High Magnesium Promotes the Recovery of Binocular Vision from Amblyopia via TRPM7.

Abnormal visual experience during the critical period can cause deficits in visual function, such as amblyopia. High magnesium (Mg2+) supplementary can restore ocular dominance (OD) plasticity, which promotes the recovery of amblyopic eye acuity in adults. However, it remains unsolved whether Mg2+ could recover binocular vision in amblyopic adults and what the molecular mechanism is for the recovery. We found that in addition to the recovery of OD plasticity, binocular integration can be restored under the treatment of high Mg2+ in amblyopic mice. Behaviorally, Mg2+-treated amblyopic mice showed better depth perception. Moreover, the effect of high Mg2+ can be suppressed with transient receptor potential melastatin-like 7 (TRPM7) knockdown. Collectively, our results demonstrate that high Mg2+ could restore binocular visual functions from amblyopia. TRPM7 is required for the restoration of plasticity in the visual cortex after high Mg2+ treatment, which can provide possible clinical applications for future research and treatment of amblyopia.

Rail Flaw Detection via Kolmogorov Entropy of Chaotic Oscillator Based on Ultrasonic Guided Waves.

Ultrasonic guided wave (UGW) inspection is an emerging non-destructive testing(NDT) technique for rail flaw detection, where weak UGW signals under strong noise backgrounds are difficult to detect. In this study, a UGW signal identification model based on a chaotic oscillator is established. The approach integrates the UGW response into the critical state of the Duffing system to serve as a disturbance control variable. By evaluating the system's motion state before and after introducing the UGW response, identification of UGW signals can be realized. Thus, the parameters defining the critical state of Duffing oscillators are determined by Ke. Moreover, an electromagnetic transducer was specifically devised to enable unidirectional excitation for UGWs targeted at both the rail base and rail head. Experimental studies showed that the proposed methodology effectively detected and located a 0.46 mm notch at the rail base and a 1.78 mm notch at the rail head. Furthermore, Ke was directly proportional to the notch size, which could be used as a quantitative index to characterize the rail flaw.

Dual isotopes of nitrite in the Amundsen Sea in summer.

Nitrite (NO2-) is a key intermediate in the nitrogen (N) cycle, and its transformation is accomplished by microbial communities. However, due to few studies on the nitrite cycle, a clear assessment of the contribution to the marine biogeochemical cycle is missing. Here, we present data on nitrogen and oxygen isotopic composition of NO2- in the Amundsen Sea in summer, and explore the biogeochemical processes that influence the NO2- cycle. Extremely low δ15NNO2 and abnormally high δ18ONO2 were found in the upper waters of the Amundsen Sea, with δ15NNO2 as low as -58.4 ‰ and δ18ONO2 as high as 44.4 ‰. Enzymatic isotopic exchange reactions between nitrate and nitrite have been proposed to be responsible for these isotopic anomalies. The mirror-symmetrical variation between δ15NNO2 and δ18ONO2 suggests that the isotopic fractionation effects of nitrogen and oxygen are opposite in isotope exchange reactions. Dual isotopes of nitrite indicate that ammonia oxidation is the main source of nitrite, thus nitrification plays an important role in the formation of primary nitrite maximum in the upper Amundsen Sea. The nitrogen and oxygen isotopic compositions of nitrite provide support for clarifying multiple processes of marine nitrogen cycle.

Modeling guided wave propagation in functionally graded plates by state-vector formalism and the Legendre polynomial method.

A numerical method is presented for the investigation of the propagation characteristic of guided waves in functionally gradient material (FGM) plates. Based on the State-vector formalism and Legendre polynomial method, the typical non-stratified computing of dispersion curves of FGMs is realized, by introducing the univariate nonlinear regression to optimize the arbitrary gradient distribution of material component. Comparing with the conventional Matrix method, the proposed method avoids the exhausting root-locating algorithm of solving the transcendental equation by a single-variable scanning process. This method turns it into an algebraic eigenvalue problem, which mainly depends on the orthogonal completeness and strong recursive property of Legendre polynomial series. It provides a fast and flexible approach to extracting the dispersion curves, displacement distribution and stress profile, simultaneously. Results from chrome-ceramic FGM plate are compared with those from the previous articles to confirm the feasibility and accuracy of the proposed method. Then, this approach is further applied to iron based alumina FGM. The dispersion curves with different gradient function are calculated to illustrate the influence of the gradient variation. Moreover, the influence of the cut-off order of Legendre orthogonal polynomials on the convergence of dispersion curves is also revealed through numerical examples. Utilizing the mapping relationship between the gradient distribution and the propagation characteristics, it gives theoretical support for nondestructive evaluation and quantitative estimation of the structural characteristics of FGM plates.

Structural optimization and biological evaluation of 1,5-disubstituted pyrazole-3-carboxamines as potent inhibitors of human 5-lipoxygenase.

Human 5-lipoxygenase (5-LOX) is a well-validated drug target and its inhibitors are potential drugs for treating leukotriene-related disorders. Our previous work on structural optimization of the hit compound 2 from our in-house collection identified two lead compounds, 3a and 3b, exhibiting a potent inhibitory profile against 5-LOX with IC50 values less than 1 µmol/L in cell-based assays. Here, we further optimized these compounds to prepare a class of novel pyrazole derivatives by opening the fused-ring system. Several new compounds exhibited more potent inhibitory activity than the lead compounds against 5-LOX. In particular, compound 4e not only suppressed lipopolysaccharide-induced inflammation in brain inflammatory cells and protected neurons from oxidative toxicity, but also significantly decreased infarct damage in a mouse model of cerebral ischemia. Molecular docking analysis further confirmed the consistency of our theoretical results and experimental data. In conclusion, the excellent in vitro and in vivo inhibitory activities of these compounds against 5-LOX suggested that these novel chemical structures have a promising therapeutic potential to treat leukotriene-related disorders.

Novel thiophene derivatives as PTP1B inhibitors with selectivity and cellular activity.

A series of novel thiophene derivatives was designed, synthesized and their activities as competitive inhibitors of protein tyrosine phosphatase (PTPs) 1B (PTP1B) inhibitors were evaluated. All the compounds showed inhibitory potencies, and 10 of these exhibited moderate inhibitory activities with IC(50) values less than 10 microM. The activity of the most potent compound P28 (IC(50)=2.1 microM) was 15 times higher than that of the hit compound P01. Further, four representative compounds (P19, P22, P28, and P31) demonstrated remarkably high selectivities against other PTPs (e.g., PTPalpha, LAR, CD45, and TCPTP); P19 exhibited greater than sixfold selectivity over highly homologous TCPTP. More importantly, these compounds are permeable to cell membranes. The treatment of CHO-K1 cells with P28 (10 microM) resulted in increased phosphorylation of AKT, which suggested extensive cellular activity of this compound. The novel chemical entities reported in this study could be used for overcoming the poor selectivity and low cellular activity of PTP1B inhibitors and might represent a starting point for development of therapeutic PTP inhibitors.

Indole derivatives as potent inhibitors of 5-lipoxygenase: design, synthesis, biological evaluation, and molecular modeling.

A series of novel indole derivatives was designed, synthesized and evaluated by cell-based assays for their inhibitory activities against 5-LOX in rat peritoneal leukocytes. Most of them (30 out of 35) showed an inhibitory potency higher than the initial screening hit 1a (IC(50)=74 microM). Selected compounds for concentration-response studies showed prominent inhibitory activities with IC(50) values ranging from 0.74 microM to 3.17 microM. Four compounds (1m, 1s, 4a, and 6a) exhibited the most potent inhibitory activity compared to that of the reference drug (Zileuton), with IC(50) values less than 1 microM. Molecular modeling studies for compounds 1a, 3a, 4a, and 6a were also presented. The excellent in vitro activities of this class of compounds may possess potential for the treatment of LT-related diseases.

Synthesis and antitumor evaluation of a novel series of triaminotriazine derivatives.

A series of triaminotriazine derivatives (compounds 5a-f, 6a-x, and 7a-g) was designed, synthesized, and evaluated for their inhibition activities to colorectal cancer (CRC) cell lines (HCT-116 and HT-29). Most of the synthesized compounds demonstrated moderate anti-proliferatory effects on both HCT-116 and HT-29 cell lines at the concentration of 10 microM. The inhibitory activities against HCT-116 and HT-29 cell lines were discussed to develop the structure-activity relationships of this new series. Compounds 6l and 6o exhibited prominent inhibition activities toward HCT-116, with IC50s of 0.76 and 0.92 microM, respectively. The in vivo antitumor studies and pharmacokinetics of compound 6l showed that it might be a promising new hit for further development of antitumor agents.