Physiological and biochemical characteristics of the carbon ion beam irradiation-generated mutant strain Clostridium butyricum FZM 240 in vitro and in vivo.

Clostridium butyricum (C. butyricum) represents a new generation of probiotics, which is beneficial because of its good tolerance and ability to produce beneficial metabolites, such as short-chain fatty acids and enzymes; however, its low enzyme activity limits its probiotic efficacy. In this study, a mutant strain, C. butyricum FZM 240 was obtained using carbon ion beam irradiation, which exhibited greatly improved enzyme production and tolerance. The highest filter paper, endoglucanase, and amylase activities produced by C. butyricum FZM 240 were 125.69 U/mL, 225.82 U/ mL, and 252.28 U/mL, which were 2.58, 1.95, and 2.21-fold higher, respectively, than those of the original strain. The survival rate of the strain increased by 11.40 % and 5.60 % after incubation at 90 °C for 5 min and with simulated gastric fluid at pH 2.5 for 2 h, respectively, compared with that of the original strain. Whole-genome resequencing and quantitative real-time PCR(qRT-PCR) analysis showed that the expression of genes related to enzyme synthesis (GE000348, GE001963 and GE003123) and tolerance (GE001114) was significantly up-regulated, while that of genes related to acid metabolism (GE003450) was significantly down-regulated. On this basis, homology modeling and functional prediction of the proteins encoded by the mutated genes were performed. According to the results, the properties related to the efficacy of C. butyricum as a probiotic were significantly enhanced by carbon ion beam irradiation, which is a novel strategy for the application of Clostridium spp. as feed additives.

Cell death in atherosclerosis.

A complex and evolutionary process that involves the buildup of lipids in the arterial wall and the invasion of inflammatory cells results in atherosclerosis. Cell death is a fundamental biological process that is essential to the growth and dynamic equilibrium of all living things. Serious cell damage can cause a number of metabolic processes to stop, cell structure to be destroyed, or other irreversible changes that result in cell death. It is important to note that studies have shown that the two types of programmed cell death, apoptosis and autophagy, influence the onset and progression of atherosclerosis by controlling these cells. This could serve as a foundation for the creation of fresh atherosclerosis prevention and treatment strategies. Therefore, in this review, we summarized the molecular mechanisms of cell death, including apoptosis, pyroptosis, autophagy, necroptosis, ferroptosis and necrosis, and discussed their effects on endothelial cells, vascular smooth muscle cells and macrophages in the process of atherosclerosis, so as to provide reference for the next step to reveal the mechanism of atherosclerosis.

Analysis of drug-induced posterior reversible encephalopathy syndrome using the food and drug administration adverse drug events reporting system database.

OBJECTIVE: In this retrospective pharmacovigilance study, we gathered data on drug-induced posterior reversible encephalopathy syndrome (PRES). Our goal was to identify the primary suspect drugs in PRES by analyzing the Food and Drug Administration Adverse Events Reporting System (FAERS) database. METHODS: We identified and analyzed reports of PRES listed in the FAERS database between 2004 and 2021. Using the reporting odds ratio and 95% confidence interval, we evaluated the safety signals for each of the drugs associated with PRES. RESULTS: We reviewed 11,077 reports of adverse events corresponding to PRES. The primary suspect drug categories were antineoplastics, immunosuppressants, and glucocorticoids. PRES was 24.77% more likely to occur in females than in males. Drug-induced PRES usually occurs in individuals with cancer, those who have undergone an organ/stem cell transplant, and those with autoimmune conditions. CONCLUSION: Our results show that the drugs most commonly suspected to cause PRES were antineoplastics, immunosuppressants, and glucocorticoids. Future studies are needed to illuminate the pathophysiological alterations that underlie PRES. In the meantime, prescribers and patients should be made aware of the potential risks of PRES associated with pharmaceutical therapy, and the summaries of product characteristics for individual drugs should be updated to include this information.

DeepHipp: accurate segmentation of hippocampus using 3D dense-block based on attention mechanism.

BACKGROUND: The hippocampus is a key area of the brain responsible for learning, memory, and other abilities. Accurately segmenting the hippocampus and precisely calculating the volume of the hippocampus is of great significance for predicting Alzheimer's disease and amnesia. Most of the segmentation algorithms currently involved are based on templates, such as the more popular FreeSufer. METHODS: This study proposes Deephipp, a deep learning network based on a 3D dense block using an attention mechanism for accurate segmentation of the hippocampus. DeepHipp is based on the following novelties: (i) DeepHipp adopts powerful data augmentation schemes to enhance the segmentation ability. (ii) DeepHipp is designed to incorporate 3D dense-block to capture multiple-scale features of the hippocampus. (iii) DeepHipp creatively uses the attention mechanism in the field of hippocampal image segmentation, extracting useful hippocampus information in a massive feature map, and improving the accuracy and sensitivity of the model. CONCLUSIONS: We describe the illustrative results and show extensive qualitative and quantitative comparisons with other methods. Our achievement demonstrates that the accuracy of DeepHipp can reach 83.63%, which is superior to most existing methods in terms of accuracy and efficiency of hippocampus segmentation. It is noticeable that deep learning can potentially lead to an effective segmentation of medical images.

Magnetic Resonance Deep Learning Radiomic Model Based on Distinct Metastatic Vascular Patterns for Evaluating Recurrence-Free Survival in Hepatocellular Carcinoma.

BACKGROUND: The metastatic vascular patterns of hepatocellular carcinoma (HCC) are mainly microvascular invasion (MVI) and vessels encapsulating tumor clusters (VETC). However, most existing VETC-related radiological studies still focus on the prediction of VETC status. PURPOSE: This study aimed to build and compare VETC-MVI related models (clinical, radiomics, and deep learning) associated with recurrence-free survival of HCC patients. STUDY TYPE: Retrospective. POPULATION: 398 HCC patients (349 male, 49 female; median age 51.7 years, and age range: 22-80 years) who underwent resection from five hospitals in China. The patients were randomly divided into training cohort (n = 358) and test cohort (n = 40). FIELD STRENGTH/SEQUENCE: 3-T, pre-contrast T1-weighted imaging spoiled gradient recalled echo (T1WI SPGR), T2-weighted imaging fast spin echo (T2WI FSE), and contrast enhanced arterial phase (AP), delay phase (DP). ASSESSMENT: Two radiologists performed the segmentation of HCC on T1WI, T2WI, AP, and DP images, from which radiomic features were extracted. The RFS related clinical characteristics (VETC, MVI, Barcelona stage, tumor maximum diameter, and alpha fetoprotein) and radiomic features were used to build the clinical model, clinical-radiomic (CR) nomogram, deep learning model. The follow-up process was done 1 month after resection, and every 3 months subsequently. The RFS was defined as the date of resection to the date of recurrence confirmed by radiology or the last follow-up. Patients were followed up until December 31, 2022. STATISTICAL TESTS: Univariate COX regression, least absolute shrinkage and selection operator (LASSO), Kaplan-Meier curves, log-rank test, C-index, and area under the curve (AUC). P < 0.05 was considered statistically significant. RESULTS: The C-index of deep learning model achieved 0.830 in test cohort compared with CR nomogram (0.731), radiomic signature (0.707), and clinical model (0.702). The average RFS of the overall patients was 26.77 months (range 1-80 months). DATA CONCLUSION: MR deep learning model based on VETC and MVI provides a potential tool for survival assessment. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 3.

Data mining for signal detection of adverse events for taxanes based on the food and drug administration adverse drug events reporting system database.

BACKGROUND: This study aimed to mine and compare the positive signals of adverse drug events (ADE) in paclitaxel, docetaxel, and nab-paclitaxel to evaluate the accuracy of current drug package information inserts and enable clinicians to select the appropriate treatment. RESEARCH DESIGN AND METHODS: ADE data reported from January 2006 to December 2020 were extracted from the Food and Drug Adverse Drug Events Reporting System (FAERS) database, and the reporting odds ratio (ROR) was used to detect the risk signals of the 3 taxanes. The definition relied on system organ class (SOCs) and preferred terms (PTs) by the Medical Dictionary for Regulatory Activities (MedDRA). RESULTS: A total of 39,163 case reports on paclitaxel, docetaxel and nab-paclitaxel involving 25 different system organ classes (SOCs) were retrieved from the database. The ADE paclitaxel and nab-paclitaxel reports mainly focused on 'general disorders and administration site conditions' and the docetaxel ADE reports focused on 'skin and subcutaneous tissue diseases.' Among the three taxanes, nab-paclitaxel had the highest positive signal for serious adverse events. CONCLUSIONS: Overall, the most common ADE signals and ADE mapping systems obtained in this study were consistent with the package inserts. However, some inconsistencies were noted. Further research is recommended to confirm some of the strong risk signals for ADEs for taxanes before updating the drug package information inserts.

Elevated histone demethylase KDM5C increases recurrent miscarriage risk by preventing trophoblast proliferation and invasion.

KDM5C is a histone H3K4-specific demethylase, which has been shown to play a key role in biological disease and development. However, the role of KDM5C in trophoblasts at early pregnancy is currently unknown. Here, we showed that KDM5C was upregulated in placental trophoblasts from recurrent miscarriage (RM) patients compared with healthy controls (HCs). Trophoblast proliferation and invasion was inhibited by KDM5C overexpression and was promoted by KDM5C knockdown. Transcriptome sequencing revealed that elevated KDM5C exerted anti-proliferation and anti-invasion effects by repressing the expression of essential regulatory genes. The combination analysis of RNA-seq, ChIP-seq and CUT&Tag assay showed that KDM5C overexpression leads to the reduction of H3K4me3 on the promoters and the corresponding downregulation of expression of several regulatory genes in trophoblasts. Among these genes, TGFß2 and RAGE are essential for the proliferation and invasion of trophoblasts. Importantly, overexpression of KDM5C by a systemically delivered KDM5C adenovirus vector (Ad-KDM5C) promoted embryo resorption rate in mouse. Our results support that KDM5C is an important regulator of the trophoblast function during early pregnancy, and suggesting that KDM5C activity could be responsible for epigenetic alterations seen RM disease.

A ROS-Responsive Liposomal Composite Hydrogel Integrating Improved Mitochondrial Function and Pro-Angiogenesis for Efficient Treatment of Myocardial Infarction.

Mitochondrial dysfunction of cardiomyocytes (CMs) has been identified as a significant pathogenesis of early myocardial infarction (MI). However, only a few agents or strategies have been developed to improve mitochondrial dysfunction for the effective MI treatment. Herein, a reactive oxygen species (ROS)-responsive PAMB-G-TK/4-arm-PEG-SG hydrogel is developed for localized drug-loaded liposome delivery. Notably, the liposomes contain both elamipretide (SS-31) and sphingosine-1-phosphate (S1P), where SS-31 acts as an inhibitor of mitochondrial oxidative damage and S1P as a signaling molecule for activating angiogenesis. Liposome-encapsulated PAMB-G-TK/4-arm-PEG-SG hydrogels demonstrate myocardium-like mechanical strength and electrical conductivity, and ROS-sensitive release of SS-31 and S1P-loaded liposomes. Further liposomal release of SS-31, which can target cytochrome c in the mitochondrial inner membrane of damaged CMs, inhibits pathological ROS production, improving mitochondrial dysfunction. Meanwhile, S1P released from the liposome induces endothelial cell angiogenesis by activating the S1PR1/PI3K/Akt pathway. In a rat MI model, the resulting liposomal composite hydrogel improves cardiac function by scavenging excess ROS, improving mitochondrial dysfunction, and promoting angiogenesis. This study reports for the first time a liposomal composite hydrogel that can directly target mitochondria of damaged CMs for a feedback-regulated release of encapsulated liposomes to consume the overproduced pathological ROS for improved CM activity and enhanced MI treatment.

Targeted mitochondrial drugs for treatment of myocardial ischaemia-reperfusion injury.

Myocardial ischaemia-reperfusion injury (MI/RI) refers to the further damage done to ischaemic cardiomyocytes when restoring blood flow. A large body of evidence shows that MI/RI is closely associated with excessive production of mitochondrial reactive oxygen species, mitochondrial calcium overload, disordered mitochondrial energy metabolism, mitophagy, mitochondrial fission, and mitochondrial fusion. According to the way it affects mitochondria, it can be divided into mitochondrial quality abnormalities and mitochondrial quantity abnormalities. Abnormal mitochondrial quality refers to the dysfunction caused by the severe destruction of mitochondria, which then affects the balance of mitochondrial density and number, causing an abnormal mitochondrial quantity. In the past, most of the reports were limited to the study of the mechanism of myocardial ischaemia-reperfusion injury, some of which involved mitochondria, but no specific countermeasures were proposed. In this review, we outline the mechanisms for treating myocardial ischaemia-reperfusion injury from the direction of mitochondria and focus on targeted interventions and drugs to restore mitochondrial health during abnormal mitochondrial quality control and abnormal mitochondrial quantity control. This is an update in the field of myocardial ischaemia-reperfusion injury.

cGAS-STING signaling in ischemic diseases.

Double stranded DNA (dsDNA) is known to act as a damage-associated molecular pattern (DAMP) that stimulates the body's innate immune response. In general, cyclicGMP-AMP(cGAMP)synthase(cGAS), a DNA sensor, detects these disease-causing DNA and activates the stimulator of interferon gene (STING), which in turn phosphorylates interferon regulatory factor 3 (IRF3), triggering the synthesis of type I interferon (IFN). During this process, the cGAS-STING pathway interacts with different modes of cell death, including autophagy, apoptosis, pyroptosis, and necroptosis. Importantly, cGAS might get stimulated by self-DNA, such as nuclear DNA (nuDNA) and mitochondrial DNA (mtDNA), which ensures a close association between the cGAS-STING signaling pathway and autoimmune responses. Following an ischemic attack, damaged or necrotic cells release large amounts of self-DNA that subsequently activate cGAS, resulting in a range of consequences related to an injury. The present study presents an overview of studies focused on cGAS-STING signaling and cell death, and summarizes the findings of this pathway with regard to ischemia or ischemia/reperfusion (I/R) in different organs of the body, including heart, brain, liver, kidney, and intestine.

Fabp4 contributes toward regulating inflammatory gene expression and oxidative stress in Ctenopharyngodon idella.

Fatty acid-binding protein (Fabp)-4 is a member of the FABP family. Mammalian fabp4 has been demonstrated to involve in inflammation and immunity, whereas the related data of fish fabp4 remain limited. Therefore, we further investigated the effects of fabp4 on immunity in Ctenopharyngodon idella. The fabp4 sequence spanned 405 bp was cloned first, sharing high identity to fabp4 from other fish and mammals. Fabp4 expression was the highest in the adipose tissue, followed by the heart, muscle, and liver. In vivo, lipopolysaccharide (LPS) triggered the expression of fabp4, toll-like receptor (tlr)-22, interleukin (il)-1ß, and tumor necrosis factor (tnf)-α in the kidney and spleen. In vitro, exposing C. idella CIK cells to LPS decreased their viability, and the expression of fabp4 was also increased by LPS. However, BMS309403, an inhibitor of FABP4, mitigated these effects. Furthermore, treating the cells with LPS or fabp4 overexpression plasmids resulted in reactive oxygen species (ROS) generation and upregulation of inflammatory genes expression, including tlr22, type-I interferon (ifn-1), interferon regulatory factor (irf)-7, tnfα, il-1ß, and interferon-ß promoter stimulator 1. These effects were ameliorated by preincubation with BMS309403. Moreover, incubating the cells with glutathione reduced the production of ROS and the expression of inflammatory genes that were evoked by LPS and plasmid treatments. These results showed that fabp4 acts as a pro-inflammatory molecule via elevating ROS levels, providing a novel understanding of the molecular regulation of innate immunity in teleosts.

Sphingosine-1-phosphate receptor 3 signaling.

Sphingosine-1-phosphate (S1P) is a bioactive lipid which regulates a series of physiological and pathological processes via binding to five S1P receptors (S1PR1-5). Although S1PR1-3 are widely expressed, the study of S1PRs, however, mainly addressed S1PR1 and S1PR2, and few studies focus on S1PR3-5. In recent years, a growing number of studies have shown that S1PR3 plays an important role in cell proliferation, differentiation, apoptosis, and migration, but its function is still controversial. This is the first comprehensive review paper about the role of S1PR3 signaling in cardiovascular function, tissue fibrosis, cancer, immune response, and neurological function. In addition, existing S1PR3 agonists and antagonists are listed at the end of the article, and we also put forward our opinion on the dispute of S1PR3 function.

Next-Generation Sequencing Is More Efficient at Detecting Mosaic Embryos and Improving Pregnancy Outcomes than Single-Nucleotide Polymorphism Array Analysis.

We compared chromosomal mosaicism, detected by next-generation sequencing (NGS), during preimplantation genetic testing (PGT) with that detected by single-nucleotide polymorphism (SNP) array-based PGT to assess the pregnancy outcomes associated with both platforms in a retrospective cohort study of patients undergoing in vitro fertilization in a single university-based assisted reproduction center. In total, 6427 blastocysts biopsied from 1513 patients who underwent 2833 oocyte retrievals from January 2017 to February 2019 were identified. The incidence of mosaicism was significantly higher in the NGS-based PGT group than in the SNP array-based PGT group. Furthermore, some aneuploid specimens were affected by mosaicism. The total mosaicism detection rate with NGS-based PGT (23.3%) was significantly higher than that with SNP array-based PGT (7.7%). Mosaicism rates were similar when stratified by maternal age or PGT type. The SNP array cohort showed a significantly higher spontaneous abortion rate than the NGS cohort (10.07% versus 6.33%; P = 0.0403). The ongoing pregnancy/live birth rate was higher in the NGS cohort (44.1%) than in the SNP array cohort (42.28%). Our results confirm that NGS-based PGT can detect mosaicism more frequently than SNP array-based PGT in trophectoderm specimens. Therefore, clinical application of NGS for PGT may improve pregnancy outcomes compared with that of SNP array-based PGT. More detailed blastocyst detection and classification is necessary to prioritize embryo transfers.

Response characteristics of the membrane integrity and physiological activities of the mutant strain Y217 under exogenous butanol stress.

Butanol inhibits bacterial activity by destroying the cell membrane of Clostridium acetobutylicum strains and altering functionality. Butanol toxicity also results in destruction of the phosphoenolpyruvate-carbohydrate phosphotransferase system (PTS), thereby preventing glucose transport and phosphorylation and inhibiting transmembrane transport and assimilation of sugars, amino acids, and other nutrients. In this study, based on the addition of exogenous butanol, the tangible macro indicators of changes in the carbon ion beam irradiation-mutant Y217 morphology were observed using scanning electron microscopy (SEM). The mutant has lower microbial adhesion to hydrocarbon (MATH) value than C. acetobutylicum ATCC 824 strain. FDA fluorescence intensity and conductivity studies demonstrated the intrinsically low membrane permeability of the mutant membrane, with membrane potential remaining relatively stable. Monounsaturated FAs (MUFAs) accounted for 35.17% of the mutant membrane, and the saturated fatty acids (SFA)/unsaturated fatty acids (UFA) ratio in the mutant cell membrane was 1.65. In addition, we conducted DNA-level analysis of the mutant strain Y217. Expectedly, through screening, we found gene mutant sites encoding membrane-related functions in the mutant, including ATP-binding cassette (ABC) transporter-related genes, predicted membrane proteins, and the PTS transport system. It is noteworthy that an unreported predicted membrane protein (CAC 3309) may be related to changes in mutant cell membrane properties. KEY POINTS: • Mutant Y217 exhibited better membrane integrity and permeability. • Mutant Y217 was more resistant to butanol toxicity. • Some membrane-related genes of mutant Y217 were mutated.

Characterization of Copy-Number Variations and Possible Candidate Genes in Recurrent Pregnancy Losses.

It is well established that embryonic chromosomal abnormalities (both in the number of chromosomes and the structure) account for 50% of early pregnancy losses. However, little is known regarding the potential differences in the incidence and distribution of chromosomal abnormalities between patients with sporadic abortion (SA) and recurrent pregnancy loss (RPL), let alone the role of submicroscopic copy-number variations (CNVs) in these cases. The aim of the present study was to systematically evaluate the role of embryonic chromosomal abnormalities and CNVs in the etiology of RPL compared with SA. Over a 3-year period, 1556 fresh products of conception (POCs) from miscarriage specimens were investigated using single nucleotide polymorphism array (SNP-array) and CNV sequencing (CNV-seq) in this study, along with further functional enrichment analysis. Chromosomal abnormalities were identified in 57.52% (895/1556) of all cases. Comparisons of the incidence and distributions of chromosomal abnormalities within the SA group and RPL group and within the different age groups were performed. Moreover, 346 CNVs in 173 cases were identified, including 272 duplications, 2 deletions and 72 duplications along with deletions. Duplications in 16q24.3 and 16p13.3 were significantly more frequent in RPL cases, and thereby considered to be associated with RPL. There were 213 genes and 131 signaling pathways identified as potential RPL candidate genes and signaling pathways, respectively, which were centered primarily on six functional categories. The results of the present study may improve our understanding of the etiologies of RPL and assist in the establishment of a population-based diagnostic panel of genetic markers for screening RPL amongst Chinese women.

Robust W/O/W Emulsion Stabilized by Genipin-Cross-Linked Sugar Beet Pectin-Bovine Serum Albumin Nanoparticles: Co-encapsulation of Betanin and Curcumin.

Betanin and curcumin hold promise as natural colorants and antioxidants for food purposes due to their anti-hypertensive, anti-inflammation, and anti-tumor effects. However, the thermal stability and bioavailability of betanin and curcumin still need improvement. Here, we fabricated sugar beet pectin-bovine serum albumin nanoparticles (SBNPs) with a mean particle size of 180 ± 5.2 nm through a genipin cross-linking strategy to stabilize a type of Pickering water-in-oil-in-water (W/O/W) emulsion and co-encapsulated betanin and curcumin. First, the W1/O emulsion was homogenized with gelatin (the gelling agent) in the water phase and polyglycerol polyricinoleate (a lipophilic surfactant) in the oil phase. Later, W1/O was homogenized with another water phase containing SBNPs. The microstructure of the emulsion was regulated by the particle concentration (c) and W1/O volume fraction (Φ), especially the gel-like high internal phase emulsions were formed at the Φ up to 70%. In this case, betanin was encapsulated in the internal water phase (encapsulation efficiency = 65.3%), whereas curcumin was in the medium-chain triglyceride (encapsulation efficiency = 84.1%). Meanwhile, the shelf stability of betanin and curcumin was improved. Furthermore, the stability of bioactive compounds was potentiated by an emulsion gel in simulated gastrointestinal digestion, resulting in higher bioaccessibility. The aforementioned results suggest that SBNP-stabilized Pickering W/O/W emulsions could be a potential alternative to co-encapsulate betanin and curcumin with enhancement of shelf stability and bioaccessibility.

The Hippo Pathway Orchestrates Mitochondrial Quality Control: A Novel Focus on Cardiovascular Diseases.

Mitochondria serve as a hub for cell metabolism, energy production, and reactive oxygen species generation through multiple signaling pathways that control cardiomyocyte survival and death and contribute to the pathophysiological process of cardiovascular diseases (CVDs). Therefore, maintaining mitochondrial quality control (MQC) is essential for mitochondrial homeostasis and cardiac health. The Hippo pathway is a conserved signaling cascade that regulates mitochondrial function and cardiomyocyte fate and plays a crucial role in cardiac regeneration, repair, and diseases. MQC and the Hippo pathway are tightly coupled in CVDs, and several regulatory elements of the Hippo pathway directly/indirectly regulate mitochondria-related proteins to mediate mitochondrial morphology and function. In turn, mitochondrial morphology partly influences Hippo pathway function in the heart. This review outlines the underlying mechanisms by which the Hippo pathway regulates MQC from a variety of perspectives, including mitochondrial dynamics, mitophagy, mitochondrial biogenesis, mitochondrial apoptosis under oxidative stress, and mitochondrial metabolism. We also discuss the roles of the Hippo pathway in orchestrating mitochondria in CVDs, such as myocardial ischemia-reperfusion injury, septic cardiomyopathy, and diabetic cardiomyopathy, which may provide a novel therapeutic strategy.

Cannabis-Associated Psychotic-like Experiences Are Mediated by Developmental Changes in the Parahippocampal Gyrus.

OBJECTIVE: Cannabis consumption during adolescence has been reported as a risk factor for psychotic-like experiences (PLEs) and schizophrenia. However, brain developmental processes associated with cannabis-related PLEs are still poorly described. METHOD: A total of 706 adolescents from the general population who were recruited by the IMAGEN consortium had structural magnetic resonance imaging scans at both 14 and 19 years of age. We used deformation-based morphometry to map voxelwise brain changes between the two time points, using the pairwise algorithm in SPM12b. We used an a priori region-of-interest approach focusing on the hippocampus/parahippocampus to perform voxelwise linear regressions. Lifetime cannabis consumption was assessed using the European School Survey Project on Alcohol and other Drugs (ESPAD), and PLEs were assessed with the Comprehensive Assessment Psychotic-like experiences (CAPE) tool. We first tested whether hippocampus/parahippocampus development was associated with PLEs. Then we formulated and tested an a priori simple mediation model in which uncus development mediates the association between lifetime cannabis consumption and PLEs. RESULTS: We found that PLEs were associated with reduced expansion within a specific region of the right hippocampus/parahippocampus formation, the uncus (p = .002 at the cluster level, p = .018 at the peak level). The partial simple mediation model revealed a significant total effect from lifetime cannabis consumption to PLEs (b = 0.069, 95% CI = 0.04-0.1, p =2 × 10-16), as well as a small yet significant, indirect effect of right uncus development (0.004; 95% CI = 0.0004-0.01, p = .026). CONCLUSION: We show here that the uncus development is involved in the cerebral basis of PLEs in a population-based sample of healthy adolescents.

Transcriptome analysis of golden pompano (Trachinotus ovatus) liver indicates a potential regulatory target involved in HUFA uptake and deposition.

Promoting highly unsaturated fatty acid (HUFA) uptake and deposition can improve nutritional value of farmed fish and reduce dietary fish oil addition. Previously, we found that the golden pompano Trachinotus ovatus liver HUFA content increased with the increasing of dietary HUFA. Therefore, we examined the common genes and pathways responsible for HUFA uptake and deposition in T. ovatus liver using transcriptome sequencing technology after feeding with either 1.0% or 2.1% HUFA for 8 weeks. Results showed that a total of 140 and 147 genes were significantly upregulated and downregulated, respectively. Five bile acid synthesis-related genes (CYP7A1, CYP8B1, AKR1D1, SCP2 and ACOT8), which are related to dietary fat emulsification were downregulated in 2.1% HUFA group, implying that the cholate synthesized through the classical pathway might be the main bile acid form in fat emulsification. Moreover, fatty acid transport protein (FATP)-6, fatty acid binding protein (FABP)-1, -4, and -6 increased with HUFA deposition, especially FATP6 and FABP4, suggesting that the two genes may be important mediators involved in HUFA uptake and deposition. KEGG analysis showed that most of the differential genes described above were involved in peroxisome proliferator activator receptor (PPAR) signaling pathway, and PPARγ increased with HUFA deposition, indicating that PPARγ might be a key regulator of HUFA uptake and deposition by regulating the genes involved in fatty acid emulsification and transport. This study focused on the liver, which is the center of intermediary metabolism, providing a comprehensive understanding of the molecular regulation of HUFA uptake and deposition in T. ovatus, which should be further investigated to develop potential measures to improve HUFA content.

Lipid droplets participate in modulating innate immune genes in Ctenopharyngodon idella kidney cells.

Lipid droplets (LDs) are increasingly being recognized as important immune modulators in mammals, in additional to their function of lipid ester deposition. However, the role of LDs in fish immunity remains poorly understood. In this study, the function of LDs in the innate immune response of Ctenopharyngodon idella kidney (CIK) cells, which are the equivalent of myeloid cells in vertebrates, was investigated. LD number and TG content significantly increased in the CIK cells following exposure to lipopolysaccharide (LPS), peptidoglycan (PGN), and polyriboinosinic-polyribocytidylic acid (Poly [I: C]) for 24 h, accompanied by increases in the relative expression of several innate immune genes. However, fatty acid compositions of the triglycerides were not changed after treatment with these three pathogenic mimics. LPS, PGN, and Poly (I: C) did not alter the relative expressions of lipogenic (FAS, SCD, and DGAT) and lipid catabolic (PPARα, ATGL, and CPT-1) genes. However, these treatments did increase the mRNA levels of lipid transportation genes (FATP/CD36, ACSL1, and ACSL4), and also decreased the non-esterified fatty acid level in the medium. To further explore the role of LDs in the immune response, CIK cells were incubated with different concentrations (0, 100, 200, 300, 400, 500 µM) of exogenous lipid mix (LM; oleic acid [OA]:linoleic acid [LA]:linolenic acid [LNA] = 2:1:1), and were then transferred to a lipid-free medium and incubated for 24 h. LD size and number increased with the increase in lipid levels, and this was accompanied by increased expression of innate immune genes, including MyD88, IRF3, and IL-1ß, which were expressed at their highest levels in 300 µM exogenous lipid mix. Interestingly, after incubating with different fatty acids (LM, OA, LA, LNA, arachidonic acid [ARA], and docosahexaenoic acid [DHA]; 300 µM), ARA and DHA were more potent in inducing LD formation and innate immune gene expression in the CIK cells. Finally, atglistatin, an ATGL inhibitor, effectively attenuated the expression of most genes upregulated by ARA or DHA, suggesting that lipolysis may be involved in the regulation of immune genes at the transcriptional level. Overall, the findings of this study demonstrate that LDs are functional organelles that could act as modulators in the innate immune response of CIK cells. Additionally, long-chain polyunsaturated fatty acid enriched LDs play a unique role in regulating this process.