Mitotic perturbation is a key mechanism of action of decitabine in myeloid tumor treatment.

Decitabine (DAC) is clinically used to treat myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Our genome-wide CRISPR-dCas9 activation screen using MDS-derived AML cells indicates that mitotic regulation is critical for DAC resistance. DAC strongly induces abnormal mitosis (abscission failure or tripolar mitosis) in human myeloid tumors at clinical concentrations, especially in those with TP53 mutations or antecedent hematological disorders. This DAC-induced mitotic disruption and apoptosis are significantly attenuated in DNMT1-depleted cells. In contrast, overexpression of Dnmt1, but not the catalytically inactive mutant, enhances DAC-induced mitotic defects in myeloid tumors. We also demonstrate that DAC-induced mitotic disruption is enhanced by pharmacological inhibition of the ATR-CLSPN-CHK1 pathway. These data challenge the current assumption that DAC inhibits leukemogenesis through DNMT1 inhibition and subsequent DNA hypomethylation and highlight the potent activity of DAC to disrupt mitosis through aberrant DNMT1-DNA covalent bonds.

GREB1 isoform 4 is specifically transcribed by MITF and required for melanoma proliferation.

Growth regulation by estrogen in breast cancer 1 (GREB1) is involved in hormone-dependent and -independent tumor development (e.g., hepatoblastoma). In this study, we found that a GREB1 splicing variant, isoform 4 (Is4), which encodes C-terminal half of full-length GREB1, is specifically expressed via microphthalmia-associated transcription factor (MITF) in melanocytic melanoma, and that two MITF-binding E-box CANNTG motifs at the 5'-upstream region of GREB1 exon 19 are necessary for GREB1 Is4 transcription. MITF and GREB1 Is4 were strongly co-expressed in approximately 20% of the melanoma specimens evaluated (17/89 cases) and their expression was associated with tumor thickness. GREB1 Is4 silencing reduced melanoma cell proliferation in association with altered expression of cell proliferation-related genes in vitro. In addition, GREB1 Is4 targeting by antisense oligonucleotide (ASO) decreased melanoma xenograft tumor formation and GREB1 Is4 expression in a BRAFV600E; PTENflox melanoma mouse model promoted melanoma formation, demonstrating the crucial role of GREB1 Is4 for melanoma proliferation in vivo. GREB1 Is4 bound to CAD, the rate-limiting enzyme of pyrimidine metabolism, and metabolic flux analysis revealed that GREBI Is4 is necessary for pyrimidine synthesis. These results suggest that MITF-dependent GREB1 Is4 expression leads to melanoma proliferation and GREB1 Is4 represents a new molecular target in melanoma.

The sedative effect of intranasal administration of medetomidine using a mucosal atomization device in Japanese White rabbits.

To prevent aspiration in Japanese White (JW) rabbits, the maximum single volume of medetomidine administered intranasally is 0.3 mL per nostril using a mucosal atomization device (MAD). This study aimed to examine the sedative effect of intranasal administration of medetomidine using MAD in eight healthy female JW rabbits. Each rabbit received intranasal atomization (INA) of saline (Control treatment) along with three doses of 1 mg/mL medetomidine (0.3 mL to one nostril [MED0.3 treatment]; 0.3 mL each to both nostrils [MED0.6 treatment]; 0.3 mL twice to both nostrils [MED1.2 treatment]), with a washout period of at least 7 days between treatments. The actual doses of medetomidine were 82 (75-84) µg/kg (median [25th-75th percentile]), 163 (156-168) µg/kg, and 323 (295-343) µg/kg for the MED0.3, MED0.6, and MED1.2 treatments, respectively. A medetomidine-dose dependent sedative effect was detected, and the loss of righting reflex (LRR) was achieved in one rabbit at 18 min, seven rabbits at 11 (9-18) min, and eight rabbits at 7 (4-18) min after the MED0.3, MED0.6, and MED1.2 treatments, respectively. The LRR was maintained for 63 (29-71) min and 83 (68-101) min after the MED0.6 and MED1.2 treatments, respectively. Additionally, the INA of medetomidine produced a significant dose-dependent cardiorespiratory depression including a decrease in pulse rate, respiratory rate, percutaneous oxygen saturation, and arterial partial pressure of oxygen, and an increase in arterial partial pressure of carbon dioxide in the rabbits.

Use of a gum elastic bougie in a cat with severe upper airway stenosis.

Background: Gum elastic bougie (GEB) is an airway management device for patients who are difficult to intubate and its use has been reported in human medicine. However, to our knowledge, no reports in veterinary medicine have described oxygenation using GEB. We describe a case in which GEB was used to maintain oxygenation in a cat with severe upper airway stenosis. Case Description: A 10-year-old neutered male domestic shorthair cat was diagnosed with a laryngeal tumor with severe upper airway stenosis. During anesthesia induction, the normal laryngeal structure could not be confirmed; orotracheal intubation was difficult, resulting in a "cannot intubate, cannot oxygenate" status. The GEB was inserted, making it possible to oxygenate the cat until a permanent tracheostoma could be created, but hypoventilation was noted. Conclusion: Although GEB are not useful for proper ventilation, they can be useful for temporary oxygenation in veterinary medicine when airway management is difficult.

Relationship between [18F]FDG PET/CT and metabolomics in patients with colorectal cancer.

INTRODUCTION: Advances in metabolomics have significantly improved cancer detection, diagnosis, treatment, and prognosis. OBJECTIVES: To investigate the relationship between metabolic tumor volume (MTV) using 2-deoxy-2-[18F]fluoro-D-glucose (FDG) positron emission tomography (PET)/ computed tomography (CT) and metabolomics data in patients with colorectal cancer (CRC). METHODS: The metabolome in tumor tissues was analyzed using capillary electrophoresis time-of-flight mass spectrometry in 33 patients with newly diagnosed CRC who underwent FDG PET/CT before treatment and had tumor tissue post-surgery. Based on the FDG PET data, MTV was calculated and was dichotomized according to the median value, and tumors were divided into low-MTV and high-MTV tumors. Metabolomics data were compared between the low-MTV and high-MTV tumors. RESULTS: The levels of most glycolysis-related metabolites were not different between low-MTV and high-MTV tumors. The level of component of the initial part of the tricarboxylic acid (TCA) cycle, citrate, was significantly lower in the high-MTV tumor than in the low-MTV tumor. The TCA intermediate succinate level was significantly higher in the high-MTV tumor than in the low-MTV tumor. In contrast, the TCA intermediate fumarate level was significantly lower in the high-MTV tumor than in the low-MTV tumor. The levels of many amino acids were significantly higher in the high-MTV tumor than in the low-MTV tumor. CONCLUSIONS: Although preliminary, these results suggest that tumors with high FDG metabolism in CRC may obtain more energy by using a reverse reaction of the TCA cycle and amino-acid metabolism. However, further research is required to clarify this relationship.

Evaluation of caudal vena cava size using computed tomography in dogs under general anesthesia.

This study investigated the association between caudal vena cava (CVC) size and circulatory dynamics in dogs using computed tomography (CT) under general anesthesia. The subjects were 104 dogs who had undergone CT under general anesthesia in the past. The ratio of short diameter of the CVC to aortic diameter (CVCS/Ao) and the ratio of long to short diameter of the CVC (CVCL/CVCS) in the thorax and abdomen, respectively, were calculated using factors such as mean blood pressure (MBP), shock index (SI), anemia, hypoproteinemia, presence of intra-abdominal mass, and cardiac disease. There was a significant but negligible negative correlation between CVCS/Ao and MBP. In contrast, no significant correlation was found between CVC size and SI. The low MBP group had significantly higher CVCS/Ao of the thorax than the normal MBP group. The group with intra-abdominal mass had significantly lower CVCS/Ao of the abdomen than the group without intra-abdominal mass. The group with cardiac disease had significantly lower CVCL/CVCS of the thorax than the group without cardiac disease. In multiple regression analysis, low MBP, cardiac disease, intra-abdominal mass, and anemia were significant factors for CVCS/Ao of the thorax, CVCL/CVCS of the thorax, CVCS/Ao of the abdomen, and CVCL/CVCS of the abdomen, respectively. In conclusion, CVC size assessment using CT in dogs under general anesthesia is influenced by various factors.

Evaluation of Renal Blood Flow in Dogs during Short-Term Human-Dose Epoprostenol Administration Using Pulsed Doppler and Contrast-Enhanced Ultrasonography.

Prostacyclin is an in vivo bioactive substance that regulates renal blood flow (RBF). Information regarding how epoprostenol, a prostacyclin preparation, affects RBF in dogs is lacking. We investigated the effects of short-term epoprostenol administration on RBF in six healthy dogs under anesthesia by administering it intravenously at human doses-2, 5, and 10 ng/kg/min for 20 min. RBF was evaluated before and during epoprostenol administration using pulsed Doppler ultrasonography, and renal perfusion was evaluated using contrast-enhanced ultrasonography. Effects on renal and systemic circulation were evaluated by measuring systolic arterial, mean arterial, diastolic arterial, pulmonary arterial, mean right atrial, and pulmonary capillary wedge pressures; heart rate; and cardiac output. Kruskal-Wallis and Bonferroni multiple comparison tests and Spearman's rank correlation coefficient were used for statistical analyses. As epoprostenol dosage increased, the peak systolic and end diastolic velocity of the renal artery, maximum and minimum venous flow velocities of the interlobular and renal veins, and heart rate all tended to increase, although not significantly. Our results indicate that human-dose epoprostenol administration in dogs does not cause significant changes in renal or systemic circulation. However, the human doses used may have been too low to produce a clinical effect in dogs.

Maximum volume of nasal administration using a mucosal atomization device without aspiration in Japanese White rabbits.

Recently, a mucosal atomization device (MAD) has been applied in veterinary medicine. In the present study, the maximum volume of nasal atomization without aspiration using MAD was examined in eight healthy female Japanese White (JW) rabbits. Each rabbit had their head and neck examined by computed tomography before and after nasal atomization with four different doses (0.15, 0.3, 0.45, and 0.6 ml per nostril) of diluted contrast medium (1:2 mixture of iohexol and saline). This was done under general anesthesia by an intramuscular administration of alfaxalone 2.5 mg/kg, medetomidine 40 µg/kg, and butorphanol 0.4 mg/kg, with a 7-day washout period between each treatment. The diluted contrast medium was distributed in the nasal cavity, external nares, and/or oral cavity in all rabbits receiving each treatment. The intranasal distribution volumes of the contrast medium were 287 (250-333) mm3 [median (interquartile range)] for 0.15 ml, 433 (243-555) mm3 for 0.3 ml, 552 (356-797) mm3 for 0.45 ml, and 529 (356-722) mm3 for 0.6 ml of treatment. The intranasal distribution volume for 0.15 ml treatment tended to be lower than that for 0.6 ml treatment (P=0.083). The contrast medium was deposited in the trachea in one rabbit (12.5%) and four rabbits (50%) receiving treatments of 0.45 and 0.6 ml per nostril, respectively. The maximum volume of nasal atomization without aspiration into the trachea was 0.3 ml per nostril for the JW rabbits.

A novel set of volatile urinary biomarkers for late-life major depressive and anxiety disorders upon the progression of frailty: a pilot study.

Mood and anxiety disorders are frequent in the elderly and increase the risk of frailty. This study aimed to identify novel biomarkers of major depressive disorder (MDD) and anxiety in the elderly. We examined 639 participants in the community-dwelling Otassha Study (518 individuals considered healthy control, 77 with depression, anxiety, etc.), mean age 75 years, 58.4% of female. After exclusion criteria, we analyzed VOCs from 18 individuals (9 healthy control, 9 of MDD/agoraphobia case). Urinary volatile and semi-volatile organic compounds (VOCs) were profiled using solid-phase microextraction and gas chromatography-mass spectrometry. Six urinary VOCs differed in the absolute area of the base peak between participants with MDD and/or agoraphobia and controls. High area under the receiver-operating characteristic curve (AUC) values were found for phenethyl isothiocyanate (AUC: 0.86, p = 0.009), hexanoic acid (AUC: 0.85, p = 0.012), texanol (AUC: 0.99, p = 0.0005), and texanol isomer (AUC: 0.89, p = 0.005). The combined indices of dimethyl sulfone, phenethyl isothiocyanate, and hexanoic acid, and texanol and texanol isomer showed AUCs of 0.91 (p = 0.003) and 0.99 (p = 0.0005) and correlated with the GRID-HAMD and the Kihon Checklist (CL score), respectively. These VOCs may be valuable biomarkers for evaluating MDD and/or agoraphobia in the elderly.

Effects of sevoflurane, propofol or alfaxalone on neuromuscular blockade produced by a single intravenous bolus of rocuronium in dogs.

OBJECTIVE: To compare the effects of sevoflurane, propofol and alfaxalone on the neuromuscular blockade induced by a single intravenous bolus of rocuronium in dogs. STUDY DESIGN: A randomized, prospective, crossover experimental study. ANIMALS: A total of eight adult Beagle dogs (four female, four male), weighing 8.9-15.3 kg and aged 5-7 years. METHODS: The dogs were anesthetized three times with 1.25× minimum alveolar concentration of sevoflurane (SEVO treatment) and 1.25× minimum infusion rate of propofol (PROP treatment) or alfaxalone (ALFX treatment) at intervals of ≥14 days. Neuromuscular function was monitored with train-of-four (TOF) stimulation of the peroneal nerve by acceleromyography. After recording the control TOF ratio (TOFRC), a single bolus dose of rocuronium (1 mg kg-1) was administered intravenously. The times from rocuronium administration to achieving TOF count 0 (onset time), from achieving TOF count 0 to the reappearance of TOF count 4 (clinical blockade period), from 25% to 75% of TOFRC (recovery index) and from achieving TOF count 0 to TOF ratio/TOFRC >0.9 (total neuromuscular blockade duration) were recorded. RESULTS: The onset time and recovery index did not differ among the treatments. The median clinical blockade period was longer in the SEVO treatment [27.3 (26.0-30.3) minutes] than in PROP [16.6 (15.4-18.0) minutes; p = 0.002] and ALFX [22.4 (18.6-23.1) minutes; p = 0.017] treatments; and longer in the ALFX treatment than in the PROP treatment (p = 0.020). The mean total neuromuscular blockade duration was longer in the SEVO treatment (43.7 ± 9.9 minutes) than in PROP (25.1 ± 2.7 minutes; p < 0.001) and ALFX (32.5 ± 8.4 minutes; p = 0.036) treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Compared with alfaxalone and propofol, sevoflurane prolonged rocuronium-induced neuromuscular blockade by a significantly greater extent in dogs.

MEK inhibition preferentially suppresses anchorage-independent growth in osteosarcoma cells and decreases tumors in vivo.

Osteosarcoma is the most common high-grade malignancy of bone, and novel therapeutic options are urgently required. Previously, we developed mouse osteosarcoma AXT cells that can proliferate both under adherent and nonadherent conditions. Based on metabolite levels, nonadherent conditions were more similar to the in vivo environment than adherent conditions. A drug screen identified MEK inhibitors, including trametinib, that preferentially decreased the viability of nonadherent AXT cells. Trametinib inhibited the cell cycle and induced apoptosis in AXT cells, and both effects were stronger under nonadherent conditions. Trametinib also potently decreased viability in U2OS cells, but its effects were less prominent in MG63 or Saos2 cells. By contrast, MG63 and Saos2 cells were more sensitive to PI3K inhibition than AXT or U2OS cells. Notably, the combination of MAPK/ERK kinase (MEK) and PI3K inhibition synergistically decreased viability in U2OS and AXT cells, but this effect was less pronounced in MG63 or Saos2 cells. Therefore, signal dependence for cell survival and crosstalk between MEK-ERK and PI3K-AKT pathways in osteosarcoma are cell context-dependent. The activation status of other kinases including CREB varied in a cell context-dependent manner, which might determine the response to MEK inhibition. A single dose of trametinib was sufficient to decrease the size of the primary tumor and circulating tumor cells in vivo. Moreover, combined administration of trametinib and rapamycin or conventional anticancer drugs further increased antitumor activity. Thus, given optimal biomarkers for predicting its effects, trametinib holds therapeutic potential for the treatment of osteosarcoma.

Light-Assisted Rechargeable Lithium Batteries: Organic Molecules for Simultaneous Energy Harvesting and Storage.

Lithium batteries that could be charged on exposure to sunlight will bring exciting new energy storage technologies. Here, we report a photorechargeable lithium battery employing nature-derived organic molecules as a photoactive and lithium storage electrode material. By absorbing sunlight of a desired frequency, lithiated tetrakislawsone electrodes generate electron-hole pairs. The holes oxidize the lithiated tetrakislawsone to tetrakislawsone while the generated electrons flow from the tetrakislawsone cathode to the Li metal anode. During electrochemical operation, the observed rise in charging current, specific capacity, and Coulombic efficiency under light irradiation in contrast to the absence of light indicates that the quinone-based organic electrode is acting as both photoactive and lithium storage material. Careful selection of electrode materials with optimal bandgap to absorb the intended frequency of sunlight and functional groups to accept Li-ions reversibly is a key to the progress of solar rechargeable batteries.

The anesthetic effects of intramuscular alfaxalone in dogs premedicated with low-dose medetomidine and/or butorphanol.

We aimed to evaluate the induction, anesthesia, and cardiorespiratory effects of intramuscular (IM) anesthetic protocol with alfaxalone following premedication with low-dose medetomidine, butorphanol, or a combination of both (medetomidine-butorphanol) in dogs. Six healthy beagles were administered 1, 2.5, or 5 mg/kg alfaxalone IM following premedication with low-dose medetomidine (5 µg/kg; MA-IM), butorphanol (0.3 mg/kg; BA-IM), or medetomidine-butorphanol (5 µg/kg and 0.3 mg/kg, respectively; MBA-IM). Each dog received 9 treatments with minimum 7-day washout period between treatments. Dogs were allowed to breath room air during anesthetic induction. We attempted endotracheal intubation after alfaxalone administration. Alfaxalone produced a dose-dependent anesthetic effect in each anesthetic protocol. Intubation was achieved in 4 out of 6 dogs that received MA-IM and BA-IM with 2.5 mg/kg alfaxalone and in all dogs that received MBA-IM with 1, 2.5, and 5 mg/kg alfaxalone. The median durations [minimum-maximum] of accepting intubation were 79 [0-89], 97 [84-120], and 117 [84-217] min, respectively. Hypotension (mean arterial blood pressure <60 mmHg) did not develop, but bradycardia (heart rate <60 beats/min) was observed in all dogs that received the MA-IM and MBA-IM protocols. Severe hypoxemia (percutaneous arterial oxygen saturation <90%) developed in 2 dogs that received MBA-IM with 5 mg/kg alfaxalone. We consider that the MA-IM and BA-IM protocols with ≥2.5 mg/kg alfaxalone and the MBA-IM protocol with 1-2.5 mg/kg alfaxalone could provide clinically useful and effective anesthesia without causing severe cardiorespiratory depression in healthy dogs.

Lithium, sodium and magnesium ion conduction in solid state mixed polymer electrolytes.

Alkali and alkaline earth metal-ion batteries are currently among the most efficient electrochemical energy storage devices. However, their stability and safety performance are greatly limited when used with volatile organic liquid electrolytes. A solid state polymer electrolyte is a prospective solution even though poor ionic conductivity at room temperature remains a bottleneck. Here we propose the mixing of two similar polymer matrices, poly(dimethyl siloxane) and poly(ethylene oxide), to address this challenge. The resulting electrolyte matrix is denser and significantly improves room-temperature ionic conductivity. Ab initio analyses of the reaction between the cations and the polymers show that oxygen sites act as entrapment sites for the cations and that ionic conduction likely occurs through hopping between adjacent oxygen sites. Molecular dynamics simulations of the dynamics of both polymers and the dynamics of the polymer mix show that the more frequent and more pronounced molecular vibrations of the polymer mix are likely responsible for reducing the time between two consecutive oxygen entrapments, thereby speeding up the conduction process. This hypothesis is experimentally validated by the practically useful ionic conductivity (σ≈ 10-4 S cm-1 at 25 °C) and the improved safety parameters exhibited by a transparent flexible multi-cation (Li+, Na+ and Mg2+) conducting solid channel made up of the above mixed polymer system.

Highly sensitive transient reflection measurement in extreme ultraviolet region for tracking carrier and coherent phonon dynamics.

A highly sensitive method for detecting transient reflection in the extreme ultraviolet (XUV) region was developed on the basis of high-order harmonics for tracking carrier and coherent phonon dynamics. The use of lock-in detection and boxcar integration enables us to observe optical modulation (ΔR/R) as high as 1 × 10-4, and the data acquisition takes only four minutes. XUV transient reflections of bismuth exhibited exponential decay originating from excited carriers and periodic oscillation originating from A1g optical phonons. The linear power dependence of the electronic and phonon amplitudes indicated that one-photon excitation occurred under the experimental conditions. The cosine of the initial phase of the phonon oscillation revealed that a displacive excitation mechanism contributed to phonon generation. The phonon parameters obtained by the XUV and NIR probes were consistent even though their penetration depths were different. The result indicated that the XUV and NIR pulses probe the same excited region, which should be near the surface due to the short penetration depth of the NIR pump pulses. The present highly sensitive means of detecting XUV transient reflections in solid-state materials could be utilized for detecting attosecond dynamics in the future.

Urinary volatilome analysis in a mouse model of anxiety and depression.

Psychiatric disorders including depression and anxiety comprise a broad range of conditions with different symptoms. We have developed a mouse model of depression/anxiety in mice deficient in the St3gal4 gene. In this study, we performed a comparative analysis of urinary volatile organic compounds (VOCs) in St3gal4-deficient (St3gal4-KO) and wild-type mice using gas chromatography-mass spectrometry, and we screened 18 putative VOCs. Principal component analysis (PCA) based on these VOCs identified a major group of 11 VOCs, from which two groups were clarified by hierarchical clustering analysis. One group including six VOCs (pentanoic acid, 4-methyl-, ethyl ester; 3-heptanone, 6-methyl; benzaldehyde; 5,9-undecadien-2-ol, 6,10-dimethyl; and unknown compounds RI1291 and RI1237) was correlated with the startle response (r = 0.620), which is related to an unconscious defensive response. The other group including two VOCs (beta-farnesene and alpha-farnesene) comprised pheromones which increased in KO mice. Next, male mice underwent a social behavior test with female mice in the estrus stage, showing reduced access of KO male mice to female mice. Comparative analysis of urinary VOCs before and after encounters revealed that the six VOCs were not changed by these encounters. However, in WT mice, the two farnesenes increased after the encounters, reaching the level observed in KO mice, which was not altered following the encounter. Taken together, these results indicated that St3gal4 was involved in modulating urinary VOCs. Moreover, VOC clusters discovered by comparison of St3gal4-KO mice with WT mice were correlated with differential emotional behaviors.

Graphene Supported MoS2 Structures with High Defect Density for an Efficient HER Electrocatalysts.

The development of novel efficient and robust electrocatalysts with sufficient active sites is one of the key parameters for hydrogen evolution reactions (HER) catalysis, which plays a key role in hydrogen production for clean energy harvesting. Recently, two-dimensional (2D) materials, especially those based upon transition metal dichalcogenides such as molybdenum disulfide (MoS2), have gained attention for the catalysis of hydrogen production because of their exceptional properties. Innovative strategies have been developed to engineer these material systems for improvements in their catalytic activity. Toward this aim, the facile growth of MoS2 clusters by sulfurization of molybdenum dioxide (MoO2) particles supported on reduced graphene oxide (rGO) foams using the chemical vapor deposition (CVD) method is reported. This approach created various morphologies of MoS2 with large edges and defect densities on the basal plane of rGO supported MoS2 structures, which are considered as active sites for HER catalysis. In addition, MoS2 nanostructures on the surface of the porous rGO network show robust physical interactions, such as van der Waals and π-π interactions between MoS2 and rGO. These features result in an improved process to yield a suitable HER catalyst. In order to gain a better understanding of the improvement of this MoS2-based HER catalyst, fully atomistic molecular dynamics (MD) simulations of different defect geometries were also performed.

Complementary behaviour of EDL and HER activity in functionalized graphene nanoplatelets.

Green hydrogen production is a vital requirement of the upcoming hydrogen fuel-based locomotion and economy. Water electrolysis facilitated by electricity derived from renewable sources and direct solar-to-hydrogen conversion centred on photochemical and photoelectrochemical water splitting is a promising pathway for sustainable hydrogen production. All these methods require a highly active noble metal catalyst to make the water-splitting process more energy-efficient and in order to make it economical, metal-free hydrogen evolution catalysts such as graphene nanoplatelets (GNPs) are essential. Herein, we report the effect of a range of functionalizations on the catalytic properties of graphene nanoplatelets (GNPs) for the hydrogen evolution reaction (HER). We also account for the effect of functionalization on the strength of the electrical double layer formation on the surface of functionalized GNPs. It is observed that the catalytic activity and the electrical double layer strength are inversely related to each other. Our first-principles-based density functional theoretical (DFT) modelling unravels the origin of the observed electrocatalytic activity and its trend and the strength of the electrical double layers in terms of free energy changes during the ion absorption/desorption events on the electrode surface. Based on our observations, minimizing the electrical double layer strength is identified as an approach to improve the catalytic performance of the catalysts.

Plasticity of histone modifications around Cidea and Cidec genes with secondary bile in the amelioration of developmentally-programmed hepatic steatosis.

We recently reported that a treatment with tauroursodeoxycholic acid (TUDCA), a secondary bile acid, improved developmentally-deteriorated hepatic steatosis in an undernourishment (UN, 40% caloric restriction) in utero mouse model after a postnatal high-fat diet (HFD). We performed a microarray analysis and focused on two genes (Cidea and Cidec) because they are enhancers of lipid droplet (LD) sizes in hepatocytes and showed the greatest up-regulation in expression by UN that were completely recovered by TUDCA, concomitant with parallel changes in LD sizes. TUDCA remodeled developmentally-induced histone modifications (dimethylation of H3K4, H3K27, or H3K36), but not DNA methylation, around the Cidea and Cidec genes in UN pups only. Changes in these histone modifications may contribute to the markedly down-regulated expression of Cidea and Cidec genes in UN pups, which was observed in the alleviation of hepatic fat deposition, even under HFD. These results provide an insight into the future of precision medicine for developmentally-programmed hepatic steatosis by targeting histone modifications.

Phosphoethanolamine Accumulation Protects Cancer Cells under Glutamine Starvation through Downregulation of PCYT2.

Tolerance to severe tumor microenvironments, including hypoxia and nutrient starvation, is a common feature of aggressive cancer cells and can be targeted. However, metabolic alterations that support cancer cells upon nutrient starvation are not well understood. Here, by comprehensive metabolome analyses, we show that glutamine deprivation leads to phosphoethanolamine (PEtn) accumulation in cancer cells via the downregulation of PEtn cytidylyltransferase (PCYT2), a rate-limiting enzyme of phosphatidylethanolamine biosynthesis. PEtn accumulation correlated with tumor growth under nutrient starvation. PCYT2 suppression was partially mediated by downregulation of the transcription factor ELF3. Furthermore, PCYT2 overexpression reduced PEtn levels and tumor growth. In addition, PEtn accumulation and PCYT2 downregulation in human breast tumors correlated with poor prognosis. Thus, we show that glutamine deprivation leads to tumor progression by regulating PE biosynthesis via the ELF3-PCYT2 axis. Furthermore, manipulating glutamine-responsive genes could be a therapeutic approach to limit cancer progression.