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Serum diamine oxidase (DAO) activity varies to a greater extent in women than in men. DAO activity during the luteal phase was higher than that during the follicular phase in healthy women. Recent reports have indicated that duodenal lipid infusion increased DAO activity in the intestinal lymph in rats. The aim of this study was to elucidate the effect of dietary nutrient intake on serum DAO activity in healthy women. Thirty-four healthy Japanese women were recruited. Food surveys were performed using dietary records for 3 d during both the follicular and luteal phases. Nutrient intake was calculated and expressed as the energy intake ratio. The correlation between DAO activity and nutrient intake was analyzed. Serum DAO activity in both phases was positively correlated with intake of long-chain fatty acids, saturated fatty acids, and monounsaturated fatty acids (P < 0.05). Intake of phosphorus, calcium, zinc, magnesium, iron, and vitamin B12 during the luteal phase was positively correlated with serum DAO activity (P < 0.05). In healthy women, serum DAO activity was influenced by dietary fatty acid and micronutrient intake. •Serum diamine oxidase (DAO) activity has been used as a marker of intestinal integrity.•The correlation between serum DAO activity and nutrient intake was analyzed in the present study.•DAO activity in both menstrual phases was positively correlated with fatty acid intake.•Micronutrient intake during the luteal phase was positively correlated with DAO activity.

Background Synaptic degeneration is characteristic of neurodegenerative diseases. Amyloid‐beta (Aβ) plaques and neurofibrillary tangles of hyperphosphorylated tau are known to induce the synapse pathologies directly or indirectly in Alzheimer’s disease (AD). EphA4 is a member of the ephrin receptor subfamily which is predominantly expressed in the brain. Activation of the EphA4 is involved in neurodegeneration in several neurological diseases, including AD. E2025 is a humanized anti‐EphA4 antibody specifically binding to EphA4. We provide evidence that our novel anti‐EphA4 antibody E2025 suppresses neurodegeneration by modulating the EphA4 via direct binding to EphA4. Method E2025 was characterized in several in vitro assays for evaluating binding property of E2025 to EphA4, receptor subfamily specificity and potential to inhibit ligand binding. The pharmacological effects of E2025 were assessed using rat primary cultured hippocampal neurons. The in vivo effects of E2025 were investigated in human Tau P301L transgenic mice (Tau tg mice) by immunohistochemical analysis. Result E2025 specifically bound to EphA4 with high affinity, inhibiting binding of its ligand to EphA4. In rat primary cultured neurons, E2025 enhanced cleavage of EphA4. In vivo experiments demonstrated that repeated injection of mouse surrogate antibody of E2025 significantly suppressed tau pathology measured by anti‐phosphorylated tau (AT8) antibody. Conclusion E2025 specifically suppresses the EphA4 pathway via multiple modes of action, and suppresses progression of tau pathology in a transgenic tau model of AD.

The oocytes of most sexually reproducing animals arrest in meiotic prophase I. Oocyte growth, which occurs during this period of arrest, enables oocytes to acquire the cytoplasmic components needed to produce healthy progeny and to gain competence to complete meiosis. In the nematode Caenorhabditis elegans, the major sperm protein hormone promotes meiotic resumption (also called meiotic maturation) and the cytoplasmic flows that drive oocyte growth. Prior work established that two related TIS11 zinc-finger RNA-binding proteins, OMA-1 and OMA-2, are redundantly required for normal oocyte growth and meiotic maturation. We affinity purified OMA-1 and identified associated mRNAs and proteins using genome-wide expression data and mass spectrometry, respectively. As a class, mRNAs enriched in OMA-1 ribonucleoprotein particles (OMA RNPs) have reproductive functions. Several of these mRNAs were tested and found to be targets of OMA-1/2-mediated translational repression, dependent on sequences in their 3′-untranslated regions (3′-UTRs). Consistent with a major role for OMA-1 and OMA-2 in regulating translation, OMA-1-associated proteins include translational repressors and activators, and some of these proteins bind directly to OMA-1 in yeast two-hybrid assays, including OMA-2. We show that the highly conserved TRIM-NHL protein LIN-41 is an OMA-1-associated protein, which also represses the translation of several OMA-1/2 target mRNAs. In the accompanying article in this issue, we show that LIN-41 prevents meiotic maturation and promotes oocyte growth in opposition to OMA-1/2. Taken together, these data support a model in which the conserved regulators of mRNA translation LIN-41 and OMA-1/2 coordinately control oocyte growth and the proper spatial and temporal execution of the meiotic maturation decision.

Seedling emergence is a critical stage in turfgrass establishment, influencing the management and use of turfs. A series of field, controlled-environment, and laboratory experiments was conducted to determine solid matrix priming (SMP) effects on turfgrass species and cultivars. Seedling emergence was investigated under field conditions for three cool-season species, 11 cultivars of Kentucky bluegrass (Poa pratensis L.) (KBG), 7 cultivars of perennial ryegrass (Lolium perenne L.) (PR), and 7 cultivars of tall fescue (Festuca arundinacea Schreb.) (TF), and three warm-season species. Priming reduced time required for emergence and improved final emergence. The degree of effects varied among species and cultivars, and under different environmental conditions. The greatest priming responses appeared in slow-emergence species under cool temperatures. Seedling emergence and growth rate of four KBG cultivars were determined under sub-optimal conditions (15/5 $\\sp\\circ$ C). Distributions of coleoptile emergence over time were significantly affected by priming, and time to 50% emergence (T $\\sb{50}$ ) was shortened by 5 to 14 days in three cultivars. In contrast, the rate of second and third leaf emergence and seedling size at 28-day after emergence did not increase, indicating no priming effects on growth rate. Priming effects on germination and post-storage viability were determined using 26 cultivars of KBG, PR, TF, and creeping bentgrass (Agrostis palustris Huds.). Final germination of primed seed increased in some cultivars but decreased in others; however, post-storage viability declined sharply in some primed cultivars compared to controls. Primed seed of PR and TF cultivars especially lost their viability (up to 86%), even under controlled conditions. To facilitate an understanding of the mechanism of priming effects, water imbibition of seed was examined under water potentials ranging from 0.0 to$-$ 1.5 MPa at 25, 15, and 5 $\\sp\\circ$ C using four KBG cultivars. Primed seed imbibed more water at a faster rate and released less electrolytes than untreated seed, especially under sub-optimal conditions. The more rapid germination of primed seed was partially attributed to more rapid water imbibition. Priming can provide practical benefits in turfgrass establishment.

Seed priming can be a practical method of improving Kentucky bluegrass germination, especially in cool weather. The use of solid-matrix priming (PMP) to prime Kentucky bluegrass is examined.

Metabolomics is a promising avenue for biomarker discovery. Although the quality of metabolomic analyses, especially global metabolomics (G-Met) using mass spectrometry (MS), largely depends on the instrumentation, potential bottlenecks still exist at several basic levels in the metabolomics workflow. Therefore, we established a precise protocol initially for the G-Met analyses of human blood plasma to overcome some these difficulties. In our protocol, samples are deproteinized in a 96-well plate using an automated liquid-handling system, and conducted either using a UHPLC-QTOF/MS system equipped with a reverse phase column or a LC-FTMS system equipped with a normal phase column. A normalization protocol of G-Met data was also developed to compensate for intra- and inter-batch differences, and the variations were significantly reduced along with our normalization, especially for the UHPLC-QTOF/MS data with a C18 reverse-phase column for positive ions. Secondly, we examined the changes in metabolomic profiles caused by the storage of EDTA-blood specimens to identify quality markers for the evaluation of the specimens' pre-analytical conditions. Forty quality markers, including lysophospholipids, dipeptides, fatty acids, succinic acid, amino acids, glucose, and uric acid were identified by G-Met for the evaluation of plasma sample quality and established the equation of calculating the quality score. We applied our quality markers to a small-scale study to evaluate the quality of clinical samples. The G-Met protocols and quality markers established here should prove useful for the discovery and development of biomarkers for a wider range of diseases.

Transcriptional dysregulation, which can be caused by genetic and epigenetic alterations, is a fundamental feature of many cancers. A key cytoprotective transcriptional activator, NRF2, is often aberrantly activated in non-small cell lung cancers (NSCLCs) and supports both aggressive tumorigenesis and therapeutic resistance. Herein, we find that persistently activated NRF2 in NSCLCs generates enhancers at gene loci that are not normally regulated by transiently activated NRF2 under physiological conditions. Elevated accumulation of CEBPB in NRF2-activated NSCLCs is found to be one of the prerequisites for establishment of the unique NRF2-dependent enhancers, among which the NOTCH3 enhancer is shown to be critical for promotion of tumor-initiating activity. Enhancer remodeling mediated by NRF2-CEBPB cooperativity promotes tumor-initiating activity and drives malignancy of NRF2-activated NSCLCs via establishment of the NRF2-NOTCH3 regulatory axis. Aberrant activation of NRF2 in cancer cells contributes to tumorigenicity and therapeutic resistance. Here, the authors show that NRF2 cooperates with CEBPB and remodels enhancers to confer tumor-initiating activity on NRF2- activated non-small cell lung cancers.

Aberrant activation of NRF2 is as a critical prognostic factor that drives the malignant progression of various cancers. Cancer cells with persistent NRF2 activation heavily rely on NRF2 activity for therapeutic resistance and aggressive tumorigenic capacity. To clarify the metabolic features of NRF2‐activated lung cancers, we conducted targeted metabolomic (T‐Met) and global metabolomic (G‐Met) analyses of non–small‐cell lung cancer (NSCLC) cell lines in combination with exome and transcriptome analyses. Exome analysis of 88 cell lines (49 adenocarcinoma, 14 large cell carcinoma, 15 squamous cell carcinoma and 10 others) identified non–synonymous mutations in the KEAP1, NRF2 and CUL3 genes. Judging from the elevated expression of NRF2 target genes, these mutations are expected to result in the constitutive stabilization of NRF2. Out of the 88 cell lines, 52 NSCLC cell lines (29 adenocarcinoma, 10 large cell carcinoma, 9 squamous cell carcinoma and 4 others) were subjected to T‐Met analysis. Classification of the 52 cell lines into three groups according to the NRF2 target gene expression enabled us to draw typical metabolomic signatures induced by NRF2 activation. From the 52 cell lines, 18 NSCLC cell lines (14 adenocarcinoma, 2 large cell carcinoma, 1 squamous cell carcinoma and 1 others) were further chosen for G‐Met and detailed transcriptome analyses. G‐Met analysis of their culture supernatants revealed novel metabolites associated with NRF2 activity, which may be potential diagnostic biomarkers of NRF2 activation. This study also provides useful information for the exploration of new metabolic nodes for selective toxicity towards NRF2‐activated NSCLC. This study examined impacts of NRF2 activation in NSCLC cell lines on their extracellular metabolites.

The mechanism of chromosomal rearrangement associated with inverted–duplication–deletion (INV–DUP–DEL) pattern formation has been investigated by many researchers, and several possible mechanisms have been proposed. Currently, fold-back and subsequent dicentric chromosome formation has been established as non-recurrent INV–DUP–DEL pattern formation mechanisms. In the present study, we analyzed the breakpoint junctions of INV–DUP–DEL patterns in five patients using long-read whole-genome sequencing and detected 2.2–6.1 kb copy-neutral regions in all five patients. At the end of the INV–DUP–DEL, two patients exhibited chromosomal translocations, which are recognized as telomere capture, and one patient showed direct telomere healing. The remaining two patients had additional small-sized intrachromosomal segments at the end of the derivative chromosomes. These findings have not been previously reported but they may only be explained by the presence of telomere capture breakage. Further investigations are required to better understand the mechanisms underlying this finding.

During macroautophagy, cytoplasmic constituents are engulfed by autophagosomes. Lysosomes fuse with closed autophagosomes but not with unclosed intermediate structures. This is achieved in part by the late recruitment of the autophagosomal SNARE syntaxin 17 (STX17) to mature autophagosomes. However, how STX17 recognizes autophagosome maturation is not known. Here, we show that this temporally regulated recruitment of STX17 depends on the positively charged C-terminal region of STX17. Consistent with this finding, mature autophagosomes are more negatively charged compared with unclosed intermediate structures. This electrostatic maturation of autophagosomes is likely driven by the accumulation of phosphatidylinositol 4-phosphate (PI4P) in the autophagosomal membrane. Accordingly, dephosphorylation of autophagosomal PI4P prevents the association of STX17 to autophagosomes. Furthermore, molecular dynamics simulations support PI4P-dependent membrane insertion of the transmembrane helices of STX17. Based on these findings, we propose a model in which STX17 recruitment to mature autophagosomes is temporally regulated by a PI4P-driven change in the surface charge of autophagosomes.