Fourteen small molecule and biological agents for psoriatic arthritis: A network meta-analysis of randomized controlled trials.

BACKGROUND: The comparative efficacy and safety of small molecule and biological agents in the treatment of psoriatic arthritis (PsA) remain unknown. OBJECTIVES: To compare the efficacy and safety of 14 small molecule and biological agents by network meta-analysis (NMA). METHODS: Relevant randomized controlled trials involving biological treatments for PsA were identified by searching PubMed, Cochrane Library, EMBASE, Web of Science, and Clinicaltrials.gov and by manual retrieval, up to June 2018. NMA was conducted with Stata 14.0 based on the frequentist method. Effect measures were odds ratios (ORs) with 95% confidence intervals (CIs). Intervention efficacy and safety were ranked according to the surface under the cumulative ranking curve (SUCRA). RESULTS: A total of 30 studies involving 10,191 adult subjects were included. According to NMA, ≥ 20% improvement in modifed American College of Rheumatology response criteria (ACR20) response, Psoriasis Area and Severity Index 75 (PASI75) response, and serious adverse events rate (SAEs) were observed. In direct comparisons, most of the biologics performed better than placebo in terms of ACR20 response rate and PASI75 response rate. Additionally, all medicines were comparable to placebo in terms of SAEs except secukinumab. In terms of mixed comparisons, with regard to the ACR20 response, etanercept (ETN) and infliximab (IFX) were more effective than golimumab (GOL), with ORs of 3.33 (95% CI: 1.17-9.48) and 1.24 (95% CI: 0.61-2.52), respectively. For PASI75 response, IFX was superior to certolizumab pegol (OR = 10.08, 95% CI: 1.54-75.48). In addition, these medicines were comparable to each other in terms of SAEs. ETN and IFX were shown to have the most favorable SUCRA for achieving improved ACR20 and PASI75 responses, respectively, while ABT-122 exhibited the best safety according to the SUCRA for SAEs. Considering both the efficacy (ACR20, PASI75) and safety (SAEs), GOL, ETN, and IFX are the top 3 treatments. CONCLUSIONS AND IMPLICATIONS: Direct and indirect comparisons and integrated results suggested that the 3 anti- tumor necrosis factor -α biologics (GOL, ETN, and IFX) can be considered the best treatments for PsA after comprehensive consideration of efficacy and safety.

Effect of catalpol on behavior and neurodevelopment in an ADHD rat model.

Studies suggest that abnormal neurodevelopment of prefrontal striatal circuits is implicated in the pathogenesis of attention deficit hyperactivity disorder (ADHD). In the present study, we investigated the effect of catalpol, an active ingredient of Rehmanniae radix preparata, which is the most frequently used Chinese medicinal herb for the treatment of ADHD, on behavior and neurodevelopment in spontaneously hypertensive rats (SHR). SHR were divided into SHR group (vehicle, i.g.), methylphenidate (MPH) group (2 mg/kg/day, i.g.), and catalpol group (50 mg/kg/day i.g.), and Wistar-Kyoto (WKY) rats were used as control group (vehicle, i.g.). Open Field Test (OFT) and Morris water maze (MWM) test were performed to assess the effect of catalpol on behavior. Results revealed that both catalpol and MPH treatment decreased average speed, time spent in the central area, rearing times, and central area visits, increased the immobility time of SHR in OFT, and increased number of visits to the annulus, and time spent in target quadrant in the MWM test. Hematoxylin and eosin (H&E) staining showed that catalpol reduced irregular neuronal arrangement, ruptured nuclear membranes, and resulted in disappearance of the nucleolus in the prefrontal cortex (PFC) and striatum of SHR. Moreover, immuno-fluorescent staining of NeuN and myelin basic protein (MBP) indicated that catalpol ameliorated neuronal loss and contributed to myelination. Finally, western blot and immunostaining analysis suggested that several regulatory proteins involved in PFC development were up-regulated by catalpol treatment, such as brain-derived neurotrophic factor (BDNF), cyclin-dependent kinase 5 (Cdk5), p35, fibroblast growth factor (FGF) 21 and its receptor (FGFR)1. Taken together, catalpol can effectively ameliorate hyperactive and impulsive behavior, improve spatial learning and memory in SHR, likely through the neurodevelopmental pathways. Nonetheless, whether catalpol could attenuate inattention in SHR and the pathway by which catalpol reduces neuronal loss remain to be further studied.

Dynamic "Scanning-Mode" Meniscus Confined Electrodepositing and Micropatterning of Individually Addressable Ultraconductive Copper Line Arrays.

Micro- and nanopatterning of cost-effective addressable metallic nanostructures has been a long endeavor in terms of both scientific understanding and industrial needs. Herein, a simple and efficient dynamic meniscus-confined electrodeposition (MCED) technique for precisely positioned copper line micropatterns with superior electrical conductivity (greater than 1.57 × 104 S/cm) on glass, silicon, and gold substrates is reported. An unexpected higher printing speed in the evaporative regime is realized for precisely positioned copper lines patterns with uniform width and height under horizontal scanning-mode. The final line height and width depend on the typical behavior of traditional flow coating process, while the surface morphologies and roughness are mainly governed by evaporation-driven electrocrystallization dynamics near the receding moving contact line. Integrated 3D structures and a rapid prototyping of 3D hot-wire anemometer are further demonstrated, which is very important for the freedom integration applications in advanced conceptual devices, such as miniaturized electronics and biomedical sensors and actuators.

Ultralow flexural properties of copper microhelices fabricated via electrodeposition-based three-dimensional direct-writing technology.

Helical metallic micro/nanostructures as functional components have considerable potential for future miniaturized devices, based on their unique mechanical and electrical properties. Thus, understanding and controlling the mechanical properties of metallic helices is desirable for their practical application. Herein, we implemented a direct-writing technique based on the electrodeposition method to grow copper microhelices with well-defined and programmable three-dimensional (3D) features. The mechanical properties of the 3D helical structures were studied by the electrically induced quasistatic and dynamic electromechanical resonance technique. These methods mainly explored the static pull-in process and the dynamic electromechanical response, respectively. It was found that the center-symmetric and vertical double copper microhelix structure with 1.2 µm wire diameter has a flexural rigidity of 0.9 × 10-14 N m2 and the single vertical copper microhelix structure with 1.1 µm wire diameter has a flexural rigidity of 0.5989 × 10-14 N m2. By comparing with microwires and other reported micro/nanohelices, we found that the copper microhelices reported here had an ultralow stiffness (about 0.13 ± 0.01 N m-1). It is found that the experimental results agree well with the finite element calculations. The proposed method can be used to fabricate and measure the flexural properties of three-dimensional complex micro/nanowire structures, and may have a profound effect on the application of microhelices in various useful microdevices such as helix-based microelectromechanical switches, sensors and actuators based on their unique mechanical properties.

Is the LysM domain of L. monocytogenes p60 protein suitable for engineering a protein with high peptidoglycan binding affinity?

Lysin motif (LysM) is a highly conserved carbohydrate binding module that is widely present in proteins from both prokaryotes and eukaryotes. LysM domains from many LysM-containing proteins can be taken out of their natural context and retain their ability to bind peptidoglycan. Therefore, LysM has enormous potential for applications in both industry and medicine. This potential has stimulated an intensive search for LysM modules with different evolutionary origins. The p60 protein (Lm-p60) is an NlpC/P60-containing peptidoglycan hydrolase secreted by Listeria monocytogenes. The N-terminus of Lm-p60 contains 2 LysM modules separated by an SH3 module. Our recent study of Lm-p60 demonstrates that the N-terminal half of Lm-p60, comprised of 2 LysM and 1 SH3 module, is able to recognize and bind peptidoglycan. The LysM domain of Lm-p60 contains only 2 LysM modules, which is the minimum number of LysM modules in most NlpC/P60-containing proteins, but it shows strong affinity for peptidoglycan. Moreover, these 2 LysM modules have only 38.64% similarity to each other. These data allowed us to conclude that the 2 LysM modules from Lm-p60 have different evolutionary origins, suggesting that they are suitable candidate peptidoglycan-binding modules for protein engineering in order to create a protein with a high binding affinity to peptidoglycan.

Vertical, capacitive microelectromechanical switches produced via direct writing of copper wires.

Three-dimensional (3D) direct writing based on the meniscus-confined electrodeposition of copper metal wires was used in this study to develop vertical capacitive microelectromechanical switches. Vertical microelectromechanical switches reduce the form factor and increase the area density of such devices in integrated circuits. We studied the electromechanical characteristics of such vertical switches by exploring the dependence of switching voltage on various device structures, particularly with regard to the length, wire diameter, and the distance between the two wires. A simple model was found to match the experimental measurements made in this study. We found that the electrodeposited copper microwires exhibit a good elastic modulus close to that of bulk copper. By optimizing the 3D structure of the electrodes, a volatile electromechanical switch with a sub-5 V switching voltage was demonstrated in a vertical microscale switch with a gap distance as small as 100 nm created with a pair of copper wires with diameters of ~1 µm and heights of 25 µm. This study establishes an innovative approach to construct microelectromechanical systems with arbitrary 3D microwire structures for various applications, including the demonstrated volatile and nonvolatile microswitches.

Domain function dissection and catalytic properties of Listeria monocytogenes p60 protein with bacteriolytic activity.

The major extracellular protein p60 of Listeria monocytogenes (Lm-p60) is an autolysin that can hydrolyze the peptidoglycan of bacterial cell wall and has been shown to be required for L. monocytogenes virulence. The predicted three-dimensional structure of Lm-p60 showed that Lm-p60 could be split into two independent structural domains at the amino acid residue 270. Conserved motif analysis showed that V30, D207, S395, and H444 are the key amino acid residues of the corresponding motifs. However, not only the actual functions of these two domains but also the catalytic properties of Lm-p60 are unclear. We try to express recombinant Lm-p60 and identify the functions of two domains by residue substitution (V30A, D207A, S395A, and H444A) and peptide truncation. The C-terminal domain was identified as catalytic element and N-terminal domain as substrate recognition and binding element. Either N-terminal domain truncation or C-terminal domain truncation presents corresponding biological activity. The catalytic activity of Lm-p60 with a malfunctioned substrate-binding domain was decreased, while the substrate binding was not affected by a mulfunctioned catalytic domain. With turbidimetric method, we determined the optimal conditions for the bacteriolytic activity of Lm-p60 against Micrococcus lysodeikficus. The assay for the effect of Lm-p60 on the bacteriolytic activity of lysozyme revealed that the combined use of Lm-p60 protein with lysozyme showed a strong synergistic effect on the bacteriolytic activity.

Phytotoxicity of 4,8-dihydroxy-1-tetralone isolated from Carya cathayensis Sarg. to various plant species.

The aqueous extract from Carya cathayensis Sarg. exocarp was centrifuged, filtered, and separated into 11 elution fractions by X-5 macroporous resin chromatography. A phenolic compound, 4,8-dihydroxy-1-tetralone (4,8-DHT) was isolated from the fractions with the strongest phytotoxicity by bioassy-guided fractionation, and investigated for phytotoxicity on lettuce (Latuca sativa L.), radish (Raphanus sativus L.), cucumber (Cucumis sativus L.), onion (Allium cepa L.) and wheat (Triticum aestivum L.). The testing results showed that the treatment with 0.6 mM 4,8-DHT could significantly depress the germination vigor of lettuce and wheat, reduce the germination rate of lettuce and cucumber, and also inhibit radicle length, plumule length, and fresh weight of seedlings of lettuce and onion, but could significantly promote plumule length and fresh weight of seedlings of cucumber (p < 0.05). For the tested five plants, the 4,8-DHT was the most active to the seed germination and seedling growth of lettuce, indicating that the phytotoxicity of 4,8-DHT had the selectivity of dosage, action target (plant type) and content (seed germination or seedling growth).

Improved atomic force microscope infrared spectroscopy for rapid nanometer-scale chemical identification.

Atomic force microscope infrared spectroscopy (AFM-IR) can perform IR spectroscopic chemical identification with sub-100 nm spatial resolution, but is relatively slow due to its low signal-to-noise ratio (SNR). In AFM-IR, tunable IR laser light is incident upon a sample, which results in a rise in temperature and thermomechanical expansion of the sample. An AFM tip in contact with the sample senses this nanometer-scale photothermal expansion. The tip motion induces cantilever vibrations, which are measured either in terms of the peak-to-peak amplitude of time-domain data or the integrated magnitude of frequency-domain data. Using a continuous Morlet wavelet transform to the cantilever dynamic response, we show that the cantilever dynamics during AFM-IR vary as a function of both time and frequency. Based on the observed cantilever response, we tailor a time-frequency-domain filter to identify the region of highest vibrational energy. This approach can increase the SNR of the AFM cantilever signal, such that the throughput is increased 32-fold compared to state-of-the art procedures. We further demonstrate significant increases in AFM-IR imaging speed and chemical identification of nanometer-scale domains in polymer films.

Modeling and measurement of geometrically nonlinear damping in a microcantilever-nanotube system.

Nonlinear mechanical systems promise broadband resonance and instantaneous hysteretic switching that can be used for high sensitivity sensing. However, to introduce nonlinear resonances in widely used microcantilever systems, such as AFM probes, requires driving the cantilever to an amplitude that is too large for any practical applications. We introduce a novel design for a microcantilever with a strong nonlinearity at small cantilever oscillation amplitude arising from the geometrical integration of a single BN nanotube. The dynamics of the system was modeled theoretically and confirmed experimentally. The system, besides providing a practical design of a nonlinear microcantilever-based probe, demonstrates also an effective method of studying the nonlinear damping properties of the attached nanotube. Beyond the typical linear mechanical damping, the nonlinear damping contribution from the attached nanotube was found to be essential for understanding the dynamical behavior of the designed system. Experimental results obtained through laser microvibrometry validated the developed model incorporating the nonlinear damping contribution.

Optimization of polysaccharides from Lycium ruthenicum fruit using RSM and its anti-oxidant activity.

Dynamic microwave-assisted extraction (DMAE) technique was employed for the extraction of polysaccharides from Lycium ruthenicum (LRP). The extracting parameters were optimized by using three-variable-three-level Box-Behnken design and response surface methodology (RSM) based on the single-factor experiments. RSM analysis indicated good correspondence between experimental and predicted values. The optimum extraction parameters for the yield of polysaccharide were ratio of water to raw material 31.5 mL/g, extracting time 25.8 min and microwave power 544.0 W. Polysaccharide was analyzed by chemical methods and Fourier-transform infrared (FT-IR). The antioxidant activities of LRP were investigated including scavenging activity of 2,2-diphenyl-1-picrylhydrazyl (DPPH), hydrogen peroxide and free radicals of superoxide anion in vitro. The results of antioxidant activity exhibited LRP had the potential to be explored as novel natural antioxidant for using in functional foods or medicine.

Atomic force microscope infrared spectroscopy on 15 nm scale polymer nanostructures.

We measure the infrared spectra of polyethylene nanostructures of height 15 nm using atomic force microscope infrared spectroscopy (AFM-IR), which is about an order of magnitude improvement over state of the art. In AFM-IR, infrared light incident upon a sample induces photothermal expansion, which is measured by an AFM tip. The thermomechanical response of the sample-tip-cantilever system results in cantilever vibrations that vary in time and frequency. A time-frequency domain analysis of the cantilever vibration signal reveals how sample thermomechanical response and cantilever dynamics affect the AFM-IR signal. By appropriately filtering the cantilever vibration signal in both the time domain and the frequency domain, it is possible to measure infrared absorption spectra on polyethylene nanostructures as small as 15 nm.

Intrinsically high-Q dynamic AFM imaging in liquid with a significantly extended needle tip.

Atomic force microscope (AFM) probe with a long and rigid needle tip was fabricated and studied for high Q factor dynamic (tapping mode) AFM imaging of samples submersed in liquid. The extended needle tip over a regular commercially available tapping-mode AFM cantilever was sufficiently long to keep the AFM cantilever from submersed in liquid, which significantly minimized the hydrodynamic damping involved in dynamic AFM imaging of samples in liquid. Dynamic AFM imaging of samples in liquid at an intrinsic Q factor of over 100 and an operational frequency of over 200 kHz was demonstrated. The method has the potential to be extended to acquire viscoelastic material properties and provide truly gentle imaging of soft biological samples in physiological environments.

Ion-induced surface relaxation: controlled bending and alignment of nanowire arrays.

It is a well-known fact that a sphere offers less surface area, and thus less surface energy, than any other arrangement of the same volume. From this perspective, all other shapes are metastable objects. In this paper, we present and discuss a manifestation of this metastability: the spontaneous alignment of free-standing amorphous nanowires towards, and ultimately parallel to, a flux of directional ion irradiation. The behavior expected from surface energy reduction is the opposite of that predicted by both theory and experiment regarding defect generation in crystalline nanowires, but is consistent with other observations on non-crystalline materials. We verify our expectations by bending and aligning finely stranded amorphous silica nanowires, noting that such nanostructures are particularly susceptible to bending through ion-induced surface energy reduction. We offer support for this mechanism through bending rate studies, thermal annealing experiments and mathematical modeling. Experimentally, we also demonstrate selective reorientation of nanowires in patterned areas, as well as conformal coating of reoriented arrays with functional materials. These capabilities offer the prospect of exploiting engineered surface anisotropies in optical, fluidic and micromechanical applications.

Energy dissipation and intrinsic loss in single walled carbon nanotubes due to anelastic relaxation.

Based on the molecular dynamics simulation and an elastic shell model, we investigated the intrinsic loss under dynamic excitations in single walled carbon nanotube (SWCNT) due to the anelastic relaxation mechanism. We quantified the anelastic property of SWCNTs, i.e., the creep compliances, and showed them to be on the order of 1 (TPa-1) and sensitive to both the radius of SWCNT and the loading rate. Furthermore, our study showed that the time scale for a SWCNT to fully achieve its equilibrium elastic property through anelastic relaxation is on the order of nanosecond. This leads to significant intrinsic loss and damping for SWCNT resonators operating at the Gigahertz frequency range. Both the loss angle and quality (Q) factor of SWCNT were found to be strongly dependent on the load frequency. A dissipation peak and thus a low Q factor were observed in the Gigahertz frequency range. On the other hand, high Q factor and low dissipation were achieved in the range of low (< 0.001 GHz) excitation frequency. The predicted influence of load frequency on the Q factor is in good agreement with the recent experimental observations.

Biofunctionalized nanoneedles for the direct and site-selective delivery of probes into living cells.

BACKGROUND: Accessing the interior of live cells with minimal intrusiveness for visualizing, probing, and interrogating biological processes has been the ultimate goal of much of the biological experimental development. SCOPE OF REVIEW: The recent development and use of the biofunctionalized nanoneedles for local and spatially controlled intracellular delivery brings in exciting new opportunities in accessing the interior of living cells. Here we review the technical aspect of this relatively new intracellular delivery method and the related demonstrations and studies and provide our perspectives on the potential wide applications of this new nanotechnology-based tool in the biological field, especially on its use for high-resolution studies of biological processes in living cells. MAJOR CONCLUSIONS: Different from the traditional micropipette-based needles for intracellular injection, a nanoneedle deploys a sub-100-nm-diameter solid nanowire as a needle to penetrate a cell membrane and to transfer and deliver the biological cargo conjugated onto its surface to the target regions inside a cell. Although the traditional micropipette-based needles can be more efficient in delivery biological cargoes, a nanoneedle-based delivery system offers an efficient introduction of biomolecules into living cells with high spatiotemporal resolution but minimal intrusion and damage. It offers a potential solution to quantitatively address biological processes at the nanoscale. GENERAL SIGNIFICANCE: The nanoneedle-based cell delivery system provides new possibilities for efficient, specific, and precise introduction of biomolecules into living cells for high-resolution studies of biological processes, and it has potential application in addressing broad biological questions. This article is part of a Special Issue entitled Nanotechnologies - Emerging Applications in Biomedicine.

Nanoneedle: a multifunctional tool for biological studies in living cells.

Studying biology in living cells is methodologically challenging but highly beneficial. Recent advances in nanobiotechnology offer exciting new opportunities to address this challenge. The nanoneedle technology, as an emerging technology that uses a cell membrane-penetrating nanoneedle to probe and manipulate biological processes in living cells, is expected to play an important role in this endeavor. Here we review the recent development and future direction of the nanoneedle technology for biological studies in living cells. The nanoneedle technology is shown to be powerful and versatile, and can offer numerous new ways to explore biological processes and biophysical properties of living cells with high spatial and temporal precision potentially reaching molecular resolution.

Meniscus-confined three-dimensional electrodeposition for direct writing of wire bonds.

Continued progress in the electronics industry depends on downsizing, to a few micrometers, the wire bonds required for wiring integrated chips into circuit boards. We developed an electrodeposition method that exploits the thermodynamic stability of a microscale or nanoscale liquid meniscus to "write" pure copper and platinum three-dimensional structures of designed shapes and sizes in an ambient air environment. We demonstrated an automated wire-bonding process that enabled wire diameters of less than 1 micrometer and bond sizes of less than 3 micrometers, with a breakdown current density of more than 10(11) amperes per square meter for the wire bonds. The technology was used to fabricate high-density and high-quality interconnects, as well as complex three-dimensional microscale and even nanoscale metallic structures.

Tunable, broadband nonlinear nanomechanical resonator.

A nanomechanical resonator incorporating intrinsically geometric nonlinearity and operated in a highly nonlinear regime is modeled and developed. The nanoresonator is capable of extreme broadband resonance, with tunable resonance bandwidth up to many times its natural frequency. Its resonance bandwidth and drop frequency (the upper jump-down frequency) are found to be very sensitive to added mass and energy dissipation due to damping. We demonstrate a prototype nonlinear mechanical nanoresonator integrating a doubly clamped carbon nanotube and show its broadband resonance over tens of MHz (over 3 times its natural resonance frequency) and its sensitivity to femtogram added mass at room temperature.