Interaction Between Leucine and Phosphodiesterase 5 Inhibition in Modulating Insulin Sensitivity and Lipid Metabolism

Purpose: Leucine activates SIRT1/AMP-activated protein kinase (AMPK) signaling and markedly potentiates the effects of other sirtuin and AMPK activators on insulin signaling and lipid metabolism. Phosphodiesterase 5 inhibition increases nitric oxide–cGMP signaling, which in turn exhibits a positive feedback loop with both SIRT1 and AMPK, thus amplifying peroxisome proliferator-activated receptor γ co-activator α (PGC1α)-mediated effects. Methods: We evaluated potential synergy between leucine and PDE5i on insulin sensitivity and lipid metabolism in vitro and in diet-induced obese (DIO) mice. Results: Leucine (0.5 mM) exhibited significant synergy with subtherapeutic doses (0.1–10 nM) of PDE5-inhibitors (sildenafil and icariin) on fat oxidation, nitric oxide production, and mitochondrial biogenesis in hepatocytes, adipocytes, and myotubes. Effects on insulin sensitivity, glycemic control, and lipid metabolism were then assessed in DIO-mice. DIO-mice exhibited fasting and postprandial hyperglycemia, insulin resistance, and hepatic steatosis, which were not affected by the addition of leucine (24 g/kg diet). However, the combination of leucine and a subtherapeutic dose of icariin (25 mg/kg diet) for 6 weeks reduced fasting glucose (38%, P,0.002), insulin (37%, P,0.05), area under the glucose tolerance curve (20%, P,0.01), and fully restored glucose response to exogenous insulin challenge. The combination also inhibited hepatic lipogenesis, stimulated hepatic and muscle fatty acid oxidation, suppressed hepatic inflammation, and reversed high-fat diet-induced steatosis. Conclusion: These robust improvements in insulin sensitivity, glycemic control, and lipid metabolism indicate therapeutic potential for leucine–PDE5 inhibitor combinations

Short-term clinical outcomes and five-year survival analysis of laparoscopic-assisted transanal natural orifice specimen extraction versus conventional laparoscopic surgery for sigmoid and rectal cancer: a single-center retrospective study

BackgroundThe cosmetic benefits of natural orifice specimen extraction (NOSE) are easily noticeable, but its principles of aseptic and tumor-free procedure have caused controversy.MethodsWe conducted a retrospective analysis of the clinical data of patients who underwent laparoscopic-assisted transanal NOSE or conventional laparoscopic surgery (CLS) for sigmoid and rectal cancer at our hospital between January 2018 and December 2018. The study aimed to compare the general characteristics, perioperative indicators, postoperative complications, and five-year follow-up results between the two groups.ResultsA total of 121 eligible patients were enrolled, with 52 underwent laparoscopic-assisted transanal NOSE and 69 underwent CLS. There were no significant differences observed between the two groups in terms of gender, age, body mass index (BMI), TNM stage, etc. (P > 0.05). However, the NOSE group exhibited significantly shorter total incision length and longer operation time compared to the CLS group (P < 0.05). There were no statistically significant differences observed between the two groups in terms of positive rate of bacterial culture, incidence rates of intraabdominal infections or anastomotic leakage (P > 0.05). Furthermore, during follow-up period there was no statistically significant difference observed between these two groups concerning overall survival rate and disease-free survival outcomes (P > 0.05).ConclusionsThe management of surgical complications in CLS is exemplary, with NOSE presenting a sole advantage in terms of incision length albeit at the cost of prolonged operative time. Therefore, NOSE may be deemed appropriate for patients who place high emphasis on postoperative cosmetic outcomes

Precision Higgs physics at the CEPC

The discovery of the Higgs boson with its mass around 125 GeV by the ATLAS and CMS Collaborations marked the beginning of a new era in high energy physics. The Higgs boson will be the subject of extensive studies of the ongoing LHC program. At the same time, lepton collider based Higgs factories have been proposed as a possible next step beyond the LHC, with its main goal to precisely measure the properties of the Higgs boson and probe potential new physics associated with the Higgs boson. The Circular Electron Positron Collider~(CEPC) is one of such proposed Higgs factories. The CEPC is an $e^+e^-$ circular collider proposed by and to be hosted in China. Located in a tunnel of approximately 100~km in circumference, it will operate at a center-of-mass energy of 240~GeV as the Higgs factory. In this paper, we present the first estimates on the precision of the Higgs boson property measurements achievable at the CEPC and discuss implications of these measurements.Comment: 46 pages, 37 figure

Fault Detection and Isolation for Redundant Inertial Measurement Unit under Quantization

Fault detection and isolation with redundant strapdown inertial measurement unit is critical for ensuring the reliability of the guidance or navigation system in the fields of both aeronautics and astronautics. Although the parity space approach is used widely, it cannot detect the soft fault which affects navigation performance under pulse quantization. This paper develops the three-channel filters to detect the soft fault and conducts theoretical implementation. The constraint conditions of their parameters are explored and the influence of the weight of different ratios is analyzed. The Monte Carlo simulation is carried out in order to verify the validity of the fault detection and isolation method. The simulation results and their analysis provide a theoretical reference for fault detection and isolation with redundant strapdown inertial measurement unit

Mice with an Na V 1.4 sodium channel null allele have latent myasthenia, without susceptibility to periodic paralysis

Over 60 mutations of SCN4A encoding the NaV1.4 sodium channel of skeletal muscle have been identified in patients with myotonia, periodic paralysis, myasthenia, or congenital myopathy. Most mutations are missense with gain-of-function defects that cause susceptibility to myotonia or periodic paralysis. Loss-of-function from enhanced inactivation or null alleles is rare and has been associated with myasthenia and congenital myopathy, while a mix of loss and gain of function changes has an uncertain relation to hypokalaemic periodic paralysis. To better define the functional consequences for a loss-of-function, we generated NaV1.4 null mice by deletion of exon 12. Heterozygous null mice have latent myasthenia and a right shift of the force-stimulus relation, without evidence of periodic paralysis. Sodium current density was half that of wild-type muscle and no compensation by retained expression of the foetal NaV1.5 isoform was detected. Mice null for NaV1.4 did not survive beyond the second postnatal day. This mouse model shows remarkable preservation of muscle function and viability for haploinsufficiency of NaV1.4, as has been reported in humans, with a propensity for pseudo-myasthenia caused by a marginal Na(+) current density to support sustained high-frequency action potentials in muscle

Nature of crystalline particle assembly in ring shaped colloidal stains from concentrated dispersions

The drying of colloidal droplet suspensions is important in many realms of practical application and has sustained the interest of researchers over two decades. The arrangements of polystyrene and silica beads, both of diameter 1 μm, 10% by volume of solid deposited on normal glass (hydrophilic), and silicone (hydrophobic) surfaces evaporated from a suspension volume of 3 μL, were investigated. Doughnut shape depositions were found, imputing the influence of strong central circulation flows that resulted in three general regions. In the central region which had strong particle build-up, the top most layers of particle arrangement was confirmed to be disordered using power spectrum and radial distribution function analysis. On closer examination, this appeared more like frustrated attempts to crystallize into larger grains rather than beads arranging in a disordered fashion throughout the piling process. With an adapted micro-bulldozing operation to progressively remove layers of particles from the heap, we found that the later efforts to crystallize through lateral capillary inter-particle forces were liable to be undone once the particles contacted the disorganized particles underneath, which were formed out of the jamming of fast particles arriving at the surface. © 2014 Elsevier B.V

Genetic diversity, forensic characteristics and phylogenetic analysis of the Qiongzhong aborigines residing in the tropical rainforests of Hainan Island via 19 autosomal STRs

Background The genetic landscape of the Qiongzhong aborigines, who reside in “the Heart of Hainan,” is still unclear. The Goldeneye™ DNA ID System 20 A is available for forensic and population genetics applications. Aim To obtain genetic polymorphisms of 19 autosomal STR loci in the Qiongzhong aborigines, and to explore the genetic relationships with a total of 69,132 people from forty-five populations. Subjects and methods Genotype data on 19 autosomal STRs were collected from 724 Qiongzhong aborigines and phylogenetic relationships were conducted by multidimensional scaling analysis (MDS), principal component analysis (PCA) and neighbor-joining (N-J) phylogenetic tree construction. Results No evidence of deviation from Hardy-Weinberg equilibrium was identified. A total of 233 distinct alleles were observed with allele frequencies ranging from 0.0007 to 0.5375. The combined power of discrimination (CPD) and combined power of exclusion (CPE) for the 19 autosomal STR loci were 1–8.28 × 10–34 and 0.999999987, respectively. Conclusion Our phylogenetic results demonstrated that (a) the populations of Southeast Asian countries have thorough integrations with southern China in terms of ethnicity and genetics due to long-term cultural and trade exchanges, and (b) based on genetic and linguistic analysis, the Qiongzhong aborigines have a close relationship with Fujian Han Chinese.Highlights The STR landscape of Qiongzhong aborigines inhabited in Hainan tropical rainforests was depicted by 19 autosomal STRs. A total of 69,132 people from forty-five populations were selected for a more extensive examination of genetic similarities and differences by multivariate statistical methods (MDS, PCA and N-J tree construction). The genetic analyses indicated that the populations of Southeast Asian countries are very genetically close to southern Chinese populations. From the genetic and linguistic perspective, the Qiongzhong aborigines have a close relationship with Han Chinese from Fujian Province

A Combination of Leucine, Metformin, and Sildenafil Treats Nonalcoholic Fatty Liver Disease and Steatohepatitis in Mice

Sirt1, AMPK, and eNOS modulate hepatic energy metabolism and inflammation and are key players in the development of NASH. L-leucine, an allosteric Sirt1 activator, synergizes with low doses of metformin or sildenafil on the AMPK-eNOS-Sirt1 pathway to reverse mild NAFLD in preclinical mouse models. Here we tested a possible multicomponent synergy to yield greater therapeutic efficacy in NAFLD/NASH. Liver cells and macrophages or an atherogenic diet induced NASH mouse model was treated with two-way and three-way combinations. The three-way combination Sild-Met-Leu increased hepatic fatty acid oxidation and reduced lipogenic gene expression and inflammatory marker in vitro. In mice, Sild-Met-Leu reduced the diet induced increases of ALT, TGFβ, PAI-1, IL1β, and TNFα, hepatic collagen expression, and nearly completely reversed hepatocyte ballooning and triglyceride accumulation, while all two-way combinations had only modest effects. Therefore, these data provide preclinical evidence for therapeutic efficacy of Sild-Met-Leu in the treatment of NAFLD and NASH