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Hyperlipidemia is a risk factor for atherosclerotic cardiovascular disease and is a major public health concern. Allium hookeri (AH) is an Allium species containing high levels of bioactive organosulfur compounds such as methiin and cycloalliin. AH exerts hypolipidemic effects in animals fed a high-fat diet. However, there exists little information on the mechanisms underlying these effects. To address this issue, we used a metabolomic approach based on ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry to identify factors mediating the lipid-lowering effects of AH. Principal component and partial least-squares discriminant analyses of serum metabolome profiles revealed 25 metabolites as potential biomarkers for the effects of AH on lipid levels. These compounds were predominantly phospholipids, including phosphatidylcholines (PCs), lysoPCs, and lysophosphatidylethanolamines. Glycerophospholipid metabolism was identified as a significantly enriched pathway. These results provide mechanistic insight into the antihyperlipidemic effects of AH and evidence for its efficacy as a therapeutic agent.

Highlights • Laser induced graphitization was used to produce graphitic carbon layers. • The high gradient of oxygen-containing functional groups and the short diffusion path enabled high power generation. • The voltage output from a 3 × 3 mm 2 GCL was 0.83 V at 82% relative humidity. A porous cellulose nanofiber (CNF) substrate was prepared by drying a TEMPO (2,2,6,6-tetramethylpiperidin-1-oxyl radical)-treated bleached pulp solution in a vacuum freeze dryer. A graphitic carbon layer (GCL) was fabricated directly onto the CNF substrate using infrared laser irradiation at ambient conditions. By focusing the laser beam on the top surface of the CNF substrate, higher conversion of the CNF to GCL was achieved on the top surface than the bottom surface. An oxygen-to-carbon ratio (O/C) gradient was established between the top and bottom surfaces during laser induced graphitization (LIG), as the O/C of the GCL decreased with laser intensity. When the GCL with the O/C gradient was exposed to water vapor, hydrolysis of the carboxyl groups in the GCL produced hydrogen ions. The resulting hydrogen ion concentration gradient between the top and bottom surfaces created electricity. At 82% relative humidity, the voltage and current outputs from a 3 × 3 mm 2 GCL were 0.83 V and 5.93 μA/cm 2 , respectively. Graphical abstract Download : Download high-res image (204KB) Download : Download full-size image

Highlights • The associations among smoking, alcohol consumption, and colorectal cancer have not been well established for women. • The duration and amount of smoking, and alcohol consumption amount were associated with colorectal cancer risk in both men and women. • Women showed a greater risk of colorectal cancer with lower amount and duration of smoking and less alcohol consumption. The current case-control study comprehensively evaluated the status, quantity, and duration of smoking and alcohol drinking for both men and women, considering the subsites of colorectal cancer. A total of 925 colorectal cancer cases and 2775 controls were included in the analysis. Odds ratios (OR) and 95% confidence intervals (CI) were computed by logistic regression models adjusting for potential confounders. In men, the risk of colorectal cancer significantly increased for heavy smokers who smoked ≥40 pack-years (OR 1.74, 95% CI 1.22–2.50), ≥40 years (OR 1.50, 95% CI 1.05–2.16), or ≥40 cigarettes/day (OR 1.92, 95% CI 1.04–3.54). Men showed a significant increase in risk, especially for rectal cancer with an increasing amount or duration of smoking. In women, distal colon cancer risk increased in smokers who smoked ≥20 years (OR 3.21, 95% CI 1.27–8.14) or ≥20 cigarettes/day (OR 4.75, 95% CI 1.09–20.57). Additionally, female smokers who smoked ≥20 cigarettes/day had an increased risk of rectal cancer (OR 6.46, 95% CI 1.64–25.46). Regarding the association of cigarettes smoked per day and the risk of rectal cancer, there was no significant difference between men and women (gender interaction p value = 0.14). Compared with never-drinkers, those who consumed alcohol at ≥40 g/day in men and ≥20 g/day in women had an OR of 2.39 (95% CI 1.68–3.41) and 3.52 (95% CI 1.56–7.96), respectively. The effect of daily alcohol consumption (g of ethanol/day) on cancer risk was not significantly different among subsites. Association of alcohol consumption quantity (g of ethanol/day) and the risk of proximal and distal colon cancer were stronger in women than in men (gender interaction p value < 0.01). There was no significant interaction in the multiplicative level when alcohol consumption and cigarette smoking were combined. The duration and amount of smoking as well as the amount of alcohol consumption were associated with an elevated risk of colorectal cancer in both men and women.

In East Asia, where aerosol concentrations are persistently high throughout the year, most satellite CO2 retrieval algorithms screen out many measurements during quality control in order to reduce retrieval errors. To reduce the retrieval errors associated with aerosols, we have modified YCAR (Yonsei Carbon Retrieval) algorithm to YCAR-CAI to retrieve XCO2 from GOSAT FTS measurements using aerosol retrievals from simultaneous Cloud and Aerosol Imager (CAI) measurements. The CAI aerosol algorithm provides aerosol type and optical depth information simultaneously for the same geometry and optical path as FTS. The YCAR-CAI XCO2 retrieval algorithm has been developed based on the optimal estimation method. The algorithm uses the VLIDORT V2.6 radiative transfer model to calculate radiances and Jacobian functions. The XCO2 results retrieved using the YCAR-CAI algorithm were evaluated by comparing them with ground-based TCCON measurements and current operational GOSAT XCO2 retrievals. The retrievals show a clear annual cycle, with an increasing trend of 2.02 to 2.39 ppm per year, which is higher than that measured at Mauna Loa, Hawaii. The YCAR-CAI results were validated against the Tsukuba and Saga TCCON sites and show an root mean square error of 2.25, a bias of −0.81 ppm, and a regression line closer to the linear identity function compared with other current algorithms. Even after post-screening, the YCAR-CAI algorithm provides a larger dataset of XCO2 compared with other retrieval algorithms by 21% to 67%, which could be substantially advantageous in validation and data analysis for the area of East Asia. Retrieval uncertainty indicates a 1.39 to 1.48 ppm at the TCCON sites. Using Carbon Tracker-Asia (CT-A) data, the sampling error was analyzed and was found to be between 0.32 and 0.36 ppm for each individual sounding.

Wearable exoskeletons have generally been designed to enhance user strength or to reduce user fatigue. Two areas that have often been overlooked are that exoskeletons should increase user safety and have increased durability for use in extreme environments. In this paper, we developed an SMA spring-based shock absorption module for an exoskeleton or a quadruped walking robot, which can provide increased protection to the user during high-impact events in an extreme environment. We analyzed the impact force during the collision between the module and the ground based on impulse and momentum theories. The shock absorber module can be reused by exploiting the inherent shape memory characteristics of the SMA spring after every use. We confirmed that the spring constant of the SMA spring and the maximum allowable length affect the impulse reduction, and the results showed that the latter has a greater influence on impulse reduction.

Abstract Patients with multiple sclerosis (MS) develop a variety of lower urinary tract symptoms (LUTS). We previously characterized a murine model of neurogenic bladder dysfunction induced by a neurotropic strain of a coronavirus. In the present study, we further study the role of long-lasting neurodegeneration on the development of neurogenic bladder dysfunction in mice with corona-virus induced encephalitis (CIE). Long-term follow up study revealed three phenotypes of neurodegenerative symptom development: recovery (REC group), chronic progression (C-PRO group) and chronic disease with relapsing-remitting episodes (C-RELAP group). The levels of IL-1β in REC group, IL-10 in C-RELAP group, and IL-1β, IL-6, IL-10 and TNF-α in C-PRO group were diminished in the brain. The levels of TNF-α in REC group and INF-γ, IL-2, TGF-β and TNF-α in the C-PRO group were also diminished in the urinary bladder. Mice in C-RELAP group showed a delayed recovery of voiding function. In vitro contractility studies determined a decreased basal detrusor tone and reduced amplitude of nerve-mediated contractions in C-RELAP group, whereas C-PRO group had elevated muscle-mediated contractions. In conclusion, mice with CIE developed three phenotypes of neurologic impairment mimicking different types of MS progression in humans and showed differential mechanisms driving neurogenic bladder dysfunction.

The brain is susceptible to methylmercury toxicity, which causes irreversible damage to neurons and glia and the leaf extract Dendropanax morbifera Léveille (DML) has various biological functions in the nervous system. In this study, we examined the effects of DML on mercury-induced proliferating cells and differentiated neuroblasts. Dimethylmercury (5 μg/kg) and galantamine (5 mg/kg) was administered intraperitoneally and/or DML (100 mg/kg) was orally to 7-week-old rats every day for 36 days. One hour after the treatment, novel object recognition test was examined. In addition, spatial probe tests were conducted on the 6th day after 5 days of continuous training in the Morris swim maze. Thereafter, the rats were euthanized for immunohistochemical staining analysis with Ki67 and doublecortin and measurement for acetylcholinesterase (AChE) activity. Dimethylmercury-treated rats showed reduced discrimination index in novel object recognition test and took longer to find the platform than did control group. Compared with dimethylmercury treatment alone, supplementation with DML or galatamine significantly ameliorated the reduction of discrimination index and reduced the time spent to find the platform. In addition, the number of platform crossings was lower in the dimethylmercury-treated group than in controls, while the administration of DML or galantamine significantly increased the number of crossings than did dimethylmercury treatment alone. Proliferating cells and differentiated neuroblasts, assessed by Ki67 and doublecortin immunohistochemical staining was significantly decreased in the dimethylmercury treated group versus controls. Supplementation with DML or galantamine significantly increased the number of proliferating cells and differentiated neuroblasts in the dentate gyrus. In addition, treatment with dimethylmercury significantly increased AChE activity in hippocampal homogenates, while treatment with dimethylmercury+DML or dimethylmercury+galantamine significantly ameliorated this increase. These results suggest that DML may be a functional food that improves dimethylmercury-induced memory impairment and ameliorates dimethylmercury-induced reduction in proliferating cells and differentiated neuroblasts, and demonstrates corresponding activation of AChE activity in the dentate gyrus.

Abstract Background Previously published results from our laboratory identified a mechano-gated two-pore domain potassium channel, TREK-1, as a main mechanosensor in the smooth muscle of the human urinary bladder. One of the limitations of in vitro experiments on isolated human detrusor included inability to evaluate in vivo effects of TREK-1 on voiding function, as the channel is also expressed in the nervous system, and may modulate micturition via neural pathways. Therefore, in the present study, we aimed to assess the role of TREK-1 channel in bladder function and voiding patterns in vivo by using TREK-1 knockout (KO) mice. Methods Adult C57BL/6 J wild-type (WT, N = 32) and TREK-1 KO (N = 33) mice were used in this study. The overall phenotype and bladder function were evaluated by gene and protein expression of TREK-1 channel, in vitro contractile experiments using detrusor strips in response to stretch and pharmacological stimuli, and cystometry in unanesthetized animals. Results TREK-1 KO animals had an elevated basal muscle tone and enhanced spontaneous activity in the detrusor without detectable changes in bladder morphology/histology. Stretch applied to isolated detrusor strips increased the amplitude of spontaneous contractions by 109% in the TREK-1 KO group in contrast to a 61% increase in WT mice (p ≤ 0.05 to respective baseline for each group). The detrusor strips from TREK-1 KO mice also generated more contractile force in response to electric field stimulation and high potassium concentration in comparison to WT group (p ≤ 0.05 for both tests). However, cystometric recordings from TREK-1 KO mice revealed a significant increase in the duration of the intermicturition interval, enhanced bladder capacity and increased number of non-voiding contractions in comparison to WT mice. Conclusions Our results provide evidence that global down-regulation of TREK-1 channels has dual effects on detrusor contractility and micturition patterns in vivo. The observed differences are likely due to expression of TREK-1 channel not only in detrusor myocytes but also in afferent and efferent neural pathways involved in regulation of micturition which may underly the “mixed” voiding phenotype in TREK-1 KO mice.

Proliferating cell nuclear antigen (PCNA) plays essential roles in eukaryotic cells during DNA replication, DNA mismatch repair (MMR), and other events at the replication fork. Earlier studies show that PCNA is regulated by posttranslational modifications, including phosphorylation of tyrosine 211 (Y211) by the epidermal growth factor receptor (EGFR). However, the functional significance of Y211-phosphorylated PCNA remains unknown. Here, we show that PCNA phosphorylation by EGFR alters its interaction with mismatch-recognition proteins MutSα and MutSβ and interferes with PCNA-dependent activation of MutLα endonuclease, thereby inhibiting MMR at the initiation step. Evidence is also provided that Y211-phosphorylated PCNA induces nucleotide misincorporation during DNA synthesis. These findings reveal a novel mechanism by which Y211-phosphorylated PCNA promotes cancer development and progression via facilitating error-prone DNA replication and suppressing the MMR function.

Alternative energy resources have become an important issue due to the limited stocks of petroleum-based fuel. Microalgae, a source of renewable biodiesel, use solar light to convert CO2 into lipid droplets (LDs). Quantification of LDs in microalgae is required for developing and optimizing algal bioprocess engineering. However, conventional quantification methods are both time and labor-intensive and difficult to apply in high-throughput screening systems. LDs in plant and mammalian cells can be visualized by staining with various fluorescence probes such as the Nile Red, BODIPY, and Seoul-Fluor (SF) series. This report describes the optimization of LD staining in Chlamydomonas reinhardtii with SF probes via systematic variations of dye concentration, staining time, temperature, and pH. A protocol for quantitative measurement of accumulation kinetics of LDs in C. reinhardtii was developed using a spectrofluorimeter and the accuracy of LD size measurement was confirmed by transmission electron microscopy (TEM). Our results indicate that our spectrofluorimeter-based measurement approach can monitor kinetics of intracellular LDs (in control and nitrogen-source-starved Chlamydomonas reinhardtii) accumulation that has not been possible in the case of conventional imaging-based methods. Our results presented here confirmed that an SF44 can be a powerful tool for in situ monitoring and tracking of intracellular LDs formation.

The hMSH2(M688R) mismatch repair (MMR) gene mutation has been found in five large families from Tenerife, Spain, suggesting it is a Lynch syndrome or hereditary non-polyposis colorectal cancer (LS/HNPCC) founder mutation. In addition to classical LS/HNPCC tumors, these families present with a high incidence of central nervous system (CNS) tumors normally associated with Turcot or constitutional mismatch repair deficiency (CMMR-D) syndromes. Turcot and CMMR-D mutations may be biallelic, knocking out both copies of the MMR gene. The hMSH2(M688R) mutation is located in the ATP hydrolysis (ATPase) domain. We show that the hMSH2(M688R)-hMSH6 heterodimer binds to mismatched nucleotides but lacks normal ATP functions and inhibits MMR in vitro when mixed with the wild-type (WT) heterodimer. Another alteration that has been associated with LS/HNPCC, hMSH2(M688I)-hMSH6, displays no identifiable differences with the WT heterodimer. Interestingly, some extracolonic tumors from hMSH2(M688R) carriers may express hMSH2-hMSH6, yet display microsatellite instability (MSI). The functional analysis along with variability in tumor expression and the high incidence of CNS tumors suggests that hMSH2(M688R) may act as a dominant negative in some tissues, while the hMSH2(M688I) is most likely a benign polymorphism.

Because of the critical role of neuroinflammation in various neurological diseases, there are continuous efforts to identify new therapeutic targets as well as new therapeutic agents to treat neuroinflammatory diseases. Here we report the discovery of inflachromene (ICM), a microglial inhibitor with anti-inflammatory effects. Using the convergent strategy of phenotypic screening with early stage target identification, we show that the direct binding target of ICM is the high mobility group box (HMGB) proteins. Mode-of-action studies demonstrate that ICM blocks the sequential processes of cytoplasmic localization and extracellular release of HMGBs by perturbing its post-translational modification. In addition, ICM effectively downregulates proinflammatory functions of HMGB and reduces neuronal damage in vivo. Our study reveals that ICM suppresses microglia-mediated inflammation and exerts a neuroprotective effect, demonstrating the therapeutic potential of ICM in neuroinflammatory diseases.

MicroRNAs (miRNAs) are critical post-transcriptional regulators and are derived from hairpin-shaped primary transcripts via a series of processing steps. However, how the production of individual miRNAs is regulated remains largely unknown. Similarly, loss or overexpression of the key mismatch repair protein MutLα (MLH1-PMS2 heterodimer) leads to genome instability and tumorigenesis, but the mechanisms controlling MutLα expression are unknown. Here we demonstrate in vitro and in vivo that MLH1 and miR-422a participate in a feedback loop that regulates the level of both molecules. Using a defined in-vitro miRNA processing system, we show that MutLα stimulates the conversion of pri-miR-422a to pre-miR-422a, as well as the processing of other miRNAs tested, implicating MutLα as a general stimulating factor for miRNA biogenesis. This newly identified MutLα function requires its ATPase and pri-miRNA binding activities. In contrast, miR-422a downregulates MutLα levels by suppressing MLH1 expression through base pairing with the MLH1 3'-untranslated region. A model depicting this feedback mechanism is discussed.

Changes in contents of the S-alk(en)yl-L-cysteine sulfoxides (ACSOs) methiin, isoalliin, propiin, and cycloalliin in onions after boiling, frying, steaming, and microwaving were investigated using Liquid Chromatography Electrospray Ionization-Tandem Mass Spectrometry (LC/ESI-MS/MS). ACSOs contents increased by 34.2-568.0% during frying, steaming and microwaving, whereas ACSOs contents decreased by 32.6-69.4% during boiling. The methiin level in heat-treated onions ranged from 0.18 to 0.47 g/100 g of dry weight (DW), and the cycloalliin concentration in heat-treated onions ranged from 0.31 to 3.50 g/100 g of DW. The amount of isoalliin in processed onions was 0.34-3.32 g/100 g of DW, and propiin was 0.15-1.67 g/100 g of DW. Changes in the ACSO concentrations were dependent on the cooking method. The quality of heat processed onions was evaluated.

The organosulfur and degradation compounds of cool- and warm-type garlic were analyzed in Korea. This garlic exhibited a wide range of organosulfur compound levels. Analytical results indicated large amounts of alliin, γ-glutamyl-S-allyl-l-cysteine (GSAC) and γ-glutamyl-S-trans-1-propenyl-l-cysteine (GSPC) in garlic. The contents of alliin, GSAC, and GSPC were in the range of 10.52–30.12, 11.46–26.45, and 9.15–41.66 mg/g garlic (dry base), respectively. Allicin was the major biological compound at 2.53–9.36mg/g (dry base). GC/MS was employed to identify allicin degradation compounds in fresh garlic. The major chemical components of fresh garlic were diallyl sulfides and methyl allyl sulfides. Differences in the pattern of organosulfur composition and degradation components of thiosulfinates from warm- and cool-type garlic were demonstrated by principle component analysis. Therefore, the results may be useful for the quality evaluation of cool- and warm-type garlic in Korea.

HPLC method for determination of ajoene isomers in garlic oil products was optimized and validated. E- and Z-Ajoene were extracted with ethyl acetate and followed by the sensitive and selective determination of 2 isomers in a single run using normal phase HPLC equipped with silica gel column. The mobile phase was n-hexane and 2-propanol (85/15, v/v) with an isocratic condition as a flow rate of 1.0 mL/min and 240 nm of HPLC UV detector. All calibration curves of E- and Z-ajoene in oil-macerated garlic showed good linearity (r=0.998). Overall, intra- and inter-day were in the range of 0.12–2.30 and 2.84–5.26%, respectively. Recovery was in range of 87.17–98.53% for E-ajoene and 85.16–99.23% for Z-ajoene. The validated method was applied to determine contents of ajoene in macerate garlic juices prepared with various vegetable oil. There were no any matrix effects in all chromatograms. The proposed method may be useful for quality control and evaluation of garlic oil products.

A rapid and reliable method for the simultaneous determination of 12 biogenic amines (BAs; agmatine, phenylethylamine, tyramine, putrescine, cadaverine, histamine, serotonin, tryptamine, spermidine, noreinephrine, dopamine, and spermine) in cheonggukjang was optimized and validated using ultra high pressure liquid chromatography-electrospray tandem mass spectrometry (UHPLC-ESI-MS/MS). The BAs were dansylated and separated on a C8 column under LC gradient of 7 min duration, and detected by MS/MS with the multiple reaction monitoring mode (MRM). This method exhibited excellent linearity for all of the analytes with correlation determination (R2) higher than 0.98. The limits of detection (LODs) were 10.8–39.6 μg/kg. The precision results were expressed as relative standard deviation (RSD), ranged from 0.3 to 14.3% for intra-day and from 0.9 to 15.4% for the interday. The proposed method will help to ensure for quality control by monitoring of BAs in cheonggukjang.

We used a transgenic approach and yeast two-hybrid experiments to study the role of the rice (Oryza sativa L.) B-function MADS-box gene, OsMADS16. Transgenic rice plants were generated that ectopically expressed OsMADS16 under the control of the maize (Zea mays L.) ubiquitin1 promoter. Microscopic observations revealed that the innermost-whorl carpels had been replaced by stamen-like organs, which resembled the flowers of the previously described Arabidopsis thaliana (L.) Heynh. mutation superman as well as those ectopically expressing the AP3 gene. These results indicate that expression of OsMADS16 in the innermost whorl induces stamen development. Occasionally, carpels had completely disappeared. In addition, ectopic expression of OsMADS16 enhanced expression of OsMADS4, another B-function gene, causing superman phenotypes. In the yeast two-hybrid system, OsMADS16 did not form a homodimer but, rather, the protein interacted with OsMADS4. OsMADS16 also interacted with OsMADS6 and OSMADS8, both of which are homologous to SEPALLATA proteins required for the proper function of class-B and class-C genes in Arabidopsis. Based on the gene expression pattern and our yeast two-hybrid data, we discuss a quartet model of MADS-domain protein interactions in the lodicule and stamen whorls of rice florets.

Neuro-tracing approach is a great option to study innervation of the visceral organs including the kidneys. Important factors contributing to the success of this technique include the choice of a neuro-tracer, and delivery methods to result in successful labeling of peripheral sensory and motor ganglia. The neuro-tracer is usually applied directly to the kidney accessed via a surgical opening of the abdominal wall under deep anesthesia. A series of local microinjections of the dye are performed followed by a wound closure, and recovery period from the surgery. An extra care should be taken to prevent neuro-tracer spillage and accidental labeling of the surrounding organs during injections of the dye. Retrograde neuro-tracers like Fast Blue do not cross synapses, therefore, only neuronal bodies located within dorsal root ganglion neurons and major peripheral ganglia will be labeled by this approach. Retrogradely labeled peripheral neurons could be freshly isolated and dissociated for electrophysiological recordings and biochemical analyses (gene and protein expression), whereas the whole fixed ganglia could be sectioned to undergo immunohisto- and immunocytochemical targeted staining.

Background

In the present study, we investigated the effects of oil products from two Allium species: Allium sativum (garlic) and Allium hookeri (Chinese chives) on cell proliferation and neuroblast differentiation in the mouse dentate gyrus.

Methods

Using corn oil as a vehicle, the essential oil from garlic (10 ml/kg), or Chinese chives (10 ml/kg) was administered orally to 9-week-old mice once a day for 3 weeks. One hour following the last treatment, a novel object recognition test was conducted and the animals were killed 2 h after the test.

Results

In comparison to the vehicle-treated group, garlic essential oil (GO) treatment resulted in significantly increased exploration time and discrimination index during the novel object recognition test, while Chinese chives essential oil (CO) reduced the exploration time and discrimination index in the same test. In addition, the number of Ki67-immunoreactive proliferating cells and doublecortin-immunoreactive neuroblasts significantly increased in the dentate gyrus of GO-treated animals. However, administration of CO significantly decreased cell proliferation and neuroblast differentiation. Administration of GO significantly increased brain-derived neurotrophic factor (BDNF) levels and decreased acetylcholinesterase (AChE) activity in the hippocampal homogenates. In contrast, administration of CO decreased BDNF protein levels and had no significant effect on AChE activity, compared to that in the vehicle-treated group.

Conclusions

These results suggest that GO significantly improves novel object recognition as well as increases cell proliferation and neuroblast differentiation, by modulating hippocampal BDNF protein levels and AChE activity, while CO impairs novel object recognition and decreases cell proliferation and neuroblast differentiation, by reducing BDNF protein levels in the hippocampus.