could be associated with the risk of adverse pregnancy outcomes, but the results remain conflicting and inconclusive. OBJECTIVE: To examine the influences of shift work and longer working hours during pregnancy on maternal and fetal health outcomes. DATA SOURCES: Five electronic databases and 3 gray literature sources were searched up to March 15, 2019. METHODS OF STUDY SELECTION: Studies of all designs (except case studies and reviews) were included, which contained information on the relevant population (women who engaged in paid work during pregnancy); exposure (rotating shift work [shifts change according to a set schedule], fixed night shift [typical working period is between 11:00 pm and 11:00 am] or longer working hours [>40 hours per week]);comparator (fixed day shift [typical working period is between 8:00 am and 6:00 pm] or standard working hours [≤40 hours per week]); and outcomes (preterm delivery, low birthweight [birthweight <2500 g], small for gestational age, miscarriage, gestational hypertension, preeclampsia, intrauterine growth restriction, stillbirth, and gestational diabetes mellitus). TABULATION, INTEGRATION, AND RESULTS: From 3305 unique citations, 62 observational studies (196,989 women) were included. "Low" to "very low" certainty evidence from these studies revealed that working rotating shifts was associated with an increased odds of preterm delivery (odds ratio, 1.13; 95% confidence interval, 1.00-1.28, I2 = 31%), an infant small for gestational age (odds ratio, 1.18, 95% confidence interval, 1.01-1.38, I2 = 0%), preeclampsia (odds ratio, 1.75, 95% confidence interval, 1.01-3.01, I2 = 75%), and gestational hypertension (odds ratio, 1.19, 95% confidence interval, 1.10-1.29, I2 = 0%), compared to those who worked a fixed day shift. Working fixed night shifts was associated with an increased odds of preterm delivery (odds ratio, 1.21; 95% confidence interval, 1.03-1.42; I2 = 36%) and miscarriage (odds ratio, 1.23; 95% confidence interval, 1.03-1.47; I2 = 37%). Compared with standard hours, working longer hours was associated with an increased odds of miscarriage (odds ratio, 1.38; 95% confidence interval, 1.08-1.77; I2 = 73%), preterm delivery (odds ratio, 1.21; 95% confidence interval, 1.11-1.33; I2 = 30%), an infant of low birthweight (odds ratio, 1.43; 95% confidence interval, 1.11-1.84; I2 = 0%), or an infant small for gestational age (odds ratio, 1.16, 95% confidence interval, 1.00-1.36, I2 = 57%). Dose-response analysis showed that women working more than 55.5 hours (vs 40 hours) per week had a 10% increase in the odds of having a preterm delivery. CONCLUSION: Pregnant women who work rotating shifts, fixed night shifts, or longer hours have an increased risk of adverse pregnancy outcomes.

Prenatal Exercise and Pre-gestational Diseases: A Systematic Review and Meta-analysis.

OBJECTIVE: This study sought to examine the effect of prenatal exercise on birth outcomes in women with pre-gestational diseases, including chronic hypertension, type 1 diabetes, and type 2 diabetes. METHODS: A structured search of online databases up to June 8, 2018 was conducted. Studies of all designs and languages were included if they contained information on the population (pregnant women with pre-gestational diseases), intervention (subjective or objective measures of frequency, intensity, duration, volume, or type of exercise), comparator (no exercise or different frequency, intensity, duration, volume, or type of exercise), and outcome (birth weight, macrosomia [birth weight >4000 g], large for gestational age, low birth weight [<2500 g], small for gestational age [<10th percentile], Apgar score, preterm birth [<37 weeks], Caesarean section (CS), preeclampsia, and glycemic control). RESULTS: A total of five studies (n = 221 women) were included. Canadian Task Classification was designated as level I. "Low" to "very low" quality evidence revealed that prenatal exercise reduced the odds of CS by 55% in women with type 1 diabetes and chronic hypertension (OR 0.45; 95% CI 0.22-0.95, I2 = 0%). The odds of low (<2500 g) or high (>4000 g) birth weight, Apgar score at 1 and 5 minutes, preeclampsia, and preterm birth were not different between women who exercised and those who did not. CONCLUSION: Prenatal exercise reduced the odds of CS and did not increase the risk of adverse maternal or neonatal outcomes in mothers with pre-gestational medical conditions. Findings are based on limited evidence, thus suggesting a need for high-quality investigations on exercise in this population of women.

Gene Expression Profiles Suggest Iron Transport Pathway in the Lactating Human Epithelial Cell.

OBJECTIVES: The molecular background of iron excretion into breast milk has not been determined in humans. We determined the expression of known iron transporters in mRNA extracted from human milk fat globules to deduce which known transporters are responsible for iron excretion into human milk. METHODS: The expression of iron transporters in mRNA from human milk fat globules and mouse mammary epithelial cell lines was determined by quantitative real-time polymerase chain reaction. RESULTS: The expression of the transferrin receptor 1 (TFRC), divalent metal transporter 1 (SLC11A2), transferrin (TF), and lactoferrin (LTF) was confirmed in RNA isolated from the human milk fat globule. Similar expression was observed in the mouse mammary epithelial cell line HC11 in resting and lactating phenotypes. No iron export protein could be determined in the RNA isolated from fat globules in human breast milk and a human mammary epithelial cell line. CONCLUSIONS: The lack of iron exporters in the human mammary epithelia, in conjunction with the presence of lactoferrin suggests that transmembrane transport is not a major route of iron excretion into human milk.

Frontostriatal circuits, resting state functional connectivity and cognitive control in internet gaming disorder.

Converging evidence has identified cognitive control deficits in internet gaming disorder (IGD). Recently, mounting evidence had revealed that resting state functional connectivity (RSFC) and structural connectivity of frontostriatal circuits could modulate cognitive control in healthy individuals. Unfortunately, relatively little is known about the thoroughly circuit-level characterization of the frontostriatal pathways (both the dorsal and ventral striatum) during resting-state and their association with cognitive control in IGD. In the current study, the differences of striatum volume and RSFC networks were investigated between 43 young IGD individuals and 44 healthy controls. Meanwhile, cognitive control deficits were assessed by Stroop task performances. The neuroimaging findings were then correlated with the Stroop task behaviors. In IGD subjects, we demonstrated an increased volume of right caudate and nucleus accumbens (NAc) as well as reduced RSFC strength of dorsal prefrontal cortex (DLPFC)-caudate and orbitofrontal cortex (OFC)-NAc. NAc volumes were positively correlated with internet addiction test scores in IGD. The caudate volume and DLPFC-caudate RSFC was correlated with the impaired cognitive control (more incongruent errors in Stroop task) in IGD. Consistent with substance use disorder (SUD) findings, we detected striatum volume and frontostriatal circuits RSFC differences between IGD and healthy controls, which provided evidence of some degree of the similarity between IGD and SUD. More importantly, the cognitive control deficits in IGD were correlated with the reduced frontostrital RSFC strength. It is hoped that our results could shed insight on the neurobiological mechanisms of IGD and suggest potential novel therapeutic targets for treatment.

Assessment of complementary feeding of Canadian infants: effects on microbiome & oxidative stress, a randomized controlled trial.

BACKGROUND: The World Health Organization recommends exclusive breastfeeding until 6 months followed by introduction of iron-rich complementary foods (CFs). The aim of this study was to determine the impact of different iron-rich CFs on infant gut inflammation and microbiota. METHODS: Eighty-seven exclusively breastfed infants were randomly assigned to receive one of the following as their first CF: iron-fortified cereal (Cer), iron-fortified cereal with fruit (Cer + Fr), or meat (M). Urine and stool samples were collected to assess reactive oxygen species (ROS) generation, gut microbiota and inflammation. RESULTS: Fecal iron differed across feeding groups (p < 0.001); levels were highest in the Cer group and lowest in M group. A significant increase of fecal ROS formation (p < 0.002) after the introduction of CFs was observed, but did not differ across feeding groups. Fecal calprotectin increased within all groups after the introduction of CFs (p = 0.004). Gut microbiota richness increased after introduction of M or Cer + Fr. Regardless of feeding group, Coriobacteriaceae were positively correlated with ROS and Staphylococcaceae were negatively correlated with calprotectin. CONCLUSIONS: Choice of first CF may influence gut inflammation and microbiota, potentially due to variations in iron absorption from different foods. Further research is warranted to fully characterize these associations and to establish implications for infant health. This study was registered in the ClinicalTrial.gov registry (Identifier No. NCT01790542 ). TRIAL REGISTRATION: This study was registered in the ClinicalTrial.gov registry under the name "Assessment of Complementary Feeding of Canadian Infants" (Identifier No. NCT01790542 ) February 6, 2013.

Effect of dietary fibre on cognitive function and mental health in children and adolescents: a systematic review and meta-analysis.

Objective: The purpose of this study is to investigate the impact of dietary fibre on the mental health and cognitive function of children and adolescents. Methods: All interventional and observational studies that contained information on the relevant population (children and adolescents), intervention/exposures (high dietary fibre consumption) and outcomes (mental and cognitive parameters) were eligible. Eight electronic databases (Embase, Medline, Pubmed, Web of Science, Scopus, PsycINFO, Cochrane Library and ClinicalTrials.gov) were searched up to December 11, 2023. Results: A total of 15 studies (n = 4628) met inclusion criteria, consisting of 9 intervention trials and 6 observational studies. According to observational studies, higher dietary fibre consumption was associated with a 49% reduction in the odds of depression compared to lower intake (P < 0.0001; OR = 0.51; 95% CI: 0.38, 0.69; I2 = 0%). Furthermore, no significant correlations were found between dietary fibre consumption and intelligence or anxiety. Among intervention studies, no significant difference was observed between fibre supplementation and placebo in terms of anxiety (standardized mean difference (SMD): -0.23; 95% CI: -0.72, 0.27), stress (SMD: 0.03; 95% CI: -0.21, 0.28), memory (SMD: 0.46; 95% CI: -0.79, 1.71), or attention (SMD: -2.72; 95% CI: -6.30, 0.86). Conclusion: Evidence from observation studies demonstrated that higher dietary fibre consumption is associated with a decreased odds of depression symptoms, both in childhood and adolescence. However, the causal relationship between dietary fibre intake and mental and cognitive function in children and adolescents still requires further clarification through high-quality intervention studies in the future.

Dietary fiber for the prevention of childhood obesity: a focus on the involvement of the gut microbiota.

Given the worldwide epidemic of overweight and obesity among children, evidence-based dietary recommendations are fundamentally important for obesity prevention. Although the significance of the human gut microbiome in shaping the physiological effects of diet and obesity has been widely recognized, nutritional therapeutics for the mitigation of pediatric obesity globally are only just starting to leverage advancements in the nutritional microbiology field. In this review, we extracted data from PubMed, EMBASE, Scopus, Web of Science, Google Scholar, CNKI, Cochrane Library and Wiley online library that focuses on the characterization of gut microbiota (including bacteria, fungi, viruses, and archaea) in children with obesity. We further review host-microbe interactions as mechanisms mediating the physiological effects of dietary fibers and how fibers alter the gut microbiota in children with obesity. Contemporary nutritional recommendations for the prevention of pediatric obesity are also discussed from a gut microbiological perspective. Finally, we propose an experimental framework for integrating gut microbiota into nutritional interventions for children with obesity and provide recommendations for the design of future studies on precision nutrition for pediatric obesity.

Age-related alterations in vortex veins on indocyanine green angiography.

To determine age-related alterations in vortex veins in healthy subjects. A total of 228 healthy subjects (aged 4 to 86 years) were recruited and divided into four groups (G1, <21 years; G2, 21-40 years; G3, 41-60 years; and G4, 61-86 years). The clinical characteristics of the participants were recorded, and parameters including the number of vortex vein roots (NVVR), the central vortex vein diameter (CVVD), the mean root area of the vortex vein (MRAVV), and the weighted mean of the thickest branch diameter (WMTBD) were obtained by marking the vortex veins on indocyanine green angiography (ICGA). The NVVR in the age group over 60 years old was significantly lower than that in other age groups (P < 0.05). The CVVD, MRAVV, and WMTBD of all age groups increased with increasing age (P < 0.05). The NVVR was unevenly distributed among the quadrants (P < 0.001). The proportions of type four vortex veins (complete systems including ampulla) and anastomotic branches of the vortex veins were significantly increased in elderly participants over 50 years of age (P < 0.05). Subfoveal choroidal thickness was significantly correlated with age, NVVR, CVVD and MRAVV (P < 0.05). This is the first study to reveal age-related alterations in vortex veins on ICGA in a healthy population. Aging may lead to partial vortex occlusion and residual vortex dilation. As age increases, anastomotic branches increasingly appear between the originally independent vortex veins. Translational relevance: Aging may lead to partial vortex occlusion and residual vortex dilation.

The orexinergic system mediates the excitatory effects of caffeine on the arousal and sympathetic activity.

Objective: Caffeine is a non-selective adenosine receptor antagonist with pro-arousal and pro-sympathetic nervous system excitatory effects, and these pharmacological effects fit well with the physiological functions of orexin. The purpose of this study was to investigate the role of the orexinergic nervous system in the pharmacological effects of caffeine. Methods: An animal model of sleepiness caused by adenosine accumulation was established by sleep deprivation, and caffeine's effects on the spontaneous activity and sympathetic nervous system of the model animals were evaluated by using the open-field experiment and gastrointestinal peristaltic observation, respectively, and the intervention of orexin receptor antagonists on the pharmacological effects of caffeine was also observed. Results: Mice with 8 h of sleep deprivation showed a significant decrease in spontaneous activity and a significant increase in gastrointestinal push distance. After caffeine intervention, the spontaneous activities of sleep-deprived mice significantly increased and gastrointestinal peristalsis significantly decreased dose-dependent, while orexin receptors antagonist blocked the pro-arousal and inhibitory gastrointestinal peristalsis effects of caffeine on sleep-deprived mice. Conclusions: Orexinergic nervous system mediated caffeine's excitatory effects on the pro-arousal and pro-sympathetic nervous systems. Orexin is likely to be an important performer in the pharmacological effects of caffeine.

Prognostic value and immune landscapes of immunogenic cell death-related lncRNAs in hepatocellular carcinoma.

BACKGROUND: Both immunogenic cell death (ICD) and long noncoding RNAs (lncRNAs) are strongly associated with tumor development, but the mechanism of action of ICD-associated lncRNAs in hepatocellular carcinoma (HCC) remains unclear. METHODS: We collected data from 365 HCC patients from The Cancer Genome Atlas (TCGA) database. We formulated a prognostic signature of ICD-associated lncRNAs and a nomogram to predict prognosis. To explore the potential mechanisms and provide clinical guidance, survival analysis, enrichment analysis, tumor microenvironment analysis, tumor mutation burden (TMB), and drug sensitivity prediction were conducted based on the subgroups obtained from the risk score. RESULTS: A prognostic signature of seven ICD-associated lncRNAs was constructed. Kaplan-Meier (K-M) survival curves showed a more unfavorable outcome in high-risk patients. The nomogram had a higher predictive value than the nomogram constructed without the risk model. Enrichment analysis confirmed that risk lncRNAs were closely associated with cell proliferation and mitosis. Most of the immune checkpoints currently used in therapy (e.g., PDCD1 and CTLA4) appeared to be elevated in high-risk patients. Tumor microenvironment analysis showed differential expression of lymphocytes (including natural killer cells, regulatory T cells, etc.) in the high-risk group. TMB had a higher incidence of mutations in the high-risk group (P=0.004). Chemotherapy drug sensitivity prediction provides effective guidelines for individual therapy. RT-qPCR of human HCC tissues verified the accuracy of the model. CONCLUSION: We constructed an effective prognostic signature for patients with HCC using seven ICD-lncRNAs, which provides guidance for the prognostic assessment and personalized treatment of patients.

Membrane metalloendopeptidase (MME) is positively correlated with systemic lupus erythematosus and may inhibit the occurrence of breast cancer.

BACKGROUND: Patients with systemic lupus erythematosus (SLE) have a lower risk of breast cancer (BRCA) than the general population. In this study, we explored the underlying molecular mechanism that is dysregulated in both diseases. METHODS: Weighted gene coexpression network analysis (WGCNA) was executed with the SLE and BRCA datasets from the Gene Expression Omnibus (GEO) website and identified the potential role of membrane metalloendopeptidase (MME) in both diseases. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of related proteins and miRNAs were performed to investigate the potential molecular pathways. RESULTS: WGCNA revealed that MME was positively related to SLE but negatively related to BRCA. In BRCA, MME expression was significantly decreased in tumor tissues, especially in luminal B and infiltrating ductal carcinoma subtypes. Receiver operating characteristic (ROC) analysis identified MME as a valuable diagnostic biomarker of BRCA, with an area under the curve (AUC) value equal to 0.984 (95% confidence interval = 0.976-0.992). KEGG enrichment analysis suggested that MME-related proteins and targeted miRNAs may reduce the incidence of BRCA in SLE patients via the PI3K/AKT/FOXO signaling pathway. Low MME expression was associated with favorable relapse-free survival (RFS) but no other clinical outcomes and may contribute to resistance to chemotherapy in BRCA, with an AUC equal to 0.527 (P value < 0.05). CONCLUSIONS: In summary, MME expression was significantly decreased in BRCA but positively correlated with SLE, and it might reduce the incidence of BRCA in SLE patients via the PI3K/AKT/FOXO signaling pathway.

Construction and validation of a model based on immunogenic cell death-associated lncRNAs to predict prognosis and direct therapy for kidney renal clear cell carcinoma.

BACKGROUND: Immunogenic cell death (ICD) is an important part of the antitumor effect, yet the role played by long noncoding RNAs (lncRNAs) remains unclear. We explored the value of ICD-related lncRNAs in tumor prognosis assessment in kidney renal clear cell carcinoma (KIRC) patients to provide a basis for answering the above questions. METHODS: Data on KIRC patients were obtained from The Cancer Genome Atlas (TCGA) database, prognostic markers were identified, and their accuracy was verified. An application-validated nomogram was developed based on this information. Furthermore, we performed enrichment analysis, tumor mutational burden (TMB) analysis, tumor microenvironment (TME) analysis, and drug sensitivity prediction to explore the mechanism of action and clinical application value of the model. RT-qPCR was performed to detect the expression of lncRNAs. RESULTS: The risk assessment model constructed using eight ICD-related lncRNAs provided insight into patient prognoses. Kaplan-Meier (K-M) survival curves showed a more unfavorable outcome in high-risk patients (p<0.001). The model had good predictive value for different clinical subgroups, and the nomogram constructed based on this model worked well (risk score AUC=0.765). Enrichment analysis revealed that mitochondrial function-related pathways were enriched in the low-risk group. The adverse prognosis of the higher-risk cohort might correspond to a higher TMB. The TME analysis revealed a higher resistance to immunotherapy in the increased-risk subgroup. Drug sensitivity analysis can guide the selection and application of antitumor drugs in different risk groups. CONCLUSIONS: This prognostic signature based on eight ICD-associated lncRNAs has significant implications for prognostic assessment and treatment selection in KIRC.

Prognostic value and immune landscapes of immunogenic cell death-associated lncRNAs in lung adenocarcinoma.

Immunogenic cell death (ICD) has been demonstrated to activate T cells to kill tumor cells, which is closely related to tumor development, and long noncoding RNAs (lncRNAs) are also involved. However, it is not known whether ICD-related lncRNAs are associated with the development of lung adenocarcinoma (LUAD). We downloaded ICD-related genes from GeneCards and the transcriptome statistics of LUAD patients from The Cancer Genome Atlas (TCGA) and subsequently developed and verified a predictive model. A successful model was used together with other clinical features to construct a nomogram for predicting patient survival. To further study the mechanism of tumor action and to guide therapy, we performed enrichment analysis, tumor microenvironment analysis, somatic mutation analysis, drug sensitivity analysis and real-time quantitative polymerase chain reaction (RT-qPCR) analysis. Nine ICD-related lncRNAs with significant prognostic relevance were selected for model construction. Survival analysis demonstrated that overall survival was substantially shorter in the high-risk group than in the low-risk group (P < 0.001). This model was predictive of prognosis across all clinical subgroups. Cox regression analysis further supported the independent prediction ability of the model. Ultimately, a nomogram depending on stage and risk score was created and showed a better predictive performance than the nomogram without the risk score. Through enrichment analysis, the enriched pathways in the high-risk group were found to be primarily associated with metabolism and DNA replication. Tumor microenvironment analysis suggested that the immune cell concentration was lower in the high-risk group. Somatic mutation analysis revealed that the high-risk group contained more tumor mutations (P = 0.00018). Tumor immune dysfunction and exclusion scores exhibited greater sensitivity to immunotherapy in the high-risk group (P < 0.001). Drug sensitivity analysis suggested that the predictive model can also be applied to the choice of chemotherapy drugs. RT-qPCR analysis also validated the accuracy of the constructed model based on nine ICD-related lncRNAs. The prognostic model constructed based on the nine ICD-related lncRNAs showed good application value in assessing prognosis and guiding clinical therapy.