Aberrant liver sirtuin 1 (SIRT1), a mammalian NAD+-dependent protein deacetylase, is implicated in the pathogenesis of alcoholic liver disease (ALD). However, the role of intestinal SIRT1 in ALD is ...presently unknown. This study investigated the involvement of intestine-specific SIRT1 in ethanol-induced liver dysfunction in mice. Ethanol feeding studies were performed on knockout mice with intestinal-specific SIRT1 deletion SIRT1i knockout (KO) and flox control wild-type (WT) mice with a chronic–plus-binge ethanol feeding protocol. After ethanol administration, hepatic inflammation and liver injury were substantially attenuated in the SIRT1iKO mice compared with the WT mice, suggesting that intestinal SIRT1 played a detrimental role in the ethanol-induced liver injury. Mechanistically, the hepatic protective effect of intestinal SIRT1 deficiency was attributable to ameliorated dysfunctional iron metabolism, increased hepatic glutathione contents, and attenuated lipid peroxidation, along with inhibition of a panel of genes implicated in the ferroptosis process in the livers of ethanol-fed mice. This study demonstrates that ablation of intestinal SIRT1 protected mice from the ethanol-induced inflammation and liver damage. The protective effects of intestinal SIRT1 deficiency are mediated, at least partially, by mitigating hepatic ferroptosis. Targeting intestinal SIRT1 or dampening hepatic ferroptosis signaling may have therapeutic potential for ALD in humans.
Concept Design of CFETR Tokamak Machine Song, Yun Tao; Wu, Song Tao; Li, Jian Gang ...
IEEE transactions on plasma science,
03/2014, Letnik:
42, Številka:
3
Journal Article
Recenzirano
China Fusion Engineering Test Reactor (CFETR) is a tokamak reactor; one design option under the consideration of the China National Integration Design Group employs superconducting magnets. The ...fusion power is at the range of 50-200 MW and the duty cycle (or burning time) was envisioned as 30%-50%. The plasma current will be 10 MA and the major and minor radii are 5.7 and 1.6 m, respectively. The concept engineering design including the magnet system, vacuum vessel (VV) system, and maintenance method has been carried out in the past years. The toroidal magnetic field strength at R 0 is 5 T and the maximum flux swing provided by central solenoid winding will be 160 VS. The main design work, including the electromagnetic analysis of the magnet system, has already been carried out. This paper mainly probes into the VV design and optimization based on three types of maintenance ports. Furthermore, the maintenance method, counted as one of the most important design studies, is presented specifically in this paper. It includes the design of the maintenance ports and the remote handling system design, and so on. The next design stage will mainly include mechanical design, conductor stability, different types of divertor system design, and so on.
Carotenoid pigments are valuable components of the human diet. A notable example is β-carotene, or provitamin A, which is converted into the derivatives astaxanthin and capsanthin, via the common ...intermediate zeaxanthin. To generate rice varieties producing diverse carotenoids beyond β-carotene, we specifically used a Capsicum β-carotene hydroxylase gene, B (CaBch) and a codon optimized version of the same gene, stB (stBch) to increase zeaxanthin synthesis. We also used a recombinant BAK gene (CaBch-2A-HpBkt), consisting of the CaBch sequence and a Haematococcus β-carotene ketolase gene (HpBkt) linked by a bicistronic 2 A sequence, as well as a codon optimized recombinant stBAK gene (stBch-2A-stBkt) to create astaxanthin synthesis. The four cassettes to seed-specifically express the B, stB, BAK and stBAK genes were individually combined with a PAC gene (CaPsy-2A-PaCrtI) cassette to previously impart β-carotene-enriched trait in rice endosperm. The single T-DNA vectors of B-PAC, stB-PAC, BAK-PAC and stBAK-PAC resulted in the accumulation of zeaxanthin and astaxanthin in the endosperm of the transgenic rice seeds. In addition, an extended version on the carotenoid pathway was introduced into rice to allow the production of capsanthin, by intercrossing a B-PAC rice line with a Ccs rice line, which harbors a Capsicum capsanthin-capsorubin synthase gene. Ultimately, we developed three functional rice varieties: B-PAC (0.8 μg/g zeaxanthin, deep yellow), stBAK-PAC (1.4 μg/g ketocarotenoids, including astaxanthin, pinkish red) and B-PAC x Ccs (0.4 μg/g of ketoxanthophylls, including capsanthin, orange-red) with the similar levels of total carotenoids to PAC rice, suggesting the capacity was dependent on β-carotene levels. Collectively, a combination of genetic engineering and conventional breeding is effective for multi-step metabolic engineering and biochemical pathway extension.
•The pathways toward zeaxanthin, astaxanthin and capsanthin beyond β-carotene were constructed in rice endosperm via stepwise metabolic engineering.•To do this, multiple gene expression strategies have taken advantage of the merits of bicistronic and multi-cassette expression and conventional breeding.•Resultant colorful rice varieties generating zeaxanthin (yellow), astaxanthin (pinkish red) and capsanthin (orange-red) in addition to β-carotene (yellow) might be attractive as new cultivars with different functions.
It is uncertain whether there is an increased retinal vessel density in patients with thyroid-associated ophthalmology (TAO), or if ocular hemodynamic changes are associated with their vision. Many ...techniques have been applied to analyze ocular hemodynamic changes in TAO patients; however, they suffer from limitations. Optical coherence tomography angiography (OCTA) is more sensitive to hemodynamic changes. We performed OCTA to determine whether there is an increased retinal vessel density in TAO patients, and investigate associations with their vision.
Twenty TAO patients (right eye) and 20 normal controls (right eye) were recruited for the study. Three-dimensional OCTA images were generated with 6 × 6-mm angiographic OCT scans of the superficial retinal layer (SRL) and deeper retinal layer (DRL) of the macular retina for each eye. We calculated the microvascular (MIR) and macrovascular (MAR) densities and compared MIR, MAR, and total MIR (TMI) density in the healthy control and TAO groups separately. We used the annular partition (C1-C6) and quadrant partition method to analyze retinal vessel density alterations. Correlation analyses were used to examine the association of MIR density and visual acuity.
In the SRL, STMI (superficial TMI) and SMIR (superficial MIR) density increased in the macular area of TAO patients ( P<.05). For the DRL, the density of DMIR (deeper MIR) increased in macular area only ( P<.05). However, with the annular partition method, TAO patients showed significantly increased SMIR density in the C1 and C2 regions ( P<.05), and increased DMIR density only in the C1 region ( P<.05). In the SRL, the correlation coefficient of the STMI/SMIR density in the TAO group was -0.538 ( r = -0.538, P = .032), and visual acuity was -0.624 ( r = -0.624, P = .010).
OCTA findings suggest that active TAO patients present with an increased retinal MIR density. Moreover, increased macular STMI and SMIR density might affect visual acuity.
CDI = color Doppler imaging; DMIR = deeper MIR; DRL = deeper retinal layer; EDV = end diastolic velocity; FAZ = foveal avascular zone; GO = Graves ophthalmopathy; MAR = macrovascular; MIR = microvascular; OCT = optical coherence tomography; OCTA = optical coherence tomography angiography; RI = resistance index; ROC = receiver operating characteristic; SMIR = superficial MIR; SOV = superior ophthalmic vein; SRL = superficial retinal layer; SSADA = split-spectrum amplitude-decor-relation angiography; STMI = superficial TMI; TAO = thyroid-associated ophthalmology; TMI = total MIR.
Lipin‐1 is a Mg2+‐dependent phosphatidic acid phosphohydrolase involved in the generation of diacylglycerol during synthesis of phospholipids and triglycerides. Ethanol‐mediated inhibitory effects on ...adipose‐specific lipin‐1 expression were associated with experimental steatohepatitis in rodents. In the present study, using an adipose‐specific lipin‐1 overexpression transgenic (Lpin1‐Tg) mouse model, we tested a hypothesis that adipose‐specific lipin‐1 overexpression in mice might dampen ethanol‐induced liver damage. Experimental alcoholic steatohepatitis was induced by pair‐feeding ethanol to Lpin1‐Tg and wild‐type (WT) mice using the chronic‐plus‐binge ethanol feeding protocol. Unexpectedly, following the chronic‐plus‐binge ethanol challenge, Lpin1‐Tg mice exhibited much more pronounced steatosis, exacerbated inflammation, augmented elevation of serum liver enzymes, hepatobiliary damage, and fibrogenic responses compared with the WT mice. Mechanistically, overexpression of adipose lipin‐1 in mice facilitated the onset of hepatic ferroptosis, which is an iron‐dependent form of cell death, and subsequently induced ferroptotic liver damage in mice under ethanol exposure. Concurrently, adipose lipin‐1 overexpression induced defective adiponectin signaling pathways in ethanol‐fed mice. Conclusion: We identified ferroptosis as a mechanism in mediating the detrimental effects of adipose‐specific lipin‐1 overexpression in mice under chronic‐plus‐binge ethanol exposure. Our present study sheds light on potential therapeutic approaches for the prevention and treatment of human alcoholic steatohepatitis.
Using an adipose tissue‐specific lipin‐1 overexpression (Lpin1‐Tg) mouse model, we identified ferroptosis as a mechanism in mediating the detrimental effects of adipose‐specific lipin‐1 overexpression in mice under chronic‐plus‐binge ethanol exposure. Our present study sheds light on potential therapeutic approaches for the prevention and treatment of human alcoholic steatohepatitis.
The OsMYBR22 (same to OsRVE1), an R1type-MYB transcription factor belonging to the rice CCA1-like family, was upregulated under blue light condition, which enhanced the chlorophyll and carotenoid ...accumulation. The overexpression of OsMYBR22 in rice (Oryza sativa, L) led to everlasting green seeds and leaves of a darker green. Transgene expression patterns showed more concordance with chlorophyll than carotenoid profiles. The transcript levels of most genes related to chlorophyll biosynthesis and degradation examined were similarly repressed in the late maturing stages of seeds. It proposed that rice seeds have the feedback regulatory mechanism for chlorophyll biosynthesis and also implied that evergreen seed traits might be caused due to the inhibition of degradation rather than the promotion of biosynthesis for chlorophylls. Metabolomics revealed that OsMYBR22 overexpression largely and simultaneously enhanced the contents of nutritional and functional metabolites such as chlorophylls, carotenoids, amino acids including lysine and threonine, and amino acid derivatives including γ-aminobutyric acid, which are mostly biosynthesized in chloroplasts. Transmission electron microscopy anatomically demonstrated greener phenotypes with an increase in the number and thickness of chloroplasts in leaves and the structurally retentive chloroplasts in tubular and cross cells of the seed inner pericarp region. In conclusion, the molecular actions of OsMYBR22/OsRVE1 provided a new strategy for the biofortified rice variety, an “Evergreen Rice,” with high accumulation of chloroplast-localized metabolites in rice grains.
•The OsMYBR22/OsRVE1 was upregulated under blue light condition, which enhanced the chlorophyll and carotenoid accumulation.•The OsMYBR22 overexpression phenotyped stay-green leaves and everlasting green grains in rice plants.•It provided an “Evergreen Rice” variety with simultaneously high contents of chloroplast-localized metabolites in grains.
In the present study, we investigated the brain interhemispheric functional connectivity changes in left eye MB versus right eye MB patients by voxel-mirrored homotopic connectivity (VMHC) methods.
A ...total of 31 patients with MB (15 with left eye MB and 16 with right eye MB), and 31 healthy controls (HCs) closely matched for age were recruited. All subjects underwent functional magnetic resonance imaging (fMRI) examinations. The VMHC method was used to evaluate directly functional interactions between the hemispheres. A one-way ANOVA was performed to determine the regions in which the VMHC differs between the three groups. Patients with MB were distinguished from HCs by a receiver operating characteristic (ROC) curve. The relationships between the mean VMHC signal values in many brain regions and clinical features in MB patients were calculated by pearson correlation analysis.
Compared with HCs, MB patients had significantly decreased VMHC values in the cuneus/calcarine/lingual gyrus. Furthermore, left eye MB showed decreased VMHC values in the cuneus/calcarine/lingual gyrus and showed increased VMHC values in the insula and middle frontal gyrus compared with HC. In addition, right eye MB showed decreased VMHC values in the cuneus/calcarine/lingual gyrus, primary motor cortex (M1)/primary somatosensory cortex (S1) and superior parietal lobule.
MB subjects showed abnormal brain interhemispheric functional connectivity in visual pathways. Furthermore, different patterns of brain interhemispheric functional connectivity occurred in the left eye and right eye MB. These VMHC values provide much useful information to explain the neural mechanism changes in MB.
Significant progress has been made in understanding the roles of crucial residues/motifs in the channel function of P2X receptors during the pre-structure era. The recent structural determination of ...P2X receptors allows us to reevaluate the role of those residues/motifs. Residues Arg-309 and Asp-85 (rat P2X4 numbering) are highly conserved throughout the P2X family and were involved in loss-of-function polymorphism in human P2X receptors. Previous studies proposed that they participated in direct ATP binding. However, the crystal structure of P2X demonstrated that those two residues form an intersubunit salt bridge located far away from the ATP-binding site. Therefore, it is necessary to reevaluate the role of this salt bridge in P2X receptors. Here, we suggest the crucial role of this structural element both in protein stability and in channel gating rather than direct ATP interaction and channel assembly. Combining mutagenesis, charge swap, and disulfide cross-linking, we revealed the stringent requirement of this salt bridge in normal P2X4 channel function. This salt bridge may contribute to stabilizing the bending conformation of the β2,3-sheet that is structurally coupled with this salt bridge and the α2-helix. Strongly kinked β2,3 is essential for domain-domain interactions between head domain, dorsal fin domain, right flipper domain, and loop β7,8 in P2X4 receptors. Disulfide cross-linking with directions opposing or along the bending angle of the β2,3-sheet toward the α2-helix led to loss-of-function and gain-of-function of P2X4 receptors, respectively. Further insertion of amino acids with bulky side chains into the linker between the β2,3-sheet or the conformational change of the α2-helix, interfering with the kinked conformation of β2,3, led to loss-of-function of P2X4 receptors. All these findings provided new insights in understanding the contribution of the salt bridge between Asp-85 and Arg-309 and its structurally coupled β2,3-sheet to the function of P2X receptors.
Aim
To evaluate the clinical efficacy and safety of laparoscopic adenomyomectomy combined with intraoperative replacement of levonorgestrel‐releasing intrauterine system (LNG‐IUS) in the treatment of ...symptomatic adenomyosis.
Methods
This is a case‐series study in a university medical center. A total of 52 patients with symptomatic adenomyosis were treated by laparoscopic adenomyomectomy combined with intraoperative replacement of LNG‐IUS from January 2015 to July 2018. Visual analog scale, menstrual flow and uterine volume were compared before and after the surgery (3, 12 and 24 months). Meanwhile, LNG‐IUS‐induced adverse reactions (e.g. irregular vaginal bleeding, amenorrhea, expulsion, and perforation) were also recorded.
Results
All operations were successfully completed via laparoscopy without conversion to laparotomy. No severe complications were noted during the surgical procedure or follow‐up period. The mean postoperative visual analog scale and menstrual flow scores and the volume of the uterus were significantly decreased (all P < 0.001) at 3, 12, and 24 months postoperatively, compared with preoperative scores. The clinical effective rates among the patients with dysmenorrhea were 98%, 96% and 96% at 3, 12 and 24 months after the operation, respectively. And the clinical effectiveness rate of menorrhagia was 97.6%, 95.2% and 95.2% at 3, 12 and 24 months after treatment, respectively. Among all related adverse reactions, amenorrhea was the most common (n = 12, 23.1%). There was one case of LNG‐IUS perforation (1.9%) and two cases of expulsion (3.8%).
Conclusion
Laparoscopic adenomyomectomy combined with intraoperative replacement of LNG‐IUS is a novel and effective conservative surgical procedure for symptomatic adenomyosis treatment.
PDF
