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ABSTRACTIntroductionAlthough there are several FDA-approved treatments for Alzheimer’s disease (AD), only recently have disease-modifying therapies received approval for use in patients. In this narrative review, we examine the history of aquaporin-4 (AQP4) as a therapeutic target for NMOSD (neuromyelitis optica spectrum disorder) and as a potential therapeutic target for AD.Areas coveredWe review the basic science and discovery of AQP4, a transmembrane water-channel essential to regulating water balance in the central nervous system (CNS). We also review the pathogenesis of NMOSD, an autoimmune disease characterized by the destruction of cells that express AQP4. Then, we review how AQP4 is likely involved in the pathogenesis of Alzheimer’s disease (AD). Finally, we discuss future challenges with drug design that would modulate AQP4 to potentially slow AD development. The literature search for this article consisted of searching Google Scholar and PubMed for permutations of the keywords ‘Alzheimer’s disease,’ ‘aquaporin-4,’ ‘neuromyelitis optica,’ and their abbreviations.Expert opinionWe place research into AQP4 into context with other recent developments in AD research. A major difficulty with drug development for Alzheimer’s is the lack of strategies to cleanly target the early pathogenesis of the disease. Targeting AQP4 may provide such a strategy.

Environmentally friendly lead-free piezoelectric materials have been attracting significant attention in recent years. Na1/2Bi1/2TiO3-based relaxor ferroelectrics have found acceptance for application in promising lead-free transducers in high-power ultrasonic devices. However, their low thermal stability, i.e., their relatively low ferroelectric-relaxor transition temperature (TF-R), hinders their practical application. Herein, a thermal-quenching approach is applied on a Na1/2Bi1/2TiO3(NBT)-based single crystal, which yields a large increase in TF-Rand dramatic enhancement of its ferroelectric ordering, leading to excellent thermal stability of its dielectric, ferroelectric, and piezoelectric properties. This behavior is mainly attributed to quenching-induced domain evolution as well as its octahedral tilt, which is linked to the increased oxygen vacancies. The substitution of long-range ordered ferroelectric domains for short-range polar nanodomains contributes to its increased coherence length and, consequently, enhancement of TF-R. This work provides an approach to the optimization of the ferroelectric ordering and thermal stability of NBT as well as an in-depth understanding of the quenching effect on the local structure, which could be applied to other relaxor-based ferroelectrics for optimization of their macroscopic properties.

In terms of how the signal varies in response to increased concentration of an analyte, sensors can be classified as either “signal-on” or “signal-off” format. While both types hold potentials to be sensitive, selective, and reusable, in many situations “signal-on” sensors are preferred for their low background signal and better selectivity. In this study, with the detection of lysozyme using its DNA aptamer as a trial system, for the first time we demonstrated that such an aptamer-based electrochemical biosensor can be converted from intrinsically “signal-off” to “signal-on” with the aid of a DNA exonuclease. The fact that the stepwise cleavage of antilysozyme aptamer catalyzed by Exonuclease I (Exo I) is entirely inhibited upon binding lysozyme leads to the selective removal of unbound DNA probes (thiolate anti-lysozyme DNA aptamer strands immobilized on gold electrode) upon the introduction of Exo I to the sensor. With the aid of electrostatically bound redox cations ([Ru(NH3)6]3+), we were able to quantitate the number of aptamer strands that are bound with lysozymes via conventional cyclic voltammetry (CV) measurements. We demonstrated that Exo I-assisted signal-on conversion protocol not only improves the sensing performance (10 times better limit of detection) but also promises a versatile strategy for DNA-based biosensor design, i.e., it can be readily adapted to other aptamer–protein binding systems (thrombin, as another example).

High-performance piezoelectric materials are pivotal to many electromechanical applications including piezoelectric actuators, sensors, and transducers. However, the general approach to achieve high piezoelectric properties by establishing morphotropic phase boundary (MPB) has limitation due to the weak anisotropy of the Gibbs free energy profile at the MPB region. Here, aliovalent Sm3+-doped 0.4Pb(Mg1/3Nb2/3)O3-(0.6–x)PbZrO3-xPbTiO3piezoelectric ceramics were fabricated by a solid-state method, where the optimized piezoelectric coefficient d33= 910 pC/N, dielectric constant εr= 4090, and Curie temperature TC= 184 °C were obtained at x= 0.352, being attributed to the synergistic contributions from the MPB and enhanced local structural heterogeneity. Rayleigh analysis was adopted to study the intrinsic and extrinsic contributions in Sm-doped PMN-PZ-PT ceramics, where the extrinsic contribution was found to be on the order of 25–67% at 4 kV/cm. Of particular significance is that a large signal d33* = 820 pm/V (at 20 kV/cm) with a minimal strain variation of 5% was achieved for a composition of x= 0.372 over the temperature range of 20–160 °C, being superior to those previously reported piezoelectric ceramic materials. This work offers a good paradigm to simultaneously achieve high piezoelectric properties with good temperature stability in ferroelectric ceramics, which have great potential for piezoelectric application at elevated temperatures.

The complete formation of stem-loop (i.e., hairpin) configuration on chip surface is of particular importance for the application of hairpin DNA (hpDNA) in building biosensors for various analytes with optimized performance. We report herein a convenient electrochemical protocol for evaluating the yield of hairpin DNA conformations upon self-assembly on electrode surface. As of the different hydrolysis capability of Exonuclease I (Exo I) toward single-stranded DNA (ssDNA) and hpDNA, we can selectively remove ssDNA from electrode but retain hpDNA strands; based on the changes in the cyclic voltammetric (CV) responses using [Ru(NH3)6]3+as redox indicators, we can then determine the fraction of hairpin configurations in mixed DNA self-assembled monolayers (SAMs). It was discovered that the molar fraction of hairpin configuration formed on the surface is considerably lower than that in the binary deposition solution (containing both ssDNA and hpDNA). The accuracy of the Exo I-assisted electrochemical quantitative protocol has been validated by standard DNA hybridization experiments; the relationship between the overall DNA packing density and the yield of hairpin configurations was also evaluated. More importantly, taking HIV-1 gene detection as a trial system, the hpDNA-based biosensor shows significantly improved detection limit and broadened response range upon the background reduction by Exo I-catalyzed hydrolysis.

Assay staining is an essential step to produce visual signals for the development of colorimetric biochips; it is, therefore, of practical importance to evaluate the conventionally adopted staining methods in terms of their quantitative performance in screening immunoassay biochips. Particularly, we have performed a systematic comparison of the color development speed, sensitivity, response range, and aging effects of three common staining protocols, i.e., gold nanoparticle-catalyzed silver deposition (silver staining), horseradish peroxidase (HRP)-catalyzed oxidation of tetramethylbenzidine (TMB staining), and alkaline phosphatase (ALP)-catalyzed reduction of tetrazolium salt (TAS staining). Our results have revealed that silver staining can afford the best screening performance in terms of sensitivity, response range, and aging effect. In comparison, TMB staining is fast in producing quantitative results (5–10 min). TAS staining can provide easily saturated signals with a low background, which is suitable for semi-quantitative or qualitative on-site applications. More importantly, we have demonstrated that the three staining methods can be adapted to the same biochip to fabricate “multichannel” colorimetric biochips for screening multiple tumor markers simultaneously.

Background: Propofol is a sedative agent that at clinical concentrations acts by allosterically activating or potentiating the γ-aminobutyric acid type A (GABAA) receptor. Mutational, modeling, and photolabeling studies with propofol and its analogues have identified potential interaction sites in the transmembrane domain of the receptor. At the "+" of the β subunit, in the β-α interface, meta-azipropofol labels the M286 residue in the third transmembrane domain. Substitution of this residue with tryptophan results in loss of potentiation by propofol. At the "-" side of the β subunit, in the α-β interface (or β-β interface, in the case of homomeric β receptors), ortho-propofol diazirine labels the H267 residue in the second transmembrane domain. Structural modeling indicates that the β(H267) residue lines a cavity that docks propofol with favorable interaction energy. Method: We used two-electrode voltage clamp to determine the functional effects of mutations to the "+" and "-" sides of the β subunit on activation of the α1β3 GABAA receptor by propofol. Results: We found that while the individual mutations had a small effect, the combination of the M286W mutation with tryptophan mutations of selected residues at the α-β interface leads to strong reduction in gating efficacy for propofol. Conclusion: We conclude that α1β3 GABAA receptors can be activated by propofol interactions with the β-β, α-β, and β-α interfaces, where distinct, non-equivalent regions control channel gating. Any interface can mediate activation, hence substitutions at all interfaces are required for loss of activation by propofol.

The blood-brain barrier (BBB) is a tight barrier that protects stability of the central nervous system (CNS), however, the mechanism impedes the delivery of drugs to the CNS. The interactions between viral proteins and cytoplasmic dynein during infection have been found. In this study, the “linker (dynein binding peptide, DBP)” between virus and dynein was reformed and connected with nanoparticles to try to penetrate the blood-brain barrier. Co-IP and intracellular studies with the designed peptides revealed their interactions with the dynein and their rapid uptake by bEnd.3 cells. And the DBP binding with the cell-penetrating peptide (CPP) exhibited the best intracellular uptake. The peptides were conjucted with DSPE-PEG2000and prepared to nanoparticles loaded with coumarin-6 (Cou-6). All of the prepared nanoparticles were around 25 nm in size, even though they had different modifications. The 10% DBP-CPP modified coumarin-6-loaded nanocarrier exhibited rapid intracellular distribution and cellular uptake. Transwell studies clearly showed the intercellular transport of the nanoparticles. The study is the first to combine DBP-CPP with a nanodelivery drug carrier and to apply it in a BBB model. The results of our in vitrostudies results revealed that DBP can mediate permeation of nanoparticles across the BBB, which may serve as a clinically viable strategy for drug delivery in the brain.

There is a general observation that the Curie temperature and piezoelectric property of the ferroelectric ceramics can be enhanced only at the expense of each other, i.e., higher piezoelectricity, lower Curie temperature, thus, limits their applications over broad temperature range. In this research, Sm-modified 0.15 Pb(Mg1/3Nb2/3)O3-(0.85-x)PbZrO3-xPbTiO3ceramics have been studied, where excellent piezoelectric coefficients d33 = 720 pC/N, d33∗ = 950 pm/V and high Curie temperature TC = 293 °C were simultaneously achieved for x = 0.42 composition by designing the morphotropic phase boundary (MPB) with local structural heterogeneity. Of particular significance is that a high thermal stability was observed with piezoelectric variation below 20% with temperature up to 280 °C, demonstrating that the x = 0.42 composition is a good candidate for piezoelectric application over broad temperature range where high temperature stability is required. This work provides a good paradigm for designing high-performance piezoelectric ceramics with high thermal stability via a combination of MPB and local structural heterogeneity.

Population stratification (PS) is a primary consideration in studies of genetic determinants of human traits. Failure to control for PS may lead to confounding, causing a study to fail for lack of significant results, or resources to be wasted following false‐positive signals. Here, historical and current approaches for addressing PS when performing genetic association studies in human populations are reviewed. Methods for detecting the presence of PS, including global and local ancestry methods, are described. Also described are approaches for accounting for PS when calculating association statistics, such that measures of association are not confounded. Many traits are being examined for the first time in minority populations, which may inherently feature PS. © 2017 by John Wiley & Sons, Inc.

This unit describes the statistical techniques necessary for performing family‐based association studies (such as the TDT) for genetic polymorphisms. Such studies have become increasingly important in the identification of genes that confer an increased risk to disease, particularly for common diseases with a complex etiology. The family‐based approach avoids some of the problems often encountered when applying the traditional case‐control design to genetic studies. The unit includes the Sib TDT (S‐TDT) method, which allows application of the principle of the TDT to sibships without parental data, and several related tests. Curr. Protoc. Hum. Genet. 58:1.12.1‐1.12.24. © 2008 by John Wiley & Sons, Inc.