Canagliflozin Regulates Ferroptosis, Potentially via Activating AMPK/PGC-1α/Nrf2 Signaling in HFpEF Rats

Aims: Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been found to ameliorate major adverse cardiovascular events in patients with heart failure with preserved ejection fraction (HFpEF), but the exact mechanism is unknown. Ferroptosis is a form of programmed necrosis. Herein, we verified that canagliflozin (CANA) ameliorates heart function in HFpEF rats, partly by regulating ferroptosis, which may be activated by AMPK/PGC-1α/Nrf2 signaling.Methods: An HFpEF model was established and subjected to CANA treatment. Blood pressure was monitored, and echocardiography was performed at the 12th week. Pathological examination was performed, and expression of ferroptosis-associated proteins and AMPK/PGC-1α/Nrf2 signaling related proteins was detected.Results: CANA had an antihypertensive effect and increased E/A ratios in HFpEF rats. Myocardial pathology was ameliorated, on the basis of decreased cross-sectional area and intercellular fibrosis. Acyl-CoA synthetase long-chain family member 4 (ACSL4) expression increased, whereas ferritin heavy chain 1 (FTH1) expression decreased in HFpEF rats, which showed iron overload. CANA reversed changes in ACSL4 and FTH1, and decreased iron accumulation, but did not alter glutathione peroxidase 4 (GPX4) expression. The expression of AMPK/PGC-1α/Nrf2 signaling related proteins and heme oxygenase 1 (HO-1) in the HFpEF group decreased but was reverted after CANA treatment.Conclusions: CANA regulates ferroptosis, potentially via activating AMPK/PGC-1α/Nrf2 signaling in HFpEF rats

Online scheduling on a single machine with one restart for all jobs to minimize the weighted makespan

In this paper, we consider the online scheduling problem on a single machine to minimize the weighted makespan. In this problem, all jobs arrive over time and they are allowed to be restarted only once. For the general case when the processing times of all jobs are arbitrary, we show that there is no online algorithm with a competitive ratio of less than 2, which matches the lower bound of the problem without restart. That is, only one restart for all jobs is invalid for improving the competitive ratio in the general case. For the special case when all jobs have the same processing time, we present the best possible online algorithm with a competitive ratio of 1.4656, which improves the competitive ratio of $\frac{1+\sqrt{5}}{2}\approx1.618$ for the problem without restart

Interface induced high temperature superconductivity in single unit-cell FeSe films on SrTiO3

Searching for superconducting materials with high transition temperature (TC) is one of the most exciting and challenging fields in physics and materials science. Although superconductivity has been discovered for more than 100 years, the copper oxides are so far the only materials with TC above 77 K, the liquid nitrogen boiling point. Here we report an interface engineering method for dramatically raising the TC of superconducting films. We find that one unit-cell (UC) thick films of FeSe grown on SrTiO3 (STO) substrates by molecular beam epitaxy (MBE) show signatures of superconducting transition above 50 K by transport measurement. A superconducting gap as large as 20 meV of the 1 UC films observed by scanning tunneling microcopy (STM) suggests that the superconductivity could occur above 77 K. The occurrence of superconductivity is further supported by the presence of superconducting vortices under magnetic field. Our work not only demonstrates a powerful way for finding new superconductors and for raising TC, but also provides a well-defined platform for systematic study of the mechanism of unconventional superconductivity by using different superconducting materials and substrates

Canagliflozin Alleviates Atherosclerosis Progression through Inflammation, Oxidative Stress, and Autophagy in Western Diet-fed ApoE −/− Mice

Purpose: This study was aimed at investigating the effect of canagliflozin (Cana) on atherosclerosis and further exploring its potential mechanism. Methods: ApoE −/− mice were fed a Western diet (WD) and randomly divided into a WD group and WD+Cana group. After 15 weeks of canagliflozin treatment, serum levels of fasting insulin and inflammatory cytokines were determined with ELISA kits. HE, Oil Red O, and Masson staining were used to estimate the extent of atherosclerosis. Immunohistochemistry, immunofluorescence, ROS staining, and RT-PCR were used to further investigate Cana’s potential mechanism. Results: Histological analysis indicated that Cana restrained atherosclerotic plaque development. Furthermore, Cana decreased the percentage of F4/80 positive cells, and the areal density of ROS and relative fluorescence intensity of P62, but enhanced the relative fluorescence intensity of LC3 in the aortic root. Analysis of factors associated with the inflammatory response mediated by AP-1, oxidative stress mediated through the ROS/Nrf2 pathway, and autophagy in the aorta indicated elevated mRNA levels of F4/80, MCP-1, VCAM-1, AP-1, ROS, NOX4, P62, NLRP3, and IL-1β, but diminished mRNA levels of Nrf2, GST, eNOS, and LC3, in the WD+Cana group. Conclusion: Canagliflozin may attenuate atherosclerosis by decreasing the inflammatory response mediated by AP-1, alleviating oxidative stress through the ROS/Nrf2 pathway, and enhancing autophagy in WD-fed ApoE −/− mice

Atomic-layered Au clusters on α-MoC as catalysts for the low-temperature water-gas shift reaction

The water-gas shift (WGS) reaction (where carbon monoxide plus water yields dihydrogen and carbon dioxide) is an essential process for hydrogen generation and carbon monoxide removal in various energy-related chemical operations. This equilibrium-limited reaction is favored at a low working temperature. Potential application in fuel cells also requires a WGS catalyst to be highly active, stable, and energy-efficient and to match the working temperature of on-site hydrogen generation and consumption units. We synthesized layered gold (Au) clusters on a molybdenum carbide (α-MoC) substrate to create an interfacial catalyst system for the ultralow-temperature WGS reaction. Water was activated over α-MoC at 303 kelvin, whereas carbon monoxide adsorbed on adjacent Au sites was apt to react with surface hydroxyl groups formed from water splitting, leading to a high WGS activity at low temperatures

Response of soil bacterial community composition and its associated geochemical parameters to rapid short-term cyclic groundwater-level oscillations: soil column experiments

Groundwater-level oscillations change geochemical conditions, carbon cycling processes and bacterial community composition, and these changes may vary vertically with depth in a soil. In this study, soil column experiments were conducted to explore variations in soil bacterial community composition and its associated geochemical parameters to rapid short-term cyclic groundwater-level oscillations driven by natural fluctuations (NF) and rainfall infiltration (RI) and the results are compared with quasi static (QS) column. Water saturation patterns in vadose and oscillated zones, and oxygen level patterns, soil total organic carbon (TOC) removal rates and soil bacterial community composition in vadose, oscillated and saturated zones were evaluated. Results showed that water saturation and oxygen level oscillated with groundwater level in NF and RI columns. TOC removal rates in RI column were the highest across vadose (~38.4%), oscillated (~35.8%) and saturated (~35.2%) zones. Deltaproteobacteria, which was significantly correlated with TOC removal (p < 0.05), exhibited relatively higher abundances in the vadose and oscillated zones of RI column than those of QS and NF columns. Soil bacterial community structure was dynamic at the class level due to water saturation, oxygen level and TOC removal. TOC removal was the driver to separate distribution of bacterial community structure in the vadose and oscillated zones of RI column from those of QS and NF columns. This study suggests that RI induced rapid short-term cyclic groundwater-level oscillations could significantly influence both soil carbon cycle and bacterial community structure in vadose and oscillated zones

Differences in the Gut Microbiota Establishment and Metabolome Characteristics Between Low- and Normal-Birth-Weight Piglets During Early-Life

Low-birth-weight (LBW) piglets are at a high-risk for postnatal growth failure, mortality, and metabolic disorders later in life. Early-life microbial exposure is a potentially effective intervention strategy for modulating the health and metabolism of the host. Yet, it has not been well elucidated whether the gut microbiota development in LBW piglets is different from their normal littermates and its possible association with metabolite profiles. In the current study, 16S rRNA gene sequencing and metabolomics was used to investigate differences in the fecal microbiota and metabolites between LBW and normal piglets during early-life, including day 3 (D3), 7 (D7), 14 (D14), 21 (D21, before weaning), and 35 (D35, after birth). Compared to their normal littermates, LBW piglets harbored low proportions of Faecalibacterium on D3, Flavonifractor on D7, Lactobacillus, Streptococcus, and Prevotella on D21, as well as Howardella on D21 and D35. However, the abundance of Campylobacter on D7 and D21, Prevotella on D14 and D35, Oscillibacter and Moryella on D14 and D21, and Bacteroides on D21 was significantly higher in LBW piglets when compared with normal piglets. The results of the metabolomics analysis suggested that LBW significantly affected fecal metabolites involved in fatty acid metabolism (e.g., linoleic acid, α-linolenic acid, and arachidonic acid), amino acid metabolism (e.g., valine, phenylalanine, and glutamic acid), as well as bile acid biosynthesis (e.g., glycocholic acid, 25-hydroxycholesterol, and chenodeoxycholic acid). Spearman correlation analysis revealed a significant negative association between Campylobacter and N1-acetylspermine on D7, Moryella and linoleic acid on D14, Prevotella and chenodeoxycholic acid on D21, and Howardella and phenylalanine on D35, respectively. Collectively, LBW piglets have a different gut bacterial community structure when compared with normal-birth-weight (NBW) piglets during early-life, especially from 7 to 21 days of age. Also, a distinctive metabolic status in LBW piglets might be partly associated with the altered intestinal microbiota. These findings may further elucidate the factors potentially associated with the impaired growth and development of LBW piglets and facilitate the development of nutritional interventions

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Single-Machine Scheduling with Rejection and an Operator Non-Availability Interval

In this paper, we study two scheduling problems on a single machine with rejection and an operator non-availability interval. In the operator non-availability interval, no job can be started or be completed. However, a crossover job is allowed such that it can be started before this interval and completed after this interval. Furthermore, we also assume that job rejection is allowed. That is, each job is either accepted and processed in-house, or is rejected by paying a rejection cost. Our task is to minimize the sum of the makespan (or the total weighted completion time) of accepted jobs and the total rejection cost of rejected jobs. For two scheduling problems with different objective functions, by borrowing the previous algorithms in the literature, we propose a pseudo-polynomial-time algorithm and a fully polynomial-time approximation scheme (FPTAS), respectively