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BACKGROUND: Acute myocardial infarction (AMI) is one of the leading causes of mortality worldwide. Undesirable myocardial damage may occur during reperfusion of the ischemic myocardium, and this is known as “ischemic reperfusion injury” (IRI). Currently, there are few effective drugs to alleviate IRI. Dl-3-n-butylphthalide (NBP) is recommended for the treatment of acute ischemic stroke in China. This study investigated the effects of NBP on IRI and its underlying mechanisms. METHODS: The left anterior descending (LAD) coronary arteries of rats were occluded for 30 minutes and reperfused for 6 hours to establish the ischemia/reperfusion (I/R) model. NBP was administered intraperitoneally 2 hours before modeling and immediately after reperfusion. At 6 hours after reperfusion, 2,3,5-triphenyltetrazolium chloride (TTC) staining, enzyme-linked immunosorbent assay (ELISA), oxidative stress index, myocardial injury index, hematoxylin and eosin (HE) staining, transmission electron microscopy (TEM), real-time polymerase chain reaction (PCR), immunofluorescence staining, and Western blot analyses were performed to investigate the protective effects of NBP against IRI. RESULTS: In the rat I/R model, NBP remarkably reduced the myocardial infarct size, alleviated myocardial injury and oxidative stress, improved the pathological alteration of cardiomyocytes and mitochondria, and upregulated mitophagy. In addition, the study demonstrated that the protective effects of NBP against IRI involved mitophagy mediated by the PTEN-induced putative kinase protein-1 (PINK1)/Parkin signaling pathway. CONCLUSIONS: NBP was able to protect the myocardium from IRI in rats through inhibiting oxidative stress and activating mitophagy, mediated by the PINK1/Parkin pathway.

Interlayer coupling in two-dimensional (2D) layered materials plays an important role in controlling their properties. 2H- and 3R-MoS

Objectives : To assess the predictive function of miR-21 rs1292037 A greater than G polymorphism in survival and ischemia-reperfusion injury (IRI) in hepatocellular carcinoma (HCC) patients. Methods : Th e experiment was carried out between July 2018 and July 2019, whereas the prospective clinical study was carried out between January 2014 and January 2019. In this study, 62 HCC patients with hepatitis B virus (HBV), 17 HCC patients without HBV, and 13 healthy controls were investigated. Micro-RNA-21 levels in the blood were identified using quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and allele specific PCR for miR-21 rs1292037. Partial hepatectomy was performed in all patients, and the tumor development indicators and survival time were evaluated in a subsequent follow-up. Cell-based simulated IRI model of HCC huh7 cell line was used to determine the functions of miR-21 with respect to IRI and proliferation. Results : Micro-RNA-21 levels were significantly increased in HCC patients. Furthermore, an miR- 21 rs1292037 A greater than G polymorphism was found to be significantly associated with HCC prognosis and severity of liver injury after hepatectomy. In vitro study revealed that miR-21 might prevent IRI from occurring, and can induce proliferation in HCC huh7 cells. These functions of miR-21 were demonstrated to be triggered by IL-12A inhibition. Conclusion : Micro-RNA-21 rs1292037 A greater than G polymorphism can predict IRI and tumor progression by regulating the miR-21/IL-12A.axis. Saudi Med J 2020; Vol. 41 (4): 383-392 doi: 10.15537/smj.2020.4.24994 How to cite this article: Wu C, Tang G, Wang X, Zhang J, Chen S, Lu C, Zhang D, Li Y. Micro-RNA-21 rs1292037 A>G polymorphism can predict hepatocellular carcinoma prognosis (HCC), and plays a key role in cell proliferation and ischemia-reperfusion injury (IRI) in HCC cell model of IRI. Saudi Med J 2020; Vol. 41 (4): 383-392. doi: 10.15537/smj.2020.4.24994

Two-dimensional (2D) materials have recently attracted significant interest in condensed-matter physics and materials science due to rich intriguing physics and potential applications. Here, by first-principles calculations, we discover a phase of transition-metal dichalcogenides (MoS2 and its family) named the 1H′ phase. We demonstrate that 1H′MoS2 monolayer has multiple topological phase transitions from a topologically trivial insulator state to a 2D type-II Dirac semimetal state, and then to a 2D ideal type-I semimetal state under a moderate tensile strain. The Dirac points are protected by the coexistence of space-inversion (P) and time-reversal (T) symmetry. Our results highlight a family of nonhoneycomb 2D Dirac semimetals with potential application in nanoelectronics.

Being human, we possess unique biological features, such as the big brain, upright walking and sophisticated language, which set us apart from our close relatives, the non-human primates since our divergence from the Pan lineage approximately 5 million years ago. Scientists have attempted to solve the mystery of our unique phenotypic traits with approaches from paleoanthropology, anatomy, psychology, behavior and social cognition etc. However, the answers are embedded in our genetic makeup. What are the genetic changes in our genome that make us human? By comparing the genomes of humans and nonhuman primates, scientists have identified a lot of genetic changes that might have contributed to the human-specific traits. These genetic changes work at different genetic levels, including sequence changes in protein-coding genes, gene expression changes, gene losses and gene duplications. Natural selection is the driving force pushing fixation of these genetic changes during human evolution, and they may have important contribution to human’s unique phenotypes. In this review, we mainly discuss the relationship between human-specific phenotypes and genetic changes. We summarize our current findings and understandings of genes with human-specific mutations and their possible functional effects. For example, a set of brain-size regulating genes have been identified and many of them showed strong signatures of Darwinian positive selection during primate evolution and human origin. These human-specific mutations likely work their ways through human brain development and eventually form a large brain. Another fascinating example is the language gene FOXP2 that has two human specific mutations, which may lead to a unique developmental pattern change of the human brain region responsible for human language ability. Furthermore, besides protein coding genes, there are other genetic changes, and many identified fast-evolving regions in the human genome are not located in the coding sequences. Instead they are distributed in regulatory sequences likely involved in gene expression regulation which affect the temporal and spatial pattern of human development. Finally, we introduce the recent advance of technologies that can be used to study the functional outcomes of the human specific mutations. These technologies provide useful tools that may reproduce the scenes of human evolution in the laboratory. The in vitro analysis of humanized iPSCs can to some extend mimic the in vivo development of the human brain. Notably, the newly developed gene editing tools including CRISPR-Cas9 and TALEN are promising in studying the human-specific traits using transgenic animal models, especially the transgenic monkey models which may provide much more mechanistic information than the traditional mouse model. The human-specific genetic changes accumulated during human evolution occurred at different levels, but they must work together to produce the human-specific traits. Future studies may establish the links by figuring out how changes at different genetic levels coordinate with each other to make us human.

Recently the metastable 1T'-type VIB-group transition metal dichalcogenides (TMDs) have attracted extensive attention due to their rich and intriguing physical properties, including superconductivity, valleytronics physics, and topological physics. Here, a new layered WS

Topological states of quantum matter have attracted great attention in condensed matter physics and materials science. The study of time-reversal-invariant topological states in quantum materials has made tremendous progress. However, the study of magnetic topological states falls much behind due to the complex magnetic structures. Here, we predict the tetradymite-type compound MnBi_{2}Te_{4} and its related materials host topologically nontrivial magnetic states. The magnetic ground state of MnBi_{2}Te_{4} is an antiferromagetic topological insulator state with a large topologically nontrivial energy gap (∼0.2 eV). It presents the axion state, which has gapped bulk and surface states, and the quantized topological magnetoelectric effect. The ferromagnetic phase of MnBi_{2}Te_{4} might lead to a minimal ideal Weyl semimetal.

The dynamic responses of railway vehicles under crosswinds are investigated by using multibody dynamic simulations and compared with the experimental data. A new gust model is also proposed to predict aerodynamic forces acting on railway vehicles under tunnel exit winds. The dynamic responses of a model vehicle under tunnel exit winds are firstly predicted by multibody dynamic simulations and the predicted rolling angles of the vehicle by the identified structural parameters show good agreement with those from the running vehicle test. The dynamic responses of a commuter rail under natural winds are then studied and the calculated wheel unloading ratios match favorably with those from the field test. Finally, a dynamic amplification factor (DAF) for railway vehicles under tunnel exit winds is proposed and systematically investigated. It is found that DAF decreases as the passing time as well as the damping ratio and natural frequency of railway vehicle increase. A simple formula is also proposed to predict DAF of railway vehicles under tunnel exit winds.

The corrosion inhibition of a new benzimidazole derivative, 6-(dodecyloxy)-1H-benzo[d]imidazole (DBI), for mild steel in 1 M HCl was investigated in this paper. Computational chemistry was performed to explore the adsorption of DBI on metal surface. Inhibition performance of DBI is attributed to both the direct interaction of benzimidazole segment with iron surface and the barrier effect of the non-polar long chain against aggressive solution. Compared to the protonated form, the molecular form of DBI could more tightly interact with iron surface. These results show that the long-chain alkyl-substituted benzimidazole derivative is of great potential application as corrosion inhibitor.

Polyaniline/polypyrrole (PAni/PPy), polyaniline-phosphotungstate/polypyrrole (PAni-PW 12 /PPy) and PAni/PPy-PW 12 have been successfully electrodeposited on mild steel (MS) by cyclic voltammetry in aqueous oxalic acid solutions. It was found that the incorporation of PW 12 enhanced the corrosion resistance of PAni/PPy coating. Moreover, in comparison to PAni-PW 12 /PPy, PAni/PPy-PW 12 coating exhibited better corrosion resistance for mild steel. After immersion of 36 h in 0.1 M HCl, for instance, the polarization resistance of PAni/PPy-PW 12 coating reached 1695 Ω cm 2 , more than those of both PAni/PPy and PAni-PW 12 /PPy.

The influence of polyepoxysuccinic acid (PESA) on the phase composition and crystal morphology of calcium oxalate was investigated in this paper. It was found that the presence of PESA inhibited the growth of the monoclinic calcium oxalate monohydrate (COM) crystal and promoted the nucleation of the tetragonal calcium oxalate dihydrate (COD). In addition, with the increase in PESA concentration, the aggregation of COD crystals was reduced but the particle size was increased. Under the conditions of low calcium-to-oxalate ratio and high CaOx concentration, PESA could not effectively stabilize the formation of COD. Based on molecular dynamic simulations, the adsorption of PESA on CaOx crystal faces was confirmed.

Recently the metastable 1T'-type VIB-group transition metal dichalcogenides (TMDs) have attracted extensive attention due to their rich and intriguing physical properties, including superconductivity, valleytronics physics, and topological physics. Here, a new layered WS2 dubbed "2M" WS2 , is constructed from 1T' WS2 monolayers, is synthesized. Its phase is defined as 2M based on the number of layers in each unit cell and the subordinate crystallographic system. Intrinsic superconductivity is observed in 2M WS2 with a transition temperature Tc of 8.8 K, which is the highest among TMDs not subject to any fine-tuning process. Furthermore, the electronic structure of 2M WS2 is found by Shubnikov-de Haas oscillations and first-principles calculations to have a strong anisotropy. In addition, topological surface states with a single Dirac cone, protected by topological invariant Z2 , are predicted through first-principles calculations. These findings reveal that the new 2M WS2 might be an interesting topological superconductor candidate from the VIB-group transition metal dichalcogenides.

Weyl semimetals are new states of matter which feature novel Fermi arcs and exotic transport phenomena. Based on first-principles calculations, we report that the chalcopyrites CuTlSe_{2}, AgTlTe_{2}, AuTlTe_{2}, and ZnPbAs_{2} are ideal Weyl semimetals, having largely separated Weyl points (∼0.05 Å^{-1}) and uncovered Fermi arcs that are amenable to experimental detections. We also construct a minimal effective model to capture the low-energy physics of this class of Weyl semimetals. Our discovery is a major step toward a perfect playground of intriguing Weyl semimetals and potential applications for low-power and high-speed electronics.

We recently reported a series of 1,6-disubstituted indoline-based thiophene amidine compounds (5) as selective neuronal nitric oxide synthase (nNOS) inhibitors to mitigate the cardiovascular liabilities associated with hERG K+ channel inhibition (IC50 = 4.7 μM) with previously reported tetrahydroquinoline-based selective nNOS inhibitors (4). The extended structure–activity relationship studies within the indoline core led to the identification of 43 as a selection candidate for further evaluations. The in vivo activity in two different pain (spinal nerve ligation and migraine pain) models, the excellent physicochemical and pharmacokinetic properties, oral bioavailability (Fpo = 91%), and the in vitro safety profile disclosed in this report make 43 an ideal candidate for further evaluation in clinical applications related to migraine pain.

3,6-Disubstituted indole derivatives were designed, synthesized, and evaluated as inhibitors of human nitric oxide synthase (NOS). Bulky amine containing substitution on the 3-position of the indole ring such as an azabicyclic system showed better selectivity over 5- and 6-membered cyclic amine substitutions. Compound (-)-19 showed the best selectivity for neuronal NOS over endothelial NOS (90-fold) and inducible NOS (309-fold) among the current series. Compounds 16 and (-)-19 were shown to be either inactive or very weak inhibitors of human cytochrome P450 enzymes, indicating a low potential for drug-drug interactions. Compound 16 was shown to reverse thermal hyperalgesia in vivo in the Chung model of neuropathic pain. Compound 16 was also devoid of any significant vasoconstrictive effect in human coronary arteries, associated with the inhibition of human eNOS. These results suggest that 16 may be a useful tool for evaluating the potential role of selective nNOS inhibitors in the treatment of pain such as migraine and CTTH.

Methamphetamine (MA) abuse represents a growing problem in the USA with an increase of sudden death. To evaluate the immune function alterations due to chronic methamphetamine use, we examined C57BL/C mice with LP-BM5 retrovirus infection plus methamphetamine exposure. Mice were randomly assigned to the following groups: placebo, placebo retrovirus-infected, uninfected MA treated and retrovirus-infected MA treated. Placebo, MA-treated groups were intraperitoneally injected with saline, MA, respectively, with a gradually increasing dose from 15 to 40 mg/kg for 12 weeks (5 days/week). Con A- and LPS-induced mitogenesis of splenocytes, cytokine production by splenocytes culture and lipid peroxides in the liver were measured. Heart tissue histopathology was analyzed in all the groups with murine cytomegalovirus (CMV) superinfection. Our data showed that MA treatment significantly decreased production of IL-2 and interferon gamma (IFN-gamma) in uninfected mice but did not further suppress the reduced Th1 cytokines in retrovirus-infected mice. There were no significant effects on cytokines IL-4 and IL-6. However, tumor necrosis factor (TNF-alpha) was significantly increased in both uninfected and infected mice due to MA treatment. Lipid peroxides in liver were significantly increased both in uninfected and retrovirus-infected mice due to MA exposure. Vitamin E levels in liver were significantly decreased in uninfected mice due to MA treatment. CMV superinfection greatly increased the cardiac lesions in retrovirus-infected mice while no significant histopathology changes were detected due to MA treatment. Our data suggest that MA has immunomodulation activity, suppressing Th1 cytokine production and enhancing some Th2 cytokine secretion, as well as increasing lipid peroxides in uninfected mice. The interaction between LP-BM5 and MA remains unclear.

Cocaethylene is an active cocaine metabolite believed to play a causative role in the increased incidence of sudden cardiac death in individuals who co-administer alcohol and cocaine. Prolonged and excessive abuse of cocaine and alcohol will result in marked alteration of host immunity to increased susceptibility to infection. To test the chronic direct effect of cocaethylene on the heart function, a conductance catheter system (CCS) was used in vivo in this study. To test whether cocaethylene injection exacerbates coxsackievirus B3 (CVB3) or cytomegalovirus (CMV) cardiomyopathy during murine AIDS, female C57BL/6 mice were infected with LP-BM5 retrovirus and superinfected with CVB3 or CMV. Daily, mice were injected intraperitoneally with cocaethylene in 0.9% saline solution (concentration increased gradually from 15 to 25 mg/ml). Histopathology of heart tissue was analyzed in all groups, and cytokines of spleen were measured in the CMV-infected groups. Results showed there was little effect on the cardiovascular system after cocaethylene injection. Cocaethylene injection during murine retrovirus infection greatly exacerbated the pathogenesis of CVB3 or CMV infection, whereas CMV-infected mice showed relatively moderate cardiac pathology compared with CVB3 infection. Both CMV and retrovirus infection suppressed the Th1 response. Our data suggest that cocaethylene treatment shifts the cytokine balance and suppresses Th1 response particularly, facilitating increased CVB3- or CMV-induced myocarditis.

A family of different 3,5-disubstituted indole derivatives having 6-membered rings were designed, synthesized, and demonstrated inhibition of human nitric oxide synthase (NOS) with norepinephrine reuptake inhibitory activity (NERI). The structure-activity relationship (SAR) within the cyclohexane ring showed the cis-isomers to be more potent for neuronal NOS and selective over endothelial NOS compared to their trans-counterparts. Compounds, such as cis-(+)-37, exhibited dual nNOS and NET inhibition (IC(50) of 0.56 and 1.0 μM, respectively) and excellent selectivity (88-fold and 12-fold) over eNOS and iNOS, respectively. The lead compound (cis-(+)-37) showed lack of any direct vasoconstriction or inhibition of ACh-mediated vasorelaxation in isolated human coronary arteries. Additionally, cis-(+)-37 was effective at reversing both allodynia and thermal hyperalgesia in a standard Chung (spinal nerve ligation) rat neuropathic pain model. Overall, the data suggest that cis-(+)-37 is a promising dual action development candidate having therapeutic potential for the treatment of neuropathic pain.