A geometrical approach to control and controllability of nonlinear dynamical networks

Acknowledgements This work was supported by the ARO under Grant No. W911NF-14-1-0504. X.W. was supported by the NIH under Grant No. GM106081.Peer reviewedPublisher PD

Protective effects of resveratrol on the inhibition of hippocampal neurogenesis induced by ethanol during early postnatal life

AbstractEthanol (EtOH) exposure during early postnatal life triggers obvious neurotoxic effects on the developing hippocampus and results in long-term effects on hippocampal neurogenesis. Resveratrol (RSV) has been demonstrated to exert potential neuroprotective effects by promoting hippocampal neurogenesis. However, the effects of RSV on the EtOH-mediated impairment of hippocampal neurogenesis remain undetermined. Thus, mice were pretreated with RSV and were later exposed to EtOH to evaluate its protective effects on EtOH-mediated toxicity during hippocampal development. The results indicated that a brief exposure of EtOH on postnatal day 7 resulted in a significant impairment in hippocampal neurogenesis and a depletion of hippocampal neural precursor cells (NPCs). This effect was attenuated by pretreatment with RSV. Furthermore, EtOH exposure resulted in a reduction in spine density on the granular neurons of the dentate gyrus (DG), and the spines exhibited a less mature morphological phenotype characterized by a higher proportion of stubby spines and a lower proportion of mushroom spines. However, RSV treatment effectively reversed these responses. We further confirmed that RSV treatment reversed the EtOH-induced down-regulation of hippocampal pERK and Hes1 protein levels, which may be related to the proliferation and maintenance of NPCs. Furthermore, EtOH exposure in the C17.2 NPCs also diminished cell proliferation and activated apoptosis, which could be reversed by pretreatment of RSV. Overall, our results suggest that RSV pretreatment protects against EtOH-induced defects in neurogenesis in postnatal mice and may thus play a critical role in preventing EtOH-mediated toxicity in the developing hippocampus

Dual-Band Ten-Element MIMO Array Based on Dual-Mode IFAs for 5G Terminal Applications

A dual-band ten-element MIMO array based on dual-mode inverted-F antennas (IFAs) for 5G terminal applications is presented in this paper. The proposed dual-mode IFA is composed of two radiators, which are etched on the outer and inner surfaces of the side-edge frame. The outer part of the antenna generates the low-order mode at 3.5 GHz, while the inner part radiates another one-quarter-wavelength mode at 4.9 GHz. In this way, the IFA can achieve dual-band operation within a compact size of 10.6 × 5.3 × 0.8 mm 3 . Based on the proposed antenna, a dual-band ten-element multiple-input and multiple-output (MIMO) array is developed for 5G terminal applications. By combining neutralization line structures with decoupling branches, the isolations between the elements are improved. To validate the design concept, a prototype of the ten-element MIMO array is designed, fabricated, and measured. The experimental results show that the proposed antenna can cover the 3.3-3.6 GHz and 4.8-5.0 GHz bands with good isolation and high efficiency. Furthermore, the envelope correlation coefficient (ECC), and channel capacity are also calculated to verify the MIMO performances for 5G sub-6GHz applications

Dual-Band Eight-Element MIMO Array Using Multi-Slot Decoupling Technique for 5G Terminals

This paper presents a dual-band eight-element multiple-input multiple-output (MIMO) array using a multi-slot decoupling technique for the fifth generation (5G) mobile communication. By employing a compact dual-loop antenna element, the proposed array obtains two broad bandwidths of 12.2% and 15.4% for sub-6GHz operation. To reduce the mutual coupling between antenna elements, a novel dual-band decoupling method is proposed by employing a multi-slot structure. The proposed MIMO array achieves 15.5-dB and 19.0-dB isolations across the two operating bands. Furthermore, three decoupling modes generated by different bent slots can be independently tuned. Zero ground clearance is also realized by the coplanar arrangement of the antenna elements and decoupling structures. The proposed MIMO array was simulated, fabricated, and measured. Experimental results agree well with the simulations, showing that the dual-band MIMO array has good impedance matching, high isolation, and high efficiency. In addition, the envelope correlation coefficient and channel capacity are calculated and analyzed to validate the MIMO performance of the 5G terminal array. Such a dual-band high-isolation eight-element MIMO array with zero ground clearance is a promising candidate for 5G or future mobile applications

MTR4 drives liver tumorigenesis by promoting cancer metabolic switch through alternative splicing.

The metabolic switch from oxidative phosphorylation to glycolysis is required for tumorigenesis in order to provide cancer cells with energy and substrates of biosynthesis. Therefore, it is important to elucidate mechanisms controlling the cancer metabolic switch. MTR4 is a RNA helicase associated with a nuclear exosome that plays key roles in RNA processing and surveillance. We demonstrate that MTR4 is frequently overexpressed in hepatocellular carcinoma (HCC) and is an independent diagnostic marker predicting the poor prognosis of HCC patients. MTR4 drives cancer metabolism by ensuring correct alternative splicing of pre-mRNAs of critical glycolytic genes such as GLUT1 and PKM2. c-Myc binds to the promoter of the MTR4 gene and is important for MTR4 expression in HCC cells, indicating that MTR4 is a mediator of the functions of c-Myc in cancer metabolism. These findings reveal important roles of MTR4 in the cancer metabolic switch and present MTR4 as a promising therapeutic target for treating HCC

Probing the Role of Negatively Charged Amino Acid Residues in Ion Permeation of Skeletal Muscle Ryanodine Receptor

Sequence comparison suggests that the ryanodine receptors (RyRs) have pore architecture similar to that of the bacterial K+ channel KcsA. The lumenal loop linking the two most C-terminal transmembrane spanning segments in the RyRs has a predicted pore helix and an amino acid motif (GGGIG) similar to the selectivity filter (TVGYG) of KcsA identified by x-ray analysis. The RyRs have many negatively charged amino acid residues in the two regions linking the GGGIG motif and predicted pore helix with the two most C-terminal transmembrane spanning segments. We tested the role of these residues by generating single-site mutants, focusing on amino acid residues conserved among the mammalian RyRs. Replacement of two acidic residues immediately after the GGGIG motif in skeletal muscle ryanodine receptor (RyR1-D4899 and -E4900) with asparagine and glutamine profoundly affected ion permeation and selectivity. By comparison, mutagenesis of aspartate and glutamate residues in the putative linker regions showed a K+ conductance and selectivity for Ca2+ compared to K+ (PCa/PK) close to wild-type. The results show that the negatively charged carboxyl oxygens of D4899 and E4900 side chains are major determinants of RyR ion conductance and selectivity

Single Channel Properties of Heterotetrameric Mutant RyR1 Ion Channels Linked to Core Myopathies

Skeletal muscle excitation-contraction coupling involves activation of homotetrameric ryanodine receptor ion channels (RyR1s), resulting in the rapid release of Ca2+ from the sarcoplasmic reticulum. Previous work has shown that Ca2+ release is impaired by mutations in RyR1 linked to Central Core Disease and Multiple Minicore Disease. We studied the consequences of these mutations on RyR1 function, following their expression in human embryonic kidney 293 cells and incorporation in lipid bilayers. RyR1-G4898E, -G4898R, and -ΔV4926/I4927 mutants in the C-terminal pore region of RyR1 and N-terminal RyR1-R110W/L486V mutant all showed negligible Ca2+ permeation and loss of Ca2+-dependent channel activity but maintained reduced K+ conductances. Co-expression of wild type and mutant RyR1s resulted in Ca2+-dependent channel activities that exhibited intermediate Ca2+ selectivities compared with K+, which suggested the presence of tetrameric RyR1 complexes composed of wild type and mutant subunits. The number of wild-type subunits to maintain a functional heterotetrameric channel differed among the four RyR1 mutants. The results indicate that homozygous RyR1 mutations associated with core myopathies abolish or greatly reduce sarcoplasmic reticulum Ca2+ release during excitation-contraction coupling. They further suggest that in individuals, expressing wild type and mutant alleles, a substantial portion of RyR1 channels is able to release Ca2+ from sarcoplasmic reticulum

Characterization of recessive RYR1 mutations in core myopathies

We have characterized at the molecular level, three families with core myopathies carrying apparent recessive mutations in their RYR1 gene and studied the pharmacological properties of myotubes carrying endogenous mutations as well as the properties of mutant channels expressed in HEK293 cells. The proband of family 1 carried p.Ala1577Thr+p.Gly2060Cys in trans, having inherited a mutation from each parent. Immunoblot analysis of proteins from the patient's skeletal muscle revealed low levels of ryanodine receptor (RyR1) but neither substitution alone or in combination affected the functional properties of RyR1 channels in a discernable way. Two affected siblings in family 2 carried p.Arg109Trp+p.Met485Val substitutions in cis, inherited from the unaffected father. Interestingly, both affected siblings only transcribed the mutated paternal allele in skeletal muscle, whereas the maternal allele was silent. Single-channel measurements showed that recombinant, mutant RyR1 channels carrying both substitutions lost the ability to conduct Ca2+. In this case as well, low levels of RyR1 were present in skeletal muscle extracts. The proband of family 3 carried p.Ser71Tyr+p.Asn2283His substitutions in trans. Recombinant channels with Asn2283His substitution showed an increased activity, whereas recombinant channels with p.Ser71Tyr+p.Asn2283His substitution lost activity upon isolation. Taken together, our data suggest major differences in the ways RYR1 mutations may affect patients with core myopathies, by compromising RyR1 protein expression, stability and/or activit