LncRNA MAYA promotes iron overload and hepatocyte senescence through inhibition of YAP in non-alcoholic fatty liver disease

Although recent evidence has shown that hepatocyte senescence plays a crucial role in the pathogenesis and development of non-alcoholic fatty liver disease (NAFLD), the mechanism is still not clear. The purpose of this study was to investigate the signal transduction pathways involved in the senescence of hepatocyte, in order to provide a potential strategy for blocking the process of NAFLD. The results confirmed that hepatocyte senescence occurred in HFD-fed Golden hamsters and PA-treated LO2 cells as manifested by increased levels of senescence marker SA-β-gal, p16 and p21, heterochromatin marker H3K9me3, DNA damage marker γ-H2AX and decreased activity of telomerase. Further studies demonstrated that iron overload could promote the senescence of hepatocyte, whereas the overexpression of Yes-associated protein (YAP) could blunt iron overload and alleviate the senescence of hepatocyte. Of importance, depression of lncRNA MAYA (MAYA) reduced iron overload and cellular senescence via promotion of YAP in PA-treated hepatocytes. These effects were further supported by in vivo experiments. In conclusion, these data suggested that inhibition of MAYA could up-regulate YAP, which might repress hepatocyte senescence through modulating iron overload. In addition, these findings provided a promising option for heading off the development of NAFLD by abrogating hepatocyte senescence.     

Role of the APOE ε2/ε3/ε4 Polymorphism in the Development of Primary Open-Angle Glaucoma: Evidence from a Comprehensive Meta-Analysis

Primary open-angle glaucoma (POAG) is one of the leading causes of blindness worldwide. The association between the APOE ε2/ε3/ε4 polymorphism and the risk of POAG has been widely reported, but the results of previous studies remain controversial. To comprehensively evaluate the APOE ɛ2/ɛ3/ε4 polymorphism on the genetic risk for POAG, we performed a systematic review and meta-analysis of previously published studies. The PubMed and Web of Science databases were systematically searched to identify relevant studies. Data were extracted from these studies and odds ratios with corresponding 95% confidence intervals were computed to estimate the strength of the association. Stratified analyses according to ethnicity and sensitivity analyses were also conducted for further confirmation. A total of nine studies were eligible for the meta-analysis, and these studies included data on 1928 POAG cases and 1793 unrelated match controls. The combined results showed that there were no associations between the APOE ε2/ε3/ε4 polymorphism and POAG risk in any of the 10 comparison models. The analysis that was stratified by ethnicity subgroups also failed to reveal a significant association. The sensitivity analysis confirmed the stability and reliability of the findings. There was no risk of publication bias. Our meta-analysis provides strong evidence that the APOE ε2/ε3/ε4 polymorphism is not associated with POAG susceptibility in any populations.     

Molecular Dynamics Simulation Studies of Zeolite-A. IV. Structure and Dynamics of NH4 + ions in a Rigid Dehydrated Zeolite-A

Abstract

In recent papers [1–3] we reported molecular dynamics simulation studies of ions and water molecules adsorbed in a rigid zeolite-A framework using a simple Lennard-Jones potential plus Coulomb potential with Ewald summation to investigate the structure and dynamics of the adsorbates. In the present paper the same technique is applied to study the local structure and dynamics of NH₄ ⁺ ions in a rigid dehydrated zeolite-A. During the preliminary equilibration, the unstable NH₄(4) type ion (the 12th ion) is pushed down to near a more stable 6-ring position in the α-cage that is already associated with an NH₄(1) type ion (the 1st) in the β-cage, which moves to another 6-ring position in the β-cage that is already associated with an NH₄(2) type ion (the 7th) in the α-cage. Calculated x, y, and z coordinates of some NH₄ ⁺ ions are in good agreement with those obtained from an X-ray diffraction experiment except that no NH₄(4) type ion is found and there are six NH₄(2) type ions instead of 0.5 and 5.5 occupancy. The analyses of calculated interatomic distances and time correlation functions of these ions indicate that the NH₄(1 – 1) and NH₄(3) type ions are associated loosely with only one O (3) atom of the 6-ring and with only one O (1) atom of the 8-ring windows, respectively, while the NH₄(1–2) and NH₄(2) type ions are associated strongly with two or three O (3) atoms of the 6-ring windows in the α- and β-cages, respectively. The analysis of hydrogen bond time correlation functions of these ions indicate that about one, two or three, three, and one hydrogen bond of each NH₄(1–1), NH₄(1–2), NH₄(2) and NH₄(3) type ion is kept for 1.4, 21, 75, and 1.4 ps, respectively, before breakup of the hydrogen bond occurs and significant exchange of O atom hydrogen-bonded to the ion.     

Cortical Plasticity Induced by Spike-Triggered Microstimulation in Primate Somatosensory Cortex

Electrical stimulation of the nervous system for therapeutic purposes, such as deep brain stimulation in the treatment of Parkinson’s disease, has been used for decades. Recently, increased attention has focused on using microstimulation to restore functions as diverse as somatosensation and memory. However, how microstimulation changes the neural substrate is still not fully understood. Microstimulation may cause cortical changes that could either compete with or complement natural neural processes, and could result in neuroplastic changes rendering the region dysfunctional or even epileptic. As part of our efforts to produce neuroprosthetic devices and to further study the effects of microstimulation on the cortex, we stimulated and recorded from microelectrode arrays in the hand area of the primary somatosensory cortex (area 1) in two awake macaque monkeys. We applied a simple neuroprosthetic microstimulation protocol to a pair of electrodes in the area 1 array, using either random pulses or pulses time-locked to the recorded spiking activity of a reference neuron. This setup was replicated using a computer model of the thalamocortical system, which consisted of 1980 spiking neurons distributed among six cortical layers and two thalamic nuclei. Experimentally, we found that spike-triggered microstimulation induced cortical plasticity, as shown by increased unit-pair mutual information, while random microstimulation did not. In addition, there was an increased response to touch following spike-triggered microstimulation, along with decreased neural variability. The computer model successfully reproduced both qualitative and quantitative aspects of the experimental findings. The physiological findings of this study suggest that even simple microstimulation protocols can be used to increase somatosensory information flow.     

Naphthazarin derivatives (II): formation of glutathione conjugate, inhibition of DNA topoisomerase-I and cytotoxicity.

6-(1-Hydroxyalkyl)-5,8-dimethoxy-1,4-naphthoquinones, expressing a higher reactivity in conjugation with glutathione, showed a greater potency in the inhibition of DNA topoisomerase-I and the cytotoxicity against L1210 cells than 2-(1-hydroxyalkyl)-DMNQ derivatives, implying the participation of electrophilic arylation in the bioactivities. In further study 6-(1-Hydroxyalkyl)-5,8-dimethoxy-1,4-naphthoquinones with an alkyl group of shorter chain length (C2-C6) exerted a greater bioactivities than those with longer chain length(>C6).     

The Ighmbp2 helicase structure reveals the molecular basis for disease-causing mutations in DMSA1

Mutations in immunoglobulin µ-binding protein 2 (Ighmbp2) cause distal spinal muscular atrophy type 1 (DSMA1), an autosomal recessive disease that is clinically characterized by distal limb weakness and respiratory distress. However, despite extensive studies, the mechanism of disease-causing mutations remains elusive. Here we report the crystal structures of the Ighmbp2 helicase core with and without bound RNA. The structures show that the overall fold of Ighmbp2 is very similar to that of Upf1, a key helicase involved in nonsense-mediated mRNA decay. Similar to Upf1, domains 1B and 1C of Ighmbp2 undergo large conformational changes in response to RNA binding, rotating 30° and 10°, respectively. The RNA binding and ATPase activities of Ighmbp2 are further enhanced by the R3H domain, located just downstream of the helicase core. Mapping of the pathogenic mutations of DSMA1 onto the helicase core structure provides a molecular basis for understanding the disease-causing consequences of Ighmbp2 mutations.     

Extracellular secretion of levansucrase from Zymomonas mobilis in Escherichia coli

Secretion of levansucrase from Zymomonas mobilis in Escherichiacoli by glycine supplement was investigated. A significant amount of levansucrase (about 25% of total activity) was found in intact whole-cells. Cell fractionation experiments showed that levansucrase was found both in the periplasmic space and in the cytoplasmic fraction of E. coli. None or only trace amounts of levansucrase was detected in the extracellular culture broth at 24 h of cultivation and it accrued with the increasing concentration of glycine in the culture medium and duration of the culture period. Optimal glycine concentration for the maximum secretion of levansucrase was in the range of 0.8-1%, in which approximately 20-50% of levansucrase was released into the extracellular fraction at 24 h of cultivation, although glycine retarded the bacterial growth.     

N-Glycans and sulfated glycosaminoglycans contribute to the action of diverse Tc toxins on mammalian cells

Tc toxin is an exotoxin composed of three subunits named TcA, TcB and TcC. Structural analysis revealed that TcA can form homopentamer that mediates the cellular recognition and delivery processes, thus contributing to the host tropism of Tc toxin. N-glycans and heparan sulfates have been shown to act as receptors for several Tc toxins. Here, we performed two independent genome-wide CRISPR-Cas9 screens, and have validated glycans and sulfated glycosaminoglycans (sGAGs) as Tc toxin receptors also for previously uncharacterized Tc toxins. We found that TcdA1 form Photorhabdus luminescens W14 (TcdA1^W14) can recognize N-glycans via the RBD-D domain, corroborating previous findings. Knockout of N-glycan processing enzymes specifically blocks the intoxication of TcdA1^W14-assembled Tc toxin. On the other hand, our results showed that sGAG biosynthesis pathway is involved in the cell surface binding of TcdA2^TT01 (TcdA2 from P. luminescens TT01). Competition assays and biolayer interferometry demonstrated that the sulfation group in sGAGs is required for the binding of TcdA2^TT01. Finally, based on the conserved domains of representative TcA proteins, we have identified 1,189 putative TcAs from 1,039 bacterial genomes. These TcAs are categorized into five subfamilies. Each subfamily shows a good correlation with both genetic organization of the TcA protein(s) and taxonomic origin of the genomes, suggesting these subfamilies may utilize different mechanisms for cellular recognition. Taken together, our results support the previously described two different binding modalities of Tc toxins, leading to unique host targeting properties. We also present the bioinformatics data and receptor screening strategies for TcA proteins, provide new insights into understanding host specificity and biomedical applications of Tc toxins.