Suppression of experimental arthritis through AMP-activated protein kinase activation and autophagy modulation

Autophagy plays a central role in various disease processes. However, its contribution to inflammatory arthritides such as rheumatoid arthritis (RA) is unclear. We observed that autophagy is engaged in the K/BxN serum transfer model of RA but autophagic flux is severely impaired. Metformin is an anti-diabetic drug that has been shown to stimulate autophagy. Induction of autophagic flux, through metformin-mediated AMP-activated protein kinase (AMPK) activation and interruption of mammalian target of rapamycin (mTOR) signaling mitigated the inflammation in experimental arthritis. Further investigation into the effects of metformin suggest that the drug directly activates AMPK and dose-dependently suppressed the release of TNF-α, IL-6, and MCP-1 by macrophages while enhancing the release of IL-10 in vitro. In vivo, metformin treatment significantly suppressed clinical arthritis and inflammatory cytokine production. Mechanistic studies suggest that metformin exerts its anti-inflammatory effects by correcting the impaired autophagic flux observed in the K/BxN arthritis model and suppressing NF-κB-mediated signaling through selective degradation of IκB kinase (IKK). These findings establish a central role for autophagy in inflammatory arthritis and argue that autophagy modulators such as metformin may represent potential therapeutic agents for the treatment of RA

Quantum transport through a double Aharonov-Bohm-interferometer in the presence of Andreev reflection

Quantum transport through a double Aharonov-Bohm-interferometer in the presence of Andreev reflection is investigated in terms of the nonequilibrium Green function method with which the reflection current is obtained. Tunable Andreev reflection probabilities depending on the interdot coupling strength and magnetic flux as well are analysised in detail. It is found that the oscillation period of the reflection probability with respect to the magnetic flux for the double interferometer depends linearly on the ratio of two parts magnetic fluxes n, i.e. 2(n+1)pi, while that of a single interferometer is 2pi. The coupling strength not only affects the height and the linewidth of Andreev reflection current peaks vs gate votage but also shifts the peak positions. It is furthermore demonstrated that the Andreev reflection current peaks can be tuned by the magnetic fluxes.Comment: 13 pages, 12 figur

Recent Advances on the Machine Learning Methods in Identifying DNA Replication Origins in Eukaryotic Genomics

The initiate site of DNA replication is called origins of replication (ORI) which is regulated by a set of regulatory proteins and plays important roles in the basic biochemical process during cell growth and division in all living organisms. Therefore, the study of ORIs is essential for understanding the cell-division cycle and gene expression regulation so that scholars can develop a new strategy against genetic diseases by using the knowledge of DNA replication. Thus, the accurate identification of ORIs will provide key clues for DNA replication research and clinical medicine. Although, the conventional experiments could provide accurate results, they are time-consuming and cost ineffective. On the contrary, bioinformatics-based methods can overcome these shortcomings. Especially, with the emergence of DNA sequences in the post-genomic era, it is highly expected to develop high throughput tools to identify ORIs based on sequence information. In this review, we will summarize the current progress in computational prediction of eukaryotic ORIs including the collection of benchmark dataset, the application of machine learning-based techniques, the results obtained by these methods, and the construction of web servers. Finally, we gave the future perspectives on ORIs prediction. The review provided readers with a whole background of ORIs prediction based on machine learning methods, which will be helpful for researchers to study DNA replication in-depth and drug therapy of genetic defect

Rotation of hydrogen molecules during the dissociative adsorption on the Mg(0001) surface: A first-principles study

Using first-principles calculations, we systematically study the potential energy surfaces and dissociation processes of the hydrogen molecule on the Mg(0001) surface. It is found that during the dissociative adsorption process with the minimum energy barrier, the hydrogen molecule firstly orients perpendicular, and then rotates to be parallel to the surface. It is also found that the orientation of the hydrogen molecule at the transition state is neither perpendicular nor parallel to the surface. Most importantly, we find that the rotation causes a reduction of the calculated dissociation energy barrier for the hydrogen molecule. The underlying electronic reasons for the rotation of the hydrogen molecule is also discussed in our paper.Comment: 14 pages, 4 figure

Relationship between the expression of hTERT and EYA4 mRNA in peripheral blood mononuclear cells with the progressive stages of carcinogenesis of the esophagus

<p>Abstract</p> <p>Objective</p> <p>To establish a relationship between esophageal squamous cell diseases and the expression of human telomerase reverse transcriptase (hTERT) and Eyes absent 4 (EYA4) mRNA in peripheral blood mononuclear cells.</p> <p>Methods</p> <p>Subjects were 50 patients with esophageal squamous cell carcinoma (ESCC), 50 with dysplasia (ESCD), 50 with basal cell hyperplasia (BCH) and 50 controls. All subjects were residents of Feicheng County, Shandong Province, China , diagnosed by histopathology. Expression of hTERT and EYA4 mRNA in peripheral blood was determined by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR).</p> <p>Results</p> <p>The hTERT and EYA4 mRNA positive expression increased according to disease severity. At the cut-off value of ≥ 0.2, the positive expression rates of EYA4 were 14% for controls, 20.0% for BCH, 26% for ESCD and 52% for ESCC, respectively. At the cut-off value of ≥ 0.8, the positive expression rates of hTERT in the four groups were 24%, 30.0%, 52% and 80%, respectively. Using a positive value of 0.47 for EYA4, the testing sensitivities in the ESCD and ESCC groups were 4% and 16%, respectively, and the testing specificity increased to 100%. Using a positive value of 1.0 for hTERT, the testing sensitivities in the ESCD and ESCC groups were 48% and 60%, respectively, and the testing specificity increased to 72%. The testing sensitivities in the predicting ESCD and ESCC in the discriminant model including EYA4 and hTERT and the five traditional risk factors (sex, age, smoking, alcohol drinking, and family history of esophageal cancer) were 70% and 80%, and testing specificities were 76% and 88% respectively. However, the testing sensitivities and specificities in the predicting ESCD and ESCC in the model only including the above five traditional risk factors were lower than that in the former case.</p> <p>Conclusion</p> <p>EYA4 and hTERT mRNA expression increased with the severity of esophageal pathological changes and may be useful for identifying high-risk endoscopy candidates or for monitoring changes in premalignant esophageal lesions.</p

Ammonium 2-(2,4-dichloro­phen­oxy)acetate hemihydrate

The title compound, NH4 +·C8H7Cl2O6 −·0.5H2O, was prepared by the reaction of 2-(2,4-dichloro­phen­oxy)­acetic acid and ammonia in water at 367 K. The mol­ecular structure and packing are stabilized by N—H⋯O and O—H⋯O inter­molecular hydrogen-bond inter­actions