Data-dependent and -independent acquisition lipidomics analysis reveals the tissue-dependent effect of metformin on lipid metabolism.

INTRODUCTION: Despite the well-recognized health benefits, the mechanisms and site of action of metformin remains elusive. Metformin-induced global lipidomic changes in plasma of animal models and human subjects have been reported. However, there is a lack of systemic evaluation of metformin-induced lipidomic changes in different tissues. Metformin uptake requires active transporters such as organic cation transporters (OCTs), and hence, it is anticipated that metformin actions are tissue-dependent. In this study, we aim to characterize metformin effects in non-diabetic male mice with a special focus on lipidomics analysis. The findings from this study will help us to better understand the cell-autonomous (direct actions in target cells) or non-cell-autonomous (indirect actions in target cells) mechanisms of metformin and provide insights into the development of more potent yet safe drugs targeting a particular organ instead of systemic metabolism for metabolic regulations without major side effects. OBJECTIVES: To characterize metformin-induced lipidomic alterations in different tissues of non-diabetic male mice and further identify lipids affected by metformin through cell-autonomous or systemic mechanisms based on the correlation between lipid alterations in tissues and the corresponding in-tissue metformin concentrations. METHODS: A dual extraction method involving 80% methanol followed by MTBE (methyl tert-butyl ether) extraction enables the analysis of free fatty acids, polar metabolites, and lipids. Extracts from tissues and plasma of male mice treated with or without metformin in drinking water for 12 days were analyzed using HILIC chromatography coupled to Q Exactive Plus mass spectrometer or reversed-phase liquid chromatography coupled to MS/MS scan workflow (hybrid mode) on LC-Orbitrap Exploris 480 mass spectrometer using biologically relevant lipids-containing inclusion list for data-independent acquisition (DIA), named as BRI-DIA workflow followed by data-dependent acquisition (DDA), to maximum the coverage of lipids and minimize the negative effect of stochasticity of precursor selection on experimental consistency and reproducibility. RESULTS: Lipidomics analysis of 6 mouse tissues and plasma allowed a systemic evaluation of lipidomic changes induced by metformin in different tissues. We observed that (1) the degrees of lipidomic changes induced by metformin treatment overly correlated with tissue concentrations of metformin; (2) the impact on lysophosphatidylcholine (lysoPC) and cardiolipins was positively correlated with tissue concentrations of metformin, while neutral lipids such as triglycerides did not correlate with the corresponding tissue metformin concentrations; (3) increase of intestinal tricarboxylic acid (TCA) cycle intermediates after metformin treatment. CONCLUSION: The data collected in this study from non-diabetic mice with 12-day metformin treatment suggest that the overall metabolic effect of metformin is positively correlated with tissue concentrations and the effect on individual lipid subclass is via both cell-autonomous mechanisms (cardiolipins and lysoPC) and non-cell-autonomous mechanisms (triglycerides).

Identification of Single Nucleotide Polymorphic Loci and Candidate Genes for Seed Germination Percentage in Okra under Salt and No-Salt Stresses by Genome-Wide Association Study.

Excessive soil salinity is a major stressor inhibiting crops' growth, development, and yield. Seed germination is a critical stage of crop growth and development, as well as one of the most salt-sensitive stages. Salt stress has a significant inhibitory effect on seed germination. Okra is a nutritious vegetable, but its seed germination percentage (GP) is low, whether under salt stress conditions or suitable conditions. In this study, we used 180 okra accessions and conducted a genome-wide association study (GWAS) on the germination percentage using 20,133,859 single nucleotide polymorphic (SNP) markers under 0 (CK, diluted water), 70 (treatment 1, T1), and 140 mmol/L (treatment 2, T2) NaCl conditions. Using the mixed linear model (MLM) in Efficient Mixed-model Association eXpedated (EMMAX) and Genome-wide Efficient Mixed Model Association (GEMMA) software, 511 SNP loci were significantly associated during germination, of which 167 SNP loci were detected simultaneously by both programs. Among the 167 SNPs, SNP2619493 on chromosome 59 and SNP2692266 on chromosome 44 were detected simultaneously under the CK, T1, and T2 conditions, and were key SNP loci regulating the GP of okra seeds. Linkage disequilibrium block analysis revealed that nsSNP2626294 (C/T) in Ae59G004900 was near SNP2619493, and the amino acid changes caused by nsSNP2626294 led to an increase in the phenotypic values in some okra accessions. There was an nsSNP2688406 (A/G) in Ae44G005470 near SNP2692266, and the amino acid change caused by nsSNP2688406 led to a decrease in phenotypic values in some okra accessions. These results indicate that Ae59G004900 and Ae44G005470 regulate the GP of okra seeds under salt and no-salt stresses. The gene expression analysis further demonstrated these results. The SNP markers and genes that were identified in this study will provide reference for further research on the GP of okra, as well as new genetic markers and candidate genes for cultivating new okra varieties with high GPs under salt and no-salt stress conditions.

Association between sleep-related phenotypes and gut microbiota: a two-sample bidirectional Mendelian randomization study.

Background: An increasing body of evidence suggests a profound interrelation between the microbiome and sleep-related concerns. Nevertheless, current observational studies can merely establish their correlation, leaving causality unexplored. Study objectives: To ascertain whether specific gut microbiota are causally linked to seven sleep-related characteristics and propose potential strategies for insomnia prevention. Methods: The study employed an extensive dataset of gut microbiota genetic variations from the MiBioGen alliance, encompassing 18,340 individuals. Taxonomic classification was conducted, identifying 131 genera and 196 bacterial taxa for analysis. Sleep-related phenotype (SRP) data were sourced from the IEU OpenGWAS project, covering traits such as insomnia, chronotype, and snoring. Instrumental variables (IVs) were selected based on specific criteria, including locus-wide significance, linkage disequilibrium calculations, and allele frequency thresholds. Statistical methods were employed to explore causal relationships, including inverse variance weighted (IVW), MR-Egger, weighted median, and weighted Mode. Sensitivity analyses, pleiotropy assessments, and Bonferroni corrections ensured result validity. Reverse causality analysis and adherence to STROBE-MR guidelines were conducted to bolster the study's rigor. Results: Bidirectional Mendelian randomization (MR) analysis reveals a causative interplay between selected gut microbiota and sleep-related phenotypes. Notably, outcomes from the rigorously Bonferroni-corrected examination illuminate profound correlations amid precise compositions of the intestinal microbiome and slumber-associated parameters. Elevated abundance within the taxonomic ranks of class Negativicutes and order Selenomonadales was markedly associated with heightened susceptibility to severe insomnia (OR = 1.03, 95% CI: 1.02-1.05, p = 0.0001). Conversely, the augmented representation of the phylum Lentisphaerae stands in concord with protracted sleep duration (OR = 1.02, 95% CI: 1.01-1.04, p = 0.0005). Furthermore, heightened exposure to the genus Senegalimassilia exhibits the potential to ameliorate the manifestation of snoring symptoms (OR = 0.98, 95% CI: 0.96-0.99, p = 0.0001). Conclusion: This study has unveiled the causal relationship between gut microbiota and SRPs, bestowing significant latent value upon future endeavors in both foundational research and clinical therapy.

Using telehealth to deliver Qi Gong and Tai Chi programs: A mixed-methods systematic review on feasibility, acceptability and participant engagement factors.

INTRODUCTION: Due to the COVID-19 pandemic, the use of digitally delivered exercise classes to promote physical activity has become widespread amongst various populations as an alternative to in-person activities. OBJECTIVES: To examine the feasibility, acceptability, and participant engagement variables to delivering Qi Gong and Tai Chi programs through telehealth interventions. METHODS: Ten databases (Seven English databases; three Chinese databases) were searched between October and November 2021. Studies published in English or Chinese, or having translations in English or Chinese, were included. Titles and abstracts of identified articles were screened, relevant studies were then retrieved for full-text screening. Study selection, assessment of methodological quality, data extraction, data transformation, and data synthesis were completed following a convergent integrated approach to mixed method systematic reviews. RESULTS: Seven articles were included in review. Digital literacy of both participants and providers was found to be a significant hurdle towards digital program implementation. There were no notable issues pertaining to access to an internet connection, participant safety, program costs, or connectivity. A major theme for sustaining program engagement was found to be individual perceived relevance for intervention involvement. Online social involvement was noted to be both a facilitator for participant acceptability and engagement. Overall, participants expressed satisfaction with the use of telehealth, while providers expressed acceptability concerns regarding quality of care. CONCLUSION: It is recommended that planned measures be taken prior to program commencement to decrease digital literacy requirements while also including a participatory approach to encourage uptake. During the program, provision of technical support alongside appropriate social-environmental engagement facilitators would promote sustained adherence.

Causal association of gastroesophageal reflux disease with obstructive sleep apnea and sleep-related phenotypes: a bidirectional two-sample Mendelian randomization study.

Background: The interactions and associations between obstructive sleep apnea (OSA), sleep-related phenotypes (SRPs), and gastroesophageal reflux disease (GERD) are complex, thus it is hard to explore the effect and direction of causalities. Study objectives: A bidirectional Mendelian randomization (MR) study was performed to explore causal associations of GERD with OSA and SRPs (including insomnia, morningness, sleep duration, ease of getting up, daytime napping, daytime dozing, and snoring). Methods: First, we gathered summary statistics from publicly available databases. Subsequently, we identified single-nucleotide polymorphisms without strong linkage (r2 ≤ 0.001) by referencing relevant genome-wide association studies that met genome-wide significance criteria. Our primary analysis relied on inverse variance weighted to estimate the causal relationship. To ensure the validity of our findings, we also conducted several sensitivity analyses. These included MR Pleiotropy RESidual Sum and Outlier to detect and correct for potential pleiotropic effects, MR-Egger to assess directional pleiotropy, and weighted median analysis to further evaluate heterogeneity and pleiotropy. For the initial MR analysis, when causality was indicated by the results, instrumental variables that were significantly linked to the aforementioned confounding factors were removed. We will re-analyze the data after excluding outcome-related single nucleotide polymorphisms to confirm that the results are still consistent with the previous results. Results: GERD was found to increase the risk of OSA (OR = 1.53, 95% CI = 1.37-1.70, p = 5.3 × 10-15), insomnia (OR = 1.14, 95% CI = 1.10-1.19, p = 1.3 × 10-10), snoring (OR = 1.09, 95% CI = 1.04-1.13, p = 6.3 × 10-5) and less sleep duration (OR = 0.94, 95% CI = 0.91-0.97, p = 3.7 × 10-4). According to the reverse-direction analysis, there is an elevated risk of GERD associated with OSA (OR = 1.07, 95% CI = 1.02-1.12, p = 0.005), insomnia (OR = 1.95, 95% CI = 1.60-2.37, p = 1.92 × 10-11) and snoring (OR = 1.74, 95% CI = 1.37-2.21, p = 4.4 × 10-6). Conclusion: Genetic susceptibility to GERD can elevate the likelihood of experiencing insomnia, snoring, and OSA, in addition to diminishing sleep duration. Conversely, a reverse MR analysis indicates that ameliorating any one of insomnia, snoring, or OSA can mitigate the risk of developing GERD.

Rab27b promotes endometriosis by enhancing invasiveness of ESCs and promoting angiogenesis.

PROBLEM: Endometriosis (EMS) is an estrogen-dependent disease which is characterized with estrogen-dependent growth of ectopic endometrium and increased local estrogen production. EMS performs tumor-like biological functions such as invasiveness and angiogenesis. Rab27b is a member of the Rab family of GTPases, which is strongly associated with the growth, invasion and metastasis of a variety of tumors. However, little is known about the function of Rab27b in EMS. In this study, we intended to investigate the impact of Rab27b and its downstream molecule in the development of EMS. METHOD OF STUDY: Normal endometrium and endometriotic lesions were collected to investigate the expression levels of Rab27b. Then, ESCs were transfected with Rab27b siRNA. We analyzed the influence of Rab27b on the proliferation and invasive activity of ESCs. Conditioned media harvested from Rab27b siRNA-treated ESCs were used to treat HUVECs. HUVEC Tube formation and ELISA were performed to explored the interactions between ESCs and HUVEC. In addition, ESCs were treated with different concentrations of estrogen. Based on biological database predictions, we explored possible mechanisms through which estrogen regulates the expression of Rab27b. RESULTS: The expressions of Rab27b were significantly higher in endometriotic lesions than that in normal endometrium. Rab27b can promote the cell proliferation, migration and invasion of ESCs. The elevated expression of Rab27b, on the one hand, promotes the secretion of MMP9 and increases the invasiveness of ESCs. On the other hand, Rab27b may play a key role in the communication between ESC and endothelial cells, by simulating VEGF secretion and neovascularization. Besides, estrogen upregulated phosphorylated FOXO1 levels in ectopic ESCs, resulting in the promotion of Rab27b expression levels. CONCLUSION: Rab27b plays a key role in the development of EMS, which may provide new insights into the pathogenesis of EMS. Our findings may also contribute to the development of therapeutic interventions for EMS.

The nucleus accumbens functional connectivity in patients with insomnia using resting-state fMRI.

Background: The aim of this study was to investigate the functional abnormalities between the nucleus accumbens (NAc) and the whole brain in individuals with Insomnia Disorder (ID) using resting-state functional magnetic resonance imaging (fMRI). Additionally, the study aimed to explore the underlying neural mechanisms of ID. Methods: We enrolled 18 participants with ID and 16 normal controls (NC). Resting-state functional connectivity (FC) between the NAc and the whole brain voxels was calculated and compared between the two groups to identify differential brain region. Receiver operating characteristic (ROC) curve analysis was employed to assess the ability of differential features to distinguish between groups. Furthermore, Pearson correlation analysis was performed to examine the relationship between neurocognitive scores and differential features. Results: The ID group exhibited significantly reduced FC values in several brain regions, including the right supplementary motor area, the bilateral middle frontal gyrus, the bilateral median cingulate and paracingulate gyri and the left precuneus. The area under the curve (AUC) of the classification model based on FC in these brain regions was 83.3%. Additionally, the abnormal functional changes observed in ID patients were positively correlated with the Fatigue Severity Scale (R = 0.650, p = 0.004). Conclusion: These findings suggest that the NAc may play a crucial role in the diagnosis of ID and could serve as a potential imaging biomarker, providing insights into the underlying neural mechanisms of the disorder.

Synergy between Th1 and Th2 responses during endometriosis: A review of current understanding.

Endometriosis is widely perceived as an estrogen-dependent chronic disorder with infertility and pelvic pain. Although the etiology of endometriosis has remained elusive, many studies have proclaimed the relevance of immune system disorders with endometriosis. With the discovery that the dysregulation of multiple biological functions in endometriosis is caused by the aberrant differentiation of T helper cells, a shift towards Th2 immune response may account for the disease progression. This review attempts to present mechanisms of cytokines, chemokines, signal pathways, transcription factors and some other factors related with the derivation of Th1/Th2 immune response involved in the development of endometriosis. The current understanding of treatment approaches and potential therapeutic targets will also be outlined with brief discussion.

Uterine histotroph and conceptus development: III. Adrenomedullin stimulates proliferation, migration and adhesion of porcine trophectoderm cells via AKT-TSC2-MTOR cell signaling pathway.

Adrenomedullin (ADM) as a highly conserved peptide hormone has been reported to increase significantly in the uterine lumen during the peri-implantation period of pregnancy in pigs, but its functional roles in growth and development of porcine conceptus (embryonic/fetus and its extra-embryonic membranes) as well as underlying mechanisms remain largely unknown. Therefore, we conducted in vitro experiments using our established porcine trophectoderm cell line (pTr2) isolated from Day-12 porcine conceptuses to test the hypothesis that porcine ADM stimulates cell proliferation, migration and adhesion via activation of mechanistic target of rapamycin (MTOR) cell signaling pathway in pTr2 cells. Porcine ADM at 10-7 M stimulated (P < 0.05) pTr2 cell proliferation, migration and adhesion by 1.4-, 1.5- and 1.2-folds, respectively. These ADM-induced effects were abrogated (P < 0.05) by siRNA-mediated knockdown of ADM (siADM) and its shared receptor component calcitonin-receptor-like receptor (CALCRL; siCALCRL), as well as by rapamycin, the inhibitor of MTOR. Using siRNA-mediated knockdown of CALCRL coupled with Western blot analyses, ADM signaling transduction was determined in which ADM binds to CALCRL to increase phosphorylation of MTOR, its downstream effectors (4EBP1, P70S6K, and S6), and upstream regulators (AKT and TSC2). Collectively, these results suggest that porcine ADM in histotroph acts on its receptor component CALCRL to activate AKT-TSC2-MTOR, particularly MTORC1 signaling cascade, leading to elongation, migration and attachment of conceptuses.

MicroRNA and mRNA sequencing analyses reveal key hepatic metabolic and signaling pathways responsive to maternal undernutrition in full-term fetal pigs.

Maternal undernutrition is highly prevalent in developing countries, leading to severe fetus/infant mortality, intrauterine growth restriction, stunting, and severe wasting. However, the potential impairments of maternal undernutrition to metabolic pathways in offspring are not defined completely. In this study, 2 groups of pregnant domestic pigs received nutritionally balanced gestation diets with or without 50% feed intake restriction from 0 to 35 gestation days and 70% from 35 to 114 gestation days. Full-term fetuses were collected via C-section on day 113/114 of gestation. MicroRNA and mRNA deep sequencing were analyzed using the Illumina GAIIx system on fetal liver samples. The mRNA-miRNA correlation and associated signaling pathways were analyzed via CLC Genomics Workbench and Ingenuity Pathway Analysis Software. A total of 1189 and 34 differentially expressed mRNA and miRNAs were identified between full-nutrition (F) and restricted-nutrition (R) groups. The correlation analyses showed that metabolic and signaling pathways such as oxidative phosphorylation, death receptor signaling, neuroinflammation signaling pathway, and estrogen receptor signaling pathways were significantly modified, and the gene modifications in these pathways were associated with the miRNA changes induced by the maternal undernutrition. For example, the upregulated (P<.05) oxidative phosphorylation pathway in R group was validated using RT-qPCR, and the correlational analysis indicated that miR-221, 103, 107, 184, and 4497 correlate with their target genes NDUFA1, NDUFA11, NDUFB10 and NDUFS7 in this pathway. These results provide the framework for further understanding maternal malnutrition's negative impacts on hepatic metabolic pathways via miRNA-mRNA interactions in full-term fetal pigs.

Towards a Better Understanding of Endometriosis-Related Infertility: A Review on How Endometriosis Affects Endometrial Receptivity.

Endometriosis is the most common cause of infertility. Endometrial receptivity has been suggested to contribute to infertility and poor reproductive outcomes in affected women. Even though experimental and clinical data suggest that the endometrium differs in women with endometriosis, the pathogenesis of impaired endometrial receptivity remains incomplete. Therefore, this review summarizes the potential mechanisms that affect endometrial function and contribute to implantation failure. Contemporary data regarding hormone imbalance, inflammation, and immunoregulatory dysfunction will be reviewed here. In addition, genetic, epigenetic, glycosylation, metabolism and microRNA in endometriosis-related infertility/subfertility will be summarized. We provide a brief discussion and perspectives on their future clinical implications in the diagnosis and therapy to improve endometrial function in affected women.

Identification of Elite R-Gene Combinations against Blast Disease in Geng Rice Varieties.

Rice blast, caused by the Magnaporthe oryzae fungus, is one of the most devastating rice diseases worldwide. Developing resistant varieties by pyramiding different blast resistance (R) genes is an effective approach to control the disease. However, due to complex interactions among R genes and crop genetic backgrounds, different R-gene combinations may have varying effects on resistance. Here, we report the identification of two core R-gene combinations that will benefit the improvement of Geng (Japonica) rice blast resistance. We first evaluated 68 Geng rice cultivars at seedling stage by challenging with 58 M. oryzae isolates. To evaluate panicle blast resistance, we inoculated 190 Geng rice cultivars at boosting stage with five groups of mixed conidial suspensions (MCSs), with each containing 5-6 isolates. More than 60% cultivars displayed moderate or lower levels of susceptibility to panicle blast against the five MCSs. Most cultivars contained two to six R genes detected by the functional markers corresponding to 18 known R genes. Through multinomial logistics regression analysis, we found that Pi-zt, Pita, Pi3/5/I, and Pikh loci contributed significantly to seedling blast resistance, and Pita, Pi3/5/i, Pia, and Pit contributed significantly to panicle blast resistance. For gene combinations, Pita+Pi3/5/i and Pita+Pia yielded more stable pyramiding effects on panicle blast resistance against all five MCSs and were designated as core R-gene combinations. Up to 51.6% Geng cultivars in the Jiangsu area contained Pita, but less than 30% harbored either Pia or Pi3/5/i, leading to less cultivars containing Pita+Pia (15.8%) or Pita+Pi3/5/i (5.8%). Only a few varieties simultaneously contained Pia and Pi3/5/i, implying the opportunity to use hybrid breeding procedures to efficiently generate varieties with either Pita+Pia or Pita+Pi3/5/i. This study provides valuable information for breeders to develop Geng rice cultivars with high resistance to blast, especially panicle blast.

Effects of electroacupuncture on the ventral tegmental area- nucleus accumbens dopamine pathway in rats with chronic sleep deprivation.

BACKGROUND: Insomnia is a well-recognized clinical sleep disorder in the adult population. It has been established that acupuncture has a clinical effects in the treatment of insomnia; however, research on the underlying neural circuits involved in these effects is limited. METHODS: The modified multiple platform method (MMPM) was used to establish a rat model of chronic sleep deprivation (CSD). Forty rats were randomly divided into a control (Con) group, (untreated) CSD group, electroacupuncture-treated CSD group (CSD + EA) and estazolam-treated CSD group (CSD + Estazolam group) with n = 10 per group. In the CSD + EA group, EA was delivered at Yintang and unilateral HT7 (left and right treated every other day) with continuous waves (2 Hz frequency) for 30 min/day over 7 consecutive days. In the CSD + Estazolam groups, estazolam was administered by oral gavage (0.1 mg/kg) for 7 consecutive days. The open field test (OFT) was used to observe behavioral changes. Immunofluorescence assays and enzyme-linked immunosorbent assay (ELISA) were used to observe the effects of EA on the ventral tegmental area (VTA)-nucleus accumbens (NAc) dopamine (DA) pathway. We also assessed the effects of EA on the expression of dopamine D1 receptor (D1R) and dopamine D2 receptor (D2R) in the NAc, which are the downstream targets of the VTA-NAc DA pathway. RESULTS: After CSD was established by MMPM, rats exhibited increased autonomous activity and increased excitability of the VTA-NAc DA pathway, with increased VTA and NAc DA content, increased D1R expression and decreased D2R expression in the NAc. EA appeared to reduce the autonomous ability of CSD rats, leading to lower DA content in the VTA and NAc, reduced expression of D1R in the NAc and increased expression of D2R. Most importantly, EA produced effects similar to estazolam with respect to the general condition of rats with CSD and regulation of the VTA-NAc DA pathway. CONCLUSIONS: The therapeutic effect of EA in chronic insomnia may be mediated by reduced excitability of the VTA-NAc DA pathway, with lower DA content in the VTA and NAc, downregulated expression of D1R in the NAc and increased expression of D2R.

Data-dependent and -independent acquisition lipidomics analysis reveals the tissue-dependent effect of metformin on lipid metabolism.

Introduction: Despite the well-recognized health benefits, the mechanisms and site of action of metformin remains elusive. Metformin-induced global lipidomic changes in plasma of animal models and human subjects have been reported. However, there is a lack of systemic evaluation of metformin-induced lipidomic changes in different tissues. Metformin uptake requires active transporters such as organic cation transporters (OCTs), and hence, it is anticipated that metformin actions are tissue-dependent. In this study, we aim to characterize metformin effects in non-diabetic male mice with a special focus on lipidomics analysis. The findings from this study will help us to better understand the cell-autonomous (direct actions in target cells) or non-cell-autonomous (indirect actions in target cells) mechanisms of metformin and provide insights into the development of more potent yet safe drugs targeting a particular organ instead of systemic metabolism for metabolic regulations without major side effects. Objectives: To characterize metformin-induced lipidomic alterations in different tissues of non-diabetic male mice and further identify lipids affected by metformin through cell-autonomous or systemic mechanisms based on the correlation between lipid alterations in tissues and the corresponding in-tissue metformin concentrations. Methods: Lipids were extracted from tissues and plasma of male mice treated with or without metformin in drinking water for 12 days and analyzed using MS/MS scan workflow (hybrid mode) on LC-Orbitrap Exploris 480 mass spectrometer using biologically relevant lipids-containing inclusion list for data-independent acquisition (DIA), named as BRI-DIA workflow followed by data-dependent acquisition (DDA), to maximum the coverage of lipids and minimize the negative effect of stochasticity of precursor selection on experimental consistency and reproducibility. Results: Lipidomics analysis of 6 mouse tissues and plasma using MS/MS combining BRI-DIA and DDA allowed a systemic evaluation of lipidomic changes induced by metformin in different tissues. We observed that 1) the degrees of lipidomic changes induced by metformin treatment overly correlated with tissue concentrations of metformin; 2) the impact on lysophosphorylcholine and cardiolipins was positively correlated with tissue concentrations of metformin, while neutral lipids such as triglycerides did not correlate with the corresponding tissue metformin concentrations. Conclusion: The data collected in this study from non-diabetic mice with 12-day metformin treatment suggest that the overall metabolic effect of metformin is positively correlated with tissue concentrations and the effect on individual lipid subclass is via both cell-autonomous mechanisms (cardiolipins and lysoPC) and non-cell-autonomous mechanisms (triglycerides).

Transition from synaptic simulation to nonvolatile resistive switching behavior based on an Ag/Ag:ZnO/Pt memristor.

The advent of memristors and the continuing research and development in the field of brain-inspired computing could allow realization of a veritable "thinking machine". In this study, ZnO-based memristors were fabricated using a radio frequency magnetron sputtering method. The ZnO oxide layer was prepared by incorporating silver nanocrystals (NCs). Several synaptic functions, i.e. nonlinear transmission characteristics, short-term potentiation, long-term potentiation/depression, and pair-pulse facilitation, were imitated in the memristor successfully. Furthermore, the transition from synaptic behaviors to bipolar resistive switching behaviors of the device was also observed under repeated stimulus. It is speculated that the switching mechanism is due to the formation and rupture of the conductive Ag filaments and the corresponding electrochemical metallization. The experimental results demonstrate that the Ag/Ag:ZnO/Pt memristor with resistive switching and several synaptic behaviors has a potential application in neuromorphic computing and data storage systems.

Development of Rice Variety With Durable and Broad-Spectrum Resistance to Blast Disease Through Marker-Assisted Introduction of Pigm Gene.

Rice blast, caused by Magnaporthe oryzae (M. oryzae), is one of the most destructive diseases threatening rice production worldwide. Development of resistant cultivars using broad-spectrum resistance (R) genes with high breeding value is the most effective and economical approach to control this disease. In this study, the breeding potential of Pigm gene in geng/japonica rice breeding practice in Jiangsu province was comprehensively evaluated. Through backcross and marker-assisted selection (MAS), Pigm was introduced into two geng rice cultivars (Wuyungeng 32/WYG32 and Huageng 8/HG8). In each genetic background, five advanced backcross lines with Pigm (ABLs) and the same genotypes as the respective recurrent parent in the other 13 known R gene loci were developed. Compared with the corresponding recurrent parent, all these ABLs exhibited stronger resistance in seedling inoculation assay using 184 isolates collected from rice growing regions of the lower region of the Yangtze River. With respect to panicle blast resistance, all ABLs reached a high resistance level to blast disease in tests conducted in three consecutive years with the inoculation of seven mixed conidial suspensions collected from different regions of Jiangsu province. In natural field nursery assays, the ABLs showed significantly higher resistance than the recurrent parents. No common change on importantly morphological traits and yield-associated components was found among the ABLs, demonstrating the introduction of Pigm had no tightly linked undesirable effect on rice economically important traits and its associated grain weight reduction effect could be probably offset by others grain weight genes or at least in the background of the aforementioned two varieties. Notably, one rice line with Pigm, designated as Yangnonggeng 3091, had been authorized as a new variety in Jiangsu province in 2021, showing excellent performance on both grain yield and quality, as well as the blast resistance. Together, these results suggest that the Pigm gene has a high breeding value in developing rice varieties with durable and broad-spectrum resistance to blast disease.

PLAGL2 Promotes the Proliferation and Migration of Diffuse Large B-cell Lymphoma Cells via Wnt/ß-catenin Pathway.

OBJECTIVE: Pleomorphic adenoma gene like-2 (PLAGL2) belongs to PLAG protein family and functions as a zinc finger transcriptional factor to participate in the cellular processes, including cell transformation, migration, and apoptosis. Increasing evidence has shown the oncogenic role of PLAGL2 in various cancers, while the potential molecular mechanism and biology roles of PLAGL2 in diffuse large B-cell lymphoma (DLBCL) are still unclear. METHODS: Expression of PLAGL2 was found to be elevated in DLBCL cells. Functional assays showed that silence of PLAGL2 suppressed cell proliferation and reduced the cell migration and invasion in DLBCL. The cell proliferation and metastasis in DLBCL were promoted by over-expression of PLAGL2. Moreover, the protein expression of E-cadherin was increased, while the protein expressions of N-cadherin and vimentin were decreased in DLBCL cells by knockdown of PLAGL2. However, over-expression of PLAGL2 promoted epithelial to mesenchymal transition (EMT) of DLBCL through down-regulation of E-cadherin, and up-regulations of N-cadherin and vimentin. RESULTS: Over-expression of PLAGL2 up-regulated ß-catenin and c-myc, while down-regulated axis inhibition protein 2 (AXIN2) and adenomatous polyposis coli (APC) in DLBCL. Knockdown of PLAGL2 suppressed the activation of Wnt/ß-catenin pathway in DLBCL through downregulating ß-catenin and c-myc but upregulating AXIN2 and APC. Xenograft model also demonstrated that interference of PLAGL2 repressed the in vivo tumor growth of DLBCL. CONCLUSION: In conclusion, PLAGL2 promoted the malignancy of DLBCL through activation of Wnt/ß-catenin pathway.

Prioritize biologically relevant ions for data-independent acquisition (BRI-DIA) in LC-MS/MS-based lipidomics analysis.

INTRODUCTION: Data-dependent acquisition (DDA) is the most commonly used MS/MS scan method for lipidomics analysis on orbitrap-based instrument. However, MS instrument associated software decide the top N precursors for fragmentation, resulting in stochasticity of precursor selection and compromised consistency and reproducibility. We introduce a novel workflow using biologically relevant lipids to construct inclusion list for data-independent acquisition (DIA), named as BRI-DIA workflow. OBJECTIVES: To ensure consistent coverage of biologically relevant lipids in LC-MS/MS-based lipidomics analysis. METHODS: Biologically relevant ion list was constructed based on LIPID MAPS and lipidome atlas in MS-DIAL 4. Lipids were extracted from mouse tissues and used to assess different MS/MS scan workflow (DDA, BRI-DIA, and hybrid mode) on LC-Orbitrap Exploris 480 mass spectrometer. RESULTS: DDA resulted in more MS/MS events, but the total number of unique lipids identified by three methods (DDA, BRI-DIA, and hybrid MS/MS scan mode) is comparable (580 unique lipids across 44 lipid subclasses in mouse liver). Major cardiolipin molecular species were identified by data generated using BRI-DIA and hybrid methods and allowed calculation of cardiolipin compositions, while identification of the most abundant cardiolipin CL72:8 was missing in data generated using DDA method, leading to wrong calculation of cardiolipin composition. CONCLUSION: The method of using inclusion list comprised of biologically relevant lipids in DIA MS/MS scan is as efficient as traditional DDA method in profiling lipids, but offers better consistency of lipid identification, compared to DDA method. This study was performed using Orbitrap Exploris 480, and we will further evaluate this workflow on other platforms, and if verified by future work, this biologically relevant ion fragmentation workflow could be routinely used in many studies to improve MS/MS identification capacities.

Association of Acupuncture and Auricular Acupressure With the Improvement of Sleep Disturbances in Cancer Survivors: A Systematic Review and Meta-Analysis.

Background: Studies on the efficacy of acupuncture and auricular acupressure on sleep disturbances in cancer patients have been growing, but there is no specific and comprehensive systematic review and meta-analysis. This review aims to evaluate the efficacy and safety of acupuncture and auricular acupressure on sleep disturbances in cancer survivors based on existing randomized clinical trials (RCTs). Methods: Four English-language and four Chinese-language biomedical databases were searched for RCTs published from database inception to July 30, 2021. RCTs comparing acupuncture and auricular acupressure with sham control, drug therapy, behavior therapy, or usual care for managing cancer were included. The quality of RCTs was appraised with the Cochrane Collaboration risk of bias (ROB) tool. Mean differences (MDs) and 95% confidence intervals (CIs) were calculated for the effect sizes. Results: Thirteen RCTs with 961 patients were included. The risk of performance bias or reporting bias for most of the included trials was high or unclear. Evidence was not found for short-term effects on sleep scales compared to sham control (MD, 1.98; 95% CI, 0.33-3.64; p = 0.02; I2 = 36%), wait list control (MD, 0.40; 95% CI, -0.87-1.68; p = 0.54; I2 = 49%), drug therapy (MD, 1.18; 95% CI, -3.09-5.46; p = 0.59; I2 = 98%). For long-term effect, two sham-controlled RCTs showed no significance of acupuncture on insomnia scale scores (MD, 1.71; 95% CI, -2.38-5.81; p = 0.41; I2 = 89%). Subgroup analyses suggested no evidence that auricular acupressure (MD, 3.14; 95% CI=1.52, 4.76; p = 0.0001; I2 = 0%) or acupuncture (MD, 0.54; 95% CI=-1.27, 2.34; p = 0.56; I2 = 0%) was associated with the reduction in insomnia scale scores. Conclusions: This systematic review and meta-analysis found no evidence about acupuncture or auricular acupressure in the improvement of sleep disturbances in cancer survivors in terms of short- or long-term effect. Adverse events were minor. The finding was inconsistent with previous research and suggested that more well-designed and large-scale randomized controlled trials are needed to identify the efficacy of acupuncture and auricular acupressure for sleep disturbances in cancer survivors. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, CRD42020171612.