Genome-wide association study of image-based trait reveals the genetic architecture of dark-induced leaf senescence in rice.

Darkness is often used as an effective measure to induce leaf senescence. Although many senescence-related genes in rice have been reported, the genome-wide genetic architecture underlying leaf senescence remains poorly understood. In our study, indica and japonica rice showed contrasting responses to dark-induced leaf senescence (DILS). Genome-wide association studies (GWAS) combined with transcriptomic analyses revealed 57, 97, and 48 loci involved in the regulation of the onset, progression, and ending of DILS, respectively. Haplotype analyses showed that the senescence-related loci differentially accumulated in indica and japonica accessions and functioned additively to regulate DILS. A total of 357 candidate genes were identified that are involved in various senescence-related processes such as lipid and amino acid catabolism, photosynthesis, response to reactive oxygen species, and regulation of defense response. In addition, functional analyses of the two candidate genes, OsMYB21 and OsSUB1B, revealed that OsMYB21 positively regulates the onset of DILS, while OsSUB1B negatively regulates its progression. Thus, our results provide new insights into the genetic regulation of DILS in rice.

A Self-Learning Hyper-Heuristic Algorithm Based on a Genetic Algorithm: A Case Study on Prefabricated Modular Cabin Unit Logistics Scheduling in a Cruise Ship Manufacturer.

Hyper-heuristic algorithms are known for their flexibility and efficiency, making them suitable for solving engineering optimization problems with complex constraints. This paper introduces a self-learning hyper-heuristic algorithm based on a genetic algorithm (GA-SLHH) designed to tackle the logistics scheduling problem of prefabricated modular cabin units (PMCUs) in cruise ships. This problem can be regarded as a multi-objective fuzzy logistics collaborative scheduling problem. Hyper-heuristic algorithms effectively avoid the extensive evaluation and repair of infeasible solutions during the iterative process, which is a common issue in meta-heuristic algorithms. The GA-SLHH employs a genetic algorithm combined with a self-learning strategy as its high-level strategy (HLS), optimizing low-level heuristics (LLHs) while uncovering potential relationships between adjacent decision-making stages. LLHs utilize classic scheduling rules as solution support. Multiple sets of numerical experiments demonstrate that the GA-SLHH exhibits a stronger comprehensive optimization ability and stability when solving this problem. Finally, the validity of the GA-SLHH in addressing real-world decision-making issues in cruise ship manufacturing companies is validated through practical enterprise cases. The results of a practical enterprise case show that the scheme solved using the proposed GA-SLHH can reduce the transportation time by up to 37%.

Increased effective connectivity from the hypothalamus to the left superior frontal gyrus and its association with visual analogue scale in persons with migraines.

Background: In recent years, several functional imaging studies have shown that the hypothalamus is closely associated with migraine and have suggested that the hypothalamus may be a potential site of migraine generation. Studying the characteristics of the functional network of the hypothalamus in persons with migraines may help to understand the neural mechanisms of migraine. We thus used resting-state functional magnetic resonance imaging (rsfMRI) and Granger causal analysis to investigate the effective connectivity (EC) of the hypothalamus in persons with migraines. Methods: The study included 17 healthy volunteers and 39 persons with migraines. The EC calculation was based on rsfMRI data from a 3-T magnetic resonance imaging scanner. The brain networks of the hypothalamus were compared using a general linear model to determine if there were any differences between the two groups. We used Pearson correlation analysis to examine the correlation between EC values in abnormal brain regions and clinical variables. Results: Compared with healthy controls, those with migraines showed decreased EC from the hypothalamus to the left fusiform and increased EC from the hypothalamus to the medial frontal gyrus/orbital part, right lingual gyrus, left superior frontal gyrus, and right middle frontal gyrus (P<0.05). Meanwhile, persons with migraines also showed decreased EC from the left middle frontal gyrus and right medial frontal gyrus/orbital part to the hypothalamus (P<0.05). EC from the hypothalamus to the left superior frontal gyrus correlated significantly and positively with the visual analogue scale in those with migraines (r=-0.3820; P=0.0164). Conclusions: Disturbances in the EC between the hypothalamus and the prefrontal gyrus and visual cortex may play a key role in the neuropathological features of persons with migraines. The current study adds to our understanding of the complexity of migraine mechanisms.

Aberrant functional connectivity in anterior cingulate gyrus subregions in migraine without aura patients.

Background: The anterior cingulate gyrus (ACG) is an important regulatory region for pain-related information. However, the ACG is composed of subregions with different functions. The mechanisms underlying the brain networks of different subregions of the ACG in patients with migraine without aura (MwoA) are currently unclear. Methods: In the current study, resting-state functional magnetic resonance imaging (rsfMRI) and functional connectivity (FC) were used to investigate the functional characteristics of ACG subregions in MwoA patients. The study included 17 healthy volunteers and 28 MwoA patients. The FC calculation was based on rsfMRI data from a 3 T MRI scanner. The brain networks of the ACG subregions were compared using a general linear model to see if there were any differences between the two groups. Spearman correlation analysis was used to examine the correlation between FC values in abnormal brain regions and clinical variables. Results: Compared with healthy subjects, MwoA patients showed decreased FC between left subgenual ACG and left middle cingulate gyrus and right middle temporal gyrus. Meanwhile, MwoA patients also showed increased FC between pregenual ACG and right angular gyrus and increased FC between right pregenual ACG and right superior occipital gyrus. The FC values between pregenual ACG and right superior occipital gyrus were significantly positively correlated with the visual analogue scale. Conclusion: Disturbances of FC between ACG subregions and default model network and visual cortex may play a key role in neuropathological features, perception and affection of MwoA. The current study provides further insights into the complex scenario of MwoA mechanisms.

Vaginal and endometrial microbiome dysbiosis associated with adverse embryo transfer outcomes.

BACKGROUND: Assisted reproductive technology (ART) is the most effective method to treat infertility and the pathogenesis of implantation failure after in vitro fertilization-embryo transfer (IVF-ET) is a challenging filed in infertility. Microbes in the female reproductive tract are considered to be associated with gynecological and obstetric diseases. However, its effects on embryo implantation failure are unsured. PURPOSE: This study aimed to investigate reproductive tract dysbiosis, identify different bacteria in reproductive tract as potential biomarkers of embryo implantation failure and demonstrate the pathogenesis through metabolites analysis. METHODS: We compared the data from 16S rRNA gene and metagenome in reproductive tracts through QIIME2 and HUMAnN2 by the times of embryo implantation failure on 239 infertile patients and 17 healthy women. RESULTS: Our study revealed a strong positive correlation between Lactobacillus abundance and embryo implantation success (IS) after IVF-ET. The microbial community composition and structure in reproductive tract showed substantially difference between the embryo implantation failure (IF) and healthy control. Moreover, we established a diagnostic model through receiver operating characteristic (ROC) with 0.913 area under curve (AUC) in IS and multiple implantation failures (MIF), verified its effectiveness with an AUC = 0.784 demonstrating microbial community alterations could efficiently discriminate MIF patients. Metagenome functional analyses of vaginal samples from another independent infertile patients after IVF-ET revealed the L-lysine synthesis pathway enriched in IF patients, along with ascended vaginal pH and decreased Lactobacillus abundance. CONCLUSIONS: This study clarifies several independent relationships of bacteria in vagina and endometrial fluid on embryo implantation failure and undoubtedly broadens the understanding about female reproductive health.

Camrelizumab-induced anaphylactic reaction: a case report and literature review.

Camrelizumab is an immune checkpoint inhibitor clinically used to treat various types of tumours. In this study, the authors provided the first report of a case of an anaphylactic reaction induced by camrelizumab in the treatment of a patient with squamous cell carcinoma of the floor of the mouth. The patient, a 58-year-old man, was diagnosed with advanced squamous cell carcinoma of the floor of the mouth, with cancer infiltration and multiple metastases. He underwent treatment for nine cycles, in which cycles 1-5 he received camrelizumab, albumin-bound paclitaxel, and cisplatin (200 mg of camrelizumab each time, every 3 weeks), with no adverse reactions; in cycle 6, he received albumin-bound paclitaxel and cisplatin, with no adverse reactions; and in cycles 7-9, he received camrelizumab and albumin-bound paclitaxel. However, 30 min after 8th administration of camrelizumab (cycle 9), he suddenly developed sweating, a pale complexion, clamminess and cyanosis of the limbs (percutaneous arterial oxygen saturation [SpO2] = 82%, blood pressure [BP] = 79/49 mmHg, heart rate [HR] = 83 beats/min [bpm] and respiratory rate [RR) = 12 bpm). The patient underwent intravenous infusion of methylprednisolone (80 mg) combined with dopamine to boost the BP; he regained consciousness 20 min later, and many parts of his skin appeared smooth, with no desquamation and accompanied by itching erythema, especially on the upper limbs. Approximately 2 h after treatment, the patient's skin erythema subsided (vital sign monitoring results: SpO2 = 100%, BP = 122/84 mmHg, HR = 91 bpm and RR = 17 bpm); the patient did not complain about his obvious discomfort. Despite the rarity of acute anaphylactic reactions among immune-related adverse reactions, great importance should be given to anaphylactic reactions of camrelizumab due to its extensive clinical application.

Linking child externalising problems to psychological distress in parents: Mobile phone use by children as a mediator.

Child externalising problems, such as acting out and hostility, have been found to be significant stressors for parents, leading to increased distress levels. This cross-sectional study examined the mediating role of parents' use of mobile phones to soothe or engage children in the association between child externalising problems and distress in parents. Altogether 937 parents of children aged 5-12 reported their child's externalising problems, child's mobile phone use, and their distress through an online survey. The findings indicated that parents of children with high externalising problems are more likely to use mobile phones to soothe their children and keep them engaged in daily activities, which, in turn, is associated with higher distress in parents. Child externalising problems and distress in parents remained significantly and positively associated even after accounting for the mediating effect. The results highlight the child-driven effect on distress in parents through parenting behaviours, indicating the importance of providing alternative parenting strategies to cope with child externalising behaviours, in order to promote parental emotional well-being.

Metabolomic and biochemical changes in the plasma and liver of toxic milk mice model of Wilson disease.

Wilson disease (WD) is an inherited disorder characterized by abnormal copper metabolism with complex pathological features. Currently, this mechanism of copper overload-induced hepatic injury remains unclear. In this study, male toxic milk (TX) mice were selected as experimental subjects. Copper levels and biochemical indices were measured by atomic absorption spectroscopy (AAS) and kits. Liver tissue ultrastructure was observed by hematoxylin-eosin (H&E), sirius red staining and transmission electron microscopy. Plasma and liver metabolic profiles of TX mice were characterized by untargeted metabolomics. In addition, the expression of enzymes related to arachidonic acid metabolism in liver tissue was detected by Western blotting. The results showed the excessive copper content, concomitant oxidative stress, and hepatic tissue structural damage in TX mice. Seventy-eight metabolites were significantly different in WD, mainly involved in the metabolism of arachidonic acid, glycerophospholipids, sphingolipids, niacin and nicotinamide, and phenylalanine. Furthermore, the arachidonic acid metabolic pathway is an important pathway involved in WD metabolism. The level of arachidonic acid in the liver of TX mice was significantly lower (p < 0.01) compared to the control group. The expression of cytoplasmic phospholipase A2 (cPLA2) and arachidonic acid 12-lipoxygenase (ALOX12), related to the arachidonic acid metabolic pathway, was significantly different in the liver of TX mice (p < 0.01). Modulation of the arachidonic acid metabolic pathway could be a potential therapeutic strategy to alleviate WD symptoms.

Podocyte-specific silencing of acid sphingomyelinase gene to abrogate hyperhomocysteinemia-induced NLRP3 inflammasome activation and glomerular inflammation.

Acid sphingomyelinase (ASM) has been reported to increase tissue ceramide and thereby mediate hyperhomocysteinemia (hHcy)-induced glomerular nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome activation, inflammation, and sclerosis. In the present study, we tested whether somatic podocyte-specific silencing of Smpd1 gene (mouse ASM gene code) attenuates hHcy-induced NLRP3 inflammasome activation and associated extracellular vesicle (EV) release in podocytes and thereby suppresses glomerular inflammatory response and injury. In vivo, somatic podocyte-specific Smpd1 gene silencing almost blocked hHcy-induced glomerular NLRP3 inflammasome activation in Podocre (podocyte-specific expression of cre recombinase) mice compared with control littermates. By nanoparticle tracking analysis (NTA), floxed Smpd1 shRNA transfection was found to abrogate hHcy-induced elevation of urinary EV excretion in Podocre mice. In addition, Smpd1 gene silencing in podocytes prevented hHcy-induced immune cell infiltration into glomeruli, proteinuria, and glomerular sclerosis in Podocre mice. Such protective effects of podocyte-specific Smpd1 gene silencing were mimicked by global knockout of Smpd1 gene in Smpd1-/- mice. On the contrary, podocyte-specific Smpd1 gene overexpression exaggerated hHcy-induced glomerular pathological changes in Smpd1trg/Podocre (podocyte-specific Smpd1 gene overexpression) mice, which were significantly attenuated by transfection of floxed Smpd1 shRNA. In cell studies, we also confirmed that Smpd1 gene knockout or silencing prevented homocysteine (Hcy)-induced elevation of EV release in the primary cultures of podocyte isolated from Smpd1-/- mice or podocytes of Podocre mice transfected with floxed Smpd1 shRNA compared with WT/WT podocytes. Smpd1 gene overexpression amplified Hcy-induced EV secretion from podocytes of Smpd1trg/Podocre mice, which was remarkably attenuated by transfection of floxed Smpd1 shRNA. Mechanistically, Hcy-induced elevation of EV release from podocytes was blocked by ASM inhibitor (amitriptyline, AMI), but not by NLRP3 inflammasome inhibitors (MCC950 and glycyrrhizin, GLY). Super-resolution microscopy also showed that ASM inhibitor, but not NLRP3 inflammasome inhibitors, prevented the inhibition of lysosome-multivesicular body interaction by Hcy in podocytes. Moreover, we found that podocyte-derived inflammatory EVs (released from podocytes treated with Hcy) induced podocyte injury, which was exaggerated by T cell coculture. Interstitial infusion of inflammatory EVs into renal cortex induced glomerular injury and immune cell infiltration. In conclusion, our findings suggest that ASM in podocytes plays a crucial role in the control of NLRP3 inflammasome activation and inflammatory EV release during hHcy and that the development of podocyte-specific ASM inhibition or Smpd1 gene silencing may be a novel therapeutic strategy for treatment of hHcy-induced glomerular disease with minimized side effect.NEW & NOTEWORTHY In the present study, we tested whether podocyte-specific silencing of Smpd1 gene attenuates hyperhomocysteinemia (hHcy)-induced nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome activation and associated inflammatory extracellular vesicle (EV) release in podocytes and thereby suppresses glomerular inflammatory response and injury. Our findings suggest that acid sphingomyelinase (ASM) in podocytes plays a crucial role in the control of NLRP3 inflammasome activation and inflammatory EV release during hHcy. Based on our findings, it is anticipated that the development of podocyte-specific ASM inhibition or Smpd1 gene silencing may be a novel therapeutic strategy for treatment of hHcy-induced glomerular disease with minimized side effects.

Consolidation chemotherapy after definitive concurrent chemoradiotherapy in patients with inoperable esophageal squamous cell carcinoma: a multicenter non-inferiority phase III randomized clinical trial.

BACKGROUND: Definitive concurrent chemoradiotherapy (dCCRT) is the gold standard for the treatment of locally advanced esophageal squamous cell carcinoma (ESCC). However, the potential benefits of consolidation chemotherapy after dCCRT in patients with esophageal cancer remain debatable. Prospective randomized controlled trials comparing the outcomes of dCCRT with or without consolidation chemotherapy in patients with ESCC are lacking. In this study, we aim to generate evidence regarding consolidation chemotherapy efficacy in patients with locally advanced, inoperable ESCC. METHODS: This is a multicenter, prospective, open-label, phase-III randomized controlled trial comparing non-inferiority of dCCRT alone to consolidation chemotherapy following dCCRT. In total, 600 patients will be enrolled and randomly assigned in a 1:1 ratio to receive either consolidation chemotherapy after dCCRT (Arm A) or dCCRT alone (Arm B). Overall survival will be the primary endpoint, whereas progression-free survival, locoregional progression-free survival, distant metastasis-free survival, and treatment-related toxicity will be the secondary endpoints. DISCUSSION: This study aid in further understanding the effects of consolidation chemotherapy after dCCRT in patients with locally advanced, inoperable ESCC. TRIAL REGISTRATION: ChiCTR1800017646.

RNA N6-methyladenosine-modified-binding protein YTHDF1 promotes prostate cancer progression by regulating androgen function-related gene TRIM68.

PURPOSE: There is no report about the direct relationship between m6A modification and androgen receptor (AR)-related genes in prostate cancer (PC). We aimed to study the mechanisms of m6A methylation in regulating the pathogenesis of PC from the perspective of AR-related genes. METHODS: qRT-PCR was applied to detect the expression of m6A-related genes in PC cell with or without AR inhibitor. The effects of YTHDF1 knockdown on PC cell viability, apoptosis, migration and invasion were investigated using flow cytometry, wound healing and transwell assays, respectively. The mechanism of YTHDF1 action was investigated using m6A RNA immunoprecipitation (MeRIP) sequencing. The biological functions of YTHDF1 were also explored through in vivo experiments. RESULTS: YTHDF1 was significantly down-regulated in AR inhibitor group. YTHDF1 knockdown significantly decreased AR level, viability and m6A methylation level of PC cells. TRIM68 was identified as a direct target of YTHDF1. Both YTHDF1 and TRIM68 knockdown increased apoptosis, and decreased cell viability, migration, and invasion of PC cells, while TRIM68 overexpression reversed the effects of YTHDF1 knockdown on PC cells. In addition, knockdown of YTHDF1 or TRIM68 significantly decreased the m6A methylation level, and mRNA and protein levels of YTHDF1, TRIM68 and AR in PC cells, while TRIM68 overexpression increased the expression levels above. Furthermore, subcutaneous xenografts of nude mice also revealed that TRIM68 could reverse the effects of YTHDF1 knockdown in PC in vivo. CONCLUSION: This study suggested the key role of YTHDF1-mediated m6A modification in PC progression by regulating androgen function-related gene TRIM68 in PC.

The D ~ Sense ex-vivo viability assay application in a patient with stage IV lung adenocarcinoma: a case report.

BACKGROUND: The treatment resistance is a problem for lung cancer. In this study, we used a vitro tissue culturing system to select a new therapy strategy for a patient with tyrosine kinase inhibitors (TKIs) resistance. CASE PRESENTATION: A 42-year-old male Asian patient was diagnosed with advanced lung adenocarcinoma harboring an exon 19 deletion in the epidermal growth factor receptor (EGFR) gene. The patient was treated with Gefitinib, resulting in an almost complete remission for over a year. The patient relapsed after 13 months treatment, and received four cycles of chemotherapy. At 20 months, the patient had developed multiple lung metastases and a solitary cerebellar metastasis. An EGFR T790M mutation was identified in the peripheral blood sample. Subsequent treatment with Osimertinib resulted in a complete response of the intracranial metastasis. By 33 months, the patient had developed a mediastinal tumor mass that responded well to local radiotherapy. By 39 months, an EGFR C797S cis-mutation had been identified and the patient was treated with Brigatinib and Cetuximab. By 44 months, the tumor cells from the pleural effusion had been tested for sensitivity against 30 targeted and cytostatic drugs using the D ~ Sense ex-vivo viability assay. The assay identified 8 drugs with moderate to high sensitivity. Combination therapy of Gemcitabin and Lobaplatin had resulted in disease stabilization. CONCLUSIONS: The case showed that individualized treatment aided by D ~ Sense ex-vivo viability assay can be a viable option for patients with advanced lung adenocarcinoma with pleural effusions.

Multi-engineered Graphene Extended-Gate Field-Effect Transistor for Peroxynitrite Sensing in Alzheimer's Disease.

The expression of ß-amyloid peptides (Aß), a pathological indicator of Alzheimer's disease (AD), was reported to be inapparent in the early stage of AD. While peroxynitrite (ONOO-) is produced excessively and emerges earlier than Aß plaques in the progression of AD, it is thus significant to sensitively detect ONOO- for early diagnosis of AD and its pathological research. Herein, we unveiled an integrated sensor for monitoring ONOO-, which consisted of a commercially available field-effect transistor (FET) and a high-performance multi-engineered graphene extended-gate (EG) electrode. In the configuration of the presented EG electrode, laser-induced graphene (LIG) intercalated with MnO2 nanoparticles (MnO2/LIG) can improve the electrical properties of LIG and the sensitivity of the sensor, and graphene oxide (GO)-MnO2/Hemin nanozyme with ONOO- isomerase activity can selectively trigger the isomerization of ONOO- to NO3-. With this synergistic effect, our EG-FET sensor can respond to the ONOO- with high sensitivity and selectivity. Moreover, taking advantage of our EG-FET sensor, we modularly assembled a portable sensing platform for wireless tracking ONOO- levels in the brain tissue of AD transgenic mice at earlier stages before massive Aß plaques appeared, and we systematically explored the complex role of ONOO- in the occurrence and development of AD.

Nimotuzumab plus concurrent chemo-radiotherapy in unresectable locally advanced oesophageal squamous cell carcinoma (ESCC): interim analysis from a Phase 3 clinical trial.

BACKGROUND: This prospectively randomised, double-blinded, placebo-controlled, multicenter Phase 3 clinical trial was conducted to assess the efficacy and safety profile of nimotuzumab (nimo) plus concurrent chemo-radiotherapy (CCRT) in patients with unresectable locally advanced ESCC. METHODS: Patients were randomly assigned (1:1) to receive CCRT plus nimotuzumab or placebo. The primary endpoint was overall survival (OS). In addition, interim analysis for short-term response rate was pre-defined. RESULTS: A total of 201 patients were randomised into two groups. Eighty patients in the nimo group and eighty-two in the placebo group were evaluable. Three to six months after treatment, 26 (32.5%) patients achieved complete response (CR) in the nimo group, and 10 (12.2%) in the placebo group (P = 0.002). The ORR of the nimo group was significantly higher than the placebo group (93.8% vs. 72.0%, P < 0.001). The two groups' grade 3-5 adverse drug reactions were 11.1% vs. 10.9% (P > 0.05). CONCLUSIONS: Nimotuzumab, in combination with chemo-radiotherapy, increased the CRR and ORR with a good safety profile. The OS is needed to be followed and finally analysed. CLINICAL TRIAL REGISTRATION: NCT02409186.

Ultrafast Electronic Dynamics in Anisotropic Indirect Interlayer Excitonic States of Monolayer WSe2/ReS2 Heterojunctions.

Understanding ultrafast electronic dynamics of the interlayer excitonic states in atomically thin transition metal dichalcogenides is of importance in engineering valleytronics and developing excitonic integrated circuits. In this work, we experimentally explored the ultrafast dynamics of indirect interlayer excitonic states in monolayer type II WSe2/ReS2 heterojunctions using time-resolved photoemission electron microscopy, which reveals its anisotropic behavior. The ultrafast cooling and decay of excited-state electrons exhibit significant linear dichroism. The ab initio theoretical calculations provide unambiguous evidence that this linear dichroism result is primarily associated with the anisotropic nonradiative recombination of indirect interlayer excitonic states. Measuring time-resolved photoemission energy spectra, we have further revealed the ultrafast evolution of excited-state electrons in anisotropic indirect interlayer excitonic states. The findings have important implications for controlling the interlayer moiré excitonic effects and designing anisotropic optoelectronic devices.

Children's Daily Living Routine Mediates the Relations Between Parent-Child Relationships and Child Adjustment Problems During School Suspension in Hong Kong.

Young children's adjustment problems were found to be prevalent during the COVID-19 pandemic. Such adjustment problems may be dependent on children's relationships with their parents and children's daily living routine in the family during the pandemic-related school suspension period. This study examines how children's routine mediated the associations between parent-child relationships and child adjustment problems during the fifth wave of the COVID-19 pandemic in Hong Kong, when schools were suspended. The study collected data from 937 parents (87.8% mothers) of children aged 5-12 (M = 7.35 years, SD = 2.09; 50.5% girls). Parents reported on parent-child relationships, children's daily living routine, and child adjustment problems in an online survey. Our findings from structural equation modeling indicate that parent-child closeness was negatively related to child adjustment problems, whereas conflict was positively related to child adjustment problems. Children's routine mediated the associations between parent-child relationships (i.e., closeness and conflict) and child externalizing problems. However, children's routine did not mediate the associations between parent-child relationships (i.e., closeness and conflict) and child internalizing problems. The findings show that parents should be helped to establish routine, especially in difficult times when young children experience turbulence in their daily life, so as to reduce their adjustment problems, in particular of an externalizing nature.

The level of serum total bile acid is related to atherosclerotic lesions, prognosis and gut Lactobacillus in acute coronary syndrome patients.

BACKGROUND: Bile acids play crucial roles in various metabolisms, as well as Lactobacillus in the intestine. But studies on their roles in acute coronary syndrome (ACS) are still insufficient. The aim of this study was to investigate their role and potential association with the severity of coronary lesions and the prognosis of ACS. METHODS: Three hundred and sixty ACS patients were selected. Detection of gut Lactobacillus levels was done through 16S rDNA sequence analysis. Evaluation of the extent of lesions was done using the SYNTAX (SS) score. Mediation analysis was used to assess the relationship between serum total bile acid (TBA), Lactobacillus, atherosclerotic lesions and prognosis of ACS. RESULTS: Logistic regressive analysis disclosed that serum TBA and Lactobacillus were independent predictors of coronary lesions (high vs. low SS: serum TBA adjusted odds ratio (aOR) = 0.8, 95% confidence interval (CI): 0.6-0.9, p < .01; Lactobacillus: aOR = 0.9, 95% CI: 0.9-1.0, p = .03). According to multivariate Cox regression analysis, they were negatively correlated with the overall risk of all-cause death (serum TBA: adjusted hazard ratio (aHR) = 0.1, 95% CI: 0.0-0.6, p = .02; Lactobacillus: aHR = 0.6, 95% CI: 0.4-0.9, p = .01), especially in acute myocardial infarction (AMI) but not in unstable angina pectoris (UAP). Ulteriorly, mediation analysis showed that serum TBA played an important role as a mediation effect in the following aspects: Lactobacillus (17.0%, p < .05) â†’ SS association (per 1 standard deviation (SD) increase), Lactobacillus (43.0%, p < .05) â†’ all-cause death (per 1 SD increase) and Lactobacillus (45.4%, p < .05) â†’ cardiac death (per 1 SD increase). CONCLUSIONS: The lower serum TBA and Lactobacillus level in ACS patients, especially in AMI, was independently linked to the risk of coronary lesions, all-cause death and cardiac death. In addition, according to our mediation model, serum TBA served as a partial intermediate in predicting coronary lesions and the risk of death by Lactobacillus, which is paramount to further exploring the mechanism of Lactobacillus and bile acids in ACS.KEY MESSAGESLower level of serum total bile acid (TBA) was highly associated with the severity of coronary lesions, myocardial damage, inflammation and gut Lactobacillus in acute coronary syndrome (ACS) patients, especially in acute myocardial infarction (AMI).Lower level of serum TBA was highly associated with mortality (including all-cause death and cardiac death) in patients with ACS, especially with AMI.Serum TBA had a partial mediating effect rather than regulating effect between gut Lactobacillus and coronary lesions and prognosis of ACS.

Regulation of NLRP3 Inflammasome Activation and Inflammatory Exosome Release in Podocytes by Acid Sphingomyelinase During Obesity.

The activation of nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome has been reported to importantly contribute to glomerular inflammation and injury under different pathological conditions such as obesity. However, the mechanism mediating NLRP3 inflammasome activation in podocytes and subsequent glomerular injury remains poorly understood. Given that the ceramide signaling pathway has been reported to be implicated in obesity-related glomerulopathy (ORG), the present study was designed to test whether the ceramide-producing enzyme, acid sphingomyelinase (ASM), determines NLRP3 inflammasome activation and inflammatory exosome release in podocytes leading to glomerular inflammation and injury during ORG. In Smpd1trg/Podocre mice, podocyte-specific overexpression of Smpd1 gene which encodes ASM significantly exaggerated high-fat diet (HFD)-induced NLRP3 inflammasome activation in podocytes and immune cell infiltration in glomeruli compared to WT/WT mice. Smpd1 gene deletion, however, blocked these pathological changes induced by HFD in Smpd1-/- mice. Accompanied with NLRP3 inflammasome activation and glomerular inflammation, urinary excretion of exosomes containing podocyte marker and NLRP3 inflammasome products (IL-1ß and IL-18) in Smpd1trg/Podocre mice on the HFD was much higher than that in WT/WT mice. In contrast, Smpd1-/- mice on the HDF had significantly lower urinary exosome excretion than WT/WT mice. Correspondingly, HFD-induced podocyte injury, glomerular sclerosis, and proteinuria were more severe in Smpd1trg/Podocre mice, but milder in Smpd1-/- mice compared to WT/WT mice. Using podocytes isolated from these mice, we demonstrated that visfatin, a prototype pro-inflammatory adipokine, induced NLRP3 inflammasome activation and enrichment of multivesicular bodies (MVBs) containing IL-1ß in podocytes, which was much stronger in podocytes from Smpd1trg/Podocre mice, but weaker in those from Smpd1-/- mice than WT/WT podocytes. By quantitative analysis of exosomes, it was found that upon visfatin stimulation, podocytes from Smpd1trg/Podocre mice released much more exosomes containing NLRP3 inflammasome products, but podocytes from Smpd1-/- mice released much less exosomes compared to WT/WT podocytes. Super-resolution microscopy demonstrated that visfatin inhibited lysosome-MVB interaction in podocytes, indicating impaired MVB degradation by lysosome. The inhibition of lysosome-MVB interaction by visfatin was amplified by Smpd1 gene overexpression but attenuated by Smpd1 gene deletion. Taken together, our results suggest that ASM in podocytes is a crucial regulator of NLRP3 inflammasome activation and inflammatory exosome release that instigate glomerular inflammation and injury during obesity.

Mucilage secretion by aerial roots in sorghum (Sorghum bicolor): sugar profile, genetic diversity, GWAS and transcriptomic analysis.

Aerial root mucilage can enhance nitrogen fixation by providing sugar and low oxygen environment to the rhizosphere microbiome in Sierra Mixe maize. Aerial root mucilage has long been documented in sorghum (Sorghum bicolor), but little is known about the biological significance, genotypic variation, and genetic regulation of this biological process. In the present study, we found that a large variation of mucilage secretion capacity existed in a sorghum panel consisting of 146 accessions. Mucilage secretion occurred primarily in young aerial roots under adequately humid conditions but decreased or stopped in mature long aerial roots or under dry conditions. The main components of the mucilage-soluble were glucose and fructose, as revealed by sugar profiling of cultivated and wild sorghum. The mucilage secretion capacity of landrace grain sorghum was significantly higher than that of wild sorghum. Transcriptome analysis revealed that 1844 genes were upregulated and 2617 genes were downregulated in mucilage secreting roots. Amongst these 4461 differentially expressed genes, 82 genes belonged to glycosyltransferases and glucuronidation pathways. Sobic.010G120200, encoding a UDP-glycosyltransferase, was identified by both GWAS and transcriptome analysis as a candidate gene, which may be involved in the regulation of mucilage secretion in sorghum through a negative regulatory mechanism.

Identification of lncRNA, miRNA and mRNA expression profiles and ceRNA Networks in small cell lung cancer.

BACKGROUND: Small cell lung cancer (SCLC) is a highly lethal malignant tumor. It accounts for approximately 15% of newly diagnosed lung cancers. Long non-coding RNAs (lncRNAs) can regulate gene expression and contribute to tumorigenesis through interactions with microRNAs (miRNAs). However, there are only a few studies reporting the expression profiles of lncRNAs, miRNAs, and mRNAs in SCLC. Also, the role of differentially expressed lncRNAs, miRNAs, and mRNAs in relation to competitive endogenous RNAs (ceRNA) network in SCLC remain unclear. RESULTS: In the present study, we first performed next generation sequencing (NGS) with six pairs of SCLC tumors and adjacent non-cancerous tissues obtained from SCLC patients. Overall, 29 lncRNAs, 48 miRNAs, and 510 mRNAs were found to be differentially expressed in SCLC samples (|log2[fold change] |> 1; P < 0.05). Bioinformatics analysis was performed to predict and construct a lncRNA-miRNA-mRNA ceRNA network, which included 9 lncRNAs, 11 miRNAs, and 392 mRNAs. Four up-regulated lncRNAs and related mRNAs in the ceRNA regulatory pathways were selected and validated by quantitative PCR. In addition, we examined the role of the most upregulated lncRNA, TCONS_00020615, in SCLC cells. We found that TCONS_00020615 may regulate SCLC tumorigenesis through the TCONS_00020615-hsa-miR-26b-5p-TPD52 pathway. CONCLUSIONS: Our study provided the comprehensive analysis of the expression profiles of lncRNAs, miRNAs, and mRNAs of SCLC tumors and adjacent non-cancerous tissues. We constructed the ceRNA networks which may provide new evidence for the underlying regulatory mechanism of SCLC. We also found that the lncRNA TCONS_00020615 may regulate the carcinogenesis of SCLC.