Substrate-free dissolving microneedles with barbed shape to increase adhesion and drug-delivery efficiency to skin.

Microneedle drug delivery has recently emerged as a clinical method, and dissolving microneedles (DMNs) offer exclusive simplicity and efficiency, compared to the other kinds of microneedles. The tips of most currently available DMNs are cone/house-shaped to result in a lower penetration force. Penetration of the needle tips into the skin relies mainly on the back tape or external pressure, and their adhesion to the skin is relatively low. In addition, only the drug in the part of tips that are pierced into the dermis can be dissolved, resulting in drug waste. Inspired from the barbed structure of the honeybee stinger, we reported substrate-free DMNs with a barbed structure by a dual-molding process, which is suitable for mass production. Those DMNs showed 3-fold greater adhesion force between the needle tips and the skin, better dissolution and deeper penetration than house-shaped DMNs in vivo under the same conditions. For the in situ treatment of psoriasis in mice, the barbed DMNs required only the half dose of house-shaped DMNs to achieve similar efficacy.

Hyperbranched Dynamic Crosslinking Networks Enable Degradable, Reconfigurable, and Multifunctional Epoxy Vitrimer.

Degradation and reprocessing of thermoset polymers have long been intractable challenges to meet a sustainable future. Star strategies via dynamic cross-linking hydrogen bonds and/or covalent bonds can afford reprocessable thermosets, but often at the cost of properties or even their functions. Herein, a simple strategy coined as hyperbranched dynamic crosslinking networks (HDCNs) toward in-practice engineering a petroleum-based epoxy thermoset into degradable, reconfigurable, and multifunctional vitrimer is provided. The special characteristics of HDCNs involve spatially topological crosslinks for solvent adaption and multi-dynamic linkages for reversible behaviors. The resulting vitrimer displays mild room-temperature degradation to dimethylacetamide and can realize the cycling of carbon fiber and epoxy powder from composite. Besides, they have supra toughness and high flexural modulus, high transparency as well as fire-retardancy surpassing their original thermoset. Notably, it is noted in a chance-following that ethanol molecule can induce the reconstruction of vitrimer network by ester-exchange, converting a stiff vitrimer into elastomeric feature, and such material records an ultrahigh modulus (5.45 GPa) at -150 °C for their ultralow-temperature condition uses. This is shaping up to be a potentially sustainable advanced material to address the post-consumer thermoset waste, and also provide a newly crosslinked mode for the designs of high-performance polymer.

Optical interference phase control method with single photodetector for interference lithography.

This study designs an optical phase control method for interference lithography system accompanied with severe disturbance. The system, which is designed based on the exponential reaching law of sliding mode control(SMCE), could adjust the interference phase with single photodetector. The model of system is derived and then the stability is proved through Lyapunov theorem. This paper also analyzes the behavior of the system under different reference voltages of photodetector. Both theoretical analysis and simulation experiment results suggest that this method can non-periodically achieve interference phase control with single photodetector by the switching module. Finally, the experimental device is set up, and the superiority of the SMCE method in transient response time and disturbance-resisting ability is demonstrated compared with the proportional-integral-derivative(PID) method.

Generation of a homozygous GRIN2A gene knockout human embryonic stem cell line using CRISPR/Cas9 system.

Schizophrenia is a group of common psychosis of unknown etiology and GRIN2A gene has been a risk gene for schizophrenia. In order to understand the relationship between the GRIN2A and schizophrenia, we generated a GRIN2A-KO human embryonic stem cell line by CRISPR/Cas9 system, which could provide a valuable resource for investing pathogenic mechanisms underlying schizophrenia and facilitating the development of targeted medicine.

High-Precision Wafer Bonding Alignment Mark Using Moiré Fringes and Digital Grating.

This paper investigates a moiré-based mark for high-precision wafer bonding alignment. During alignment, the mark is combined with digital grating, which has the benefits of high precision and small size. A digital grating is superimposed on the mark to generate moiré fringes. By performing a phase calculation on the moiré fringe images corresponding to the upper and lower wafers, the relative offset of the upper and lower wafers can be accurately calculated. These moiré fringes are exceptionally stable, thereby enhancing the alignment stability. In this study, through practical experiments, we tested the rationality and practicability of the mark.

Multiplexed base editing through Cas12a variant-mediated cytosine and adenine base editors.

Cas12a can process multiple sgRNAs from a single transcript of CRISPR array, conferring advantages in multiplexed base editing when incorporated into base editor systems, which is extremely helpful given that phenotypes commonly involve multiple genes or single-nucleotide variants. However, multiplexed base editing through Cas12a-derived base editors has been barely reported, mainly due to the compromised efficiencies and restricted protospacer-adjacent motif (PAM) of TTTV for wild-type Cas12a. Here, we develop Cas12a-mediated cytosine base editor (CBE) and adenine base editor (ABE) systems with elevated efficiencies and expanded targeting scope, by combining highly active deaminases with Lachnospiraceae bacterium Cas12a (LbCas12a) variants. We confirm that these CBEs and ABEs can perform efficient C-to-T and A-to-G conversions, respectively, on targets with PAMs of NTTN, TYCN, and TRTN. Notably, multiplexed base editing can be conducted using the developed CBEs and ABEs in somatic cells and embryos. These Cas12a variant-mediated base editors will serve as versatile tools for multiplexed point mutation, which is notably important in genetic improvement, disease modeling, and gene therapy.

Screening and Identification of a Novel Anti-Siglec-15 Human Antibody 3F1 and Relevant Antitumor Activity.

Sialic acid-binding Ig-like lectin-15 is an important immunosuppressive molecule considered to be a key target in next-generation tumor immunotherapy. In this study, we screened 22 high-affinity antibodies that specifically recognize human Siglec-15 by using a large human phage antibody library, and five representative sequences were selected for further study. The results showed the binding activity of five antibodies to Siglec-15 (EC50 ranged from 0.02368 µg/mL to 0.07949 µg/mL), and in two Siglec-15-overexpressed cell lines, three antibodies had the strongest binding activity, so the two clones were discarded for further study. Subsequently, the affinity of three antibodies were measured by bio-layer interferometry technology (5-9 × 10E-09M). As the reported ligands of Siglec-15, the binding activity of Siglec-15 and sialyl-Tn, cluster of differentiation 44, myelin-associated glycoprotein, and leucine-rich repeat-containing protein 4C can be blocked by three of the antibodies. Among these, 3F1 had a competitive advantage. Then, the antibody 3F1 showed an obvious antibody-dependent cell-mediated cytotoxicity effect (EC50 was 0.85 µg/mL). Further, antibody 3F1 can reverse the inhibitory effect of Siglec-15 on lymphocyte proliferation (especially CD4+T and CD8+T) and cytokine release Interferon-γ. Given the above results, 3F1 was selected as a candidate for the in vivo pharmacodynamics study. In the tumor model of Balb/c Nude mice, 3F1 (10 mg/kg) showed certain antitumor effects [tumor growth inhibition (TGI) was 31.5%], while the combination of 3F1 (5 mg/kg) and Erbitux (5 mg/kg) showed significant antitumor effects (TGI was 48.7%) compared with the PBS group. In conclusion, novel human antibody 3F1 has antitumor activity and is expected to be an innovative candidate drug targeting Siglec-15 for tumor immunotherapy. SIGNIFICANCE STATEMENT: Siglec-15 is considered as an important target in the next generation of tumor immunotherapy. 3F1 is expected to be the most promising potential candidate for targeting Siglec-15 for cancer treatment and could provide a reference for the development of antitumor drugs.

Characterization of Low-Loss Dielectric Materials for High-Speed and High-Frequency Applications.

In this study, the Df (dissipation factor or loss tangent) and Dk (dielectric constant or permittivity) of the low-loss dielectric material from three different vendors are measured by the Fabry-Perot open resonator (FPOR) technique. Emphasis is placed on the sample preparation, data collection, and the comparison with the data sheet values provided from vendors. A coplanar waveguide with ground (CPWG) test vehicle with one of these raw dielectric materials (vendor 1) is designed (through Polar and simulation) and fabricated. The impedance of the test vehicle is measured by TDR (time-domain reflectometer), and the effective Dk of the test vehicle is calculated by the real cross-section of the metal line width, spacing, and thickness of the test vehicle and a closed-form equation. In parallel, the insertion loss and return loss are measured with the VNA (vector network analyzer) of the test vehicle. Finally, the measurement and simulation results are correlated. Some recommendations on the low-loss dielectric materials of the Dk and Df are also provided.

Acute toxicity of tire wear particles, leachates and toxicity identification evaluation of leachates to the marine copepod, Tigriopus japonicus.

Tire wear particles (TWPs) have been characterized as microplastics in recent years, and many of these TWPs will be eventually deposited in coastal areas, leading to adverse effects to marine organisms. Results of the acute toxicity test in this study showed that the 96-h LC50 values of the particles and leachate were 771.4 mg/L (95% CI = 684.4-869.6 mg/L) and 5.34 g/L (95% CI = 4.75-6.07 g/L), respectively. The chemical constituents of TWP and the leachate are very complex, and little research has been conducted to determine which of these constituents contribute to the toxicity of TWP leachate to marine organisms. Therefore, the composition of the TWP and leachate was analyzed, and a variety of chemicals were identified, including metals (Mn, Zn, etc.) and organic compounds (cyclohexanthiol, 4-ethyl-1,2-dimethylbenzene, benzothiazole, stearic acid, N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine, etc.). In addition, the marine copepod Tigriopus japonicus was applied as a model species in the toxicity identification evaluation study to characterize, identify and confirm the toxicity-causing substances in the TWP leachate. Zn was identified and confirmed as the main toxicant contributing to the toxicity. Furthermore, Zn concentrations in the leachate over time were investigated. The release of Zn from TWPs to the aquatic environment was slow, and conformed to a parabolic model with a release constant k of 2.06. The organic component, benzothiazole, exhibited an antagonistic effect with zinc in the acute toxicity of the TWP leachate.

Correlation between intraoperative mapping and monitoring and functional outcomes following supratentorial glioma surgery.

OBJECTIVES: Intraoperative neurophysiological monitoring (IONM) has long been regarded as the "gold standard" when resecting a supratentorial glioma, as it facilitates the goals of maximal tumor resection and preservation of sensorimotor function. The purpose of the present study was to evaluate the ability of motor evoked potentials (MEPs) monitoring or subcortical mapping (SCM), alone or in combination, to predict postoperative functional outcomes in glioma surgery. MATERIALS AND METHODS: We retrospectively reviewed patients with supratentorial glioma that underwent craniotomy for tumor removal with IONM. Statistical analyses were used to evaluate whether the following criteria correlated with postoperative functional outcomes: Reduced amplitude (>50% reduction) or disappearance of MEPs (criterion 1), SCM with a stimulation intensity threshold less than 3 mA (criterion 2), the presence of both two phenomena (criterion 3), or either one of the two phenomena (criterion 4). RESULTS: Ninety-two patients were included in this study, of whom 15 sustained new postoperative deficits, 4 experienced improved functional status, and 73 were unchanged. Postoperative functional status correlated significantly with all four criteria, and especially with criterion 3 (r = 0.647, P = 0.000). Sensitivity of IONM was better if using criteria 2 and 4, but specificity was better if using criteria 1 and 3. Criterion 3 had the most favorable overall results. CONCLUSION: Using statistical methodology, our study indicates that concomitant interpretation of MEPs and SCM is the most accurate predictor of functional outcomes following supratentorial glioma surgery. However, accurate interpretations of the monitoring results by experienced neurophysiologists are essential.

In-Fiber Polymer Microdisk Resonator and Its Sensing Applications of Temperature and Humidity.

We proposed and realized an all-in-fiber polymer microdisk whispering-gallery mode (WGM) resonator, which is composed of a nanoscale polymer waveguide in conjunction with a polymer microdisk. The resonator is manufactured by femtosecond laser-induced two-photon polymerization inside a single-mode optical fiber, and its transmission spectrum has been investigated theoretically and experimentally. The WGM resonance was excited successfully, exhibiting a high Q factor of 2.3 × 103 at a resonant wavelength of 1416.6 nm. The temperature and humidity responses of the resonator were tested as examples of possible application. Temperature sensitivity of -96 pm/°C when the temperature increased from 25 to 60 °C and humidity sensitivity of 54 pm/%RH when the relative humidity increased from 30 to 90% were obtained. The proposed in-fiber microdisk resonator is highly suitable for detection of microorganisms, bacteria, and single molecules.

Fiber-tip polymer clamped-beam probe for high-sensitivity nanoforce measurements.

Micromanipulation and biological, material science, and medical applications often require to control or measure the forces asserted on small objects. Here, we demonstrate for the first time the microprinting of a novel fiber-tip-polymer clamped-beam probe micro-force sensor for the examination of biological samples. The proposed sensor consists of two bases, a clamped beam, and a force-sensing probe, which were developed using a femtosecond-laser-induced two-photon polymerization (TPP) technique. Based on the finite element method (FEM), the static performance of the structure was simulated to provide the basis for the structural design. A miniature all-fiber micro-force sensor of this type exhibited an ultrahigh force sensitivity of 1.51 nm µN-1, a detection limit of 54.9 nN, and an unambiguous sensor measurement range of ~2.9 mN. The Young's modulus of polydimethylsiloxane, a butterfly feeler, and human hair were successfully measured with the proposed sensor. To the best of our knowledge, this fiber sensor has the smallest force-detection limit in direct contact mode reported to date, comparable to that of an atomic force microscope (AFM). This approach opens new avenues towards the realization of small-footprint AFMs that could be easily adapted for use in outside specialized laboratories. As such, we believe that this device will be beneficial for high-precision biomedical and material science examination, and the proposed fabrication method provides a new route for the next generation of research on complex fiber-integrated polymer devices.

Localized tilted fiber Bragg gratings induced by femtosecond laser line-by-line inscription.

Localized tilted fiber Bragg gratings (TFBGs) with low insertion loss are reported. A series of second-order TFBGs with tilt angles of 0°, 7°, 14°, and 21° was inscribed line by line directly in a single-mode fiber. For the 7° TFBG, the Bragg resonance was 2.4 dB at 1550 nm, and the maximum cladding-mode resonance reached 24.6 dB with an insertion loss of 0.8 dB, the same level as that for TFBGs fabricated by the phase-mask method. The range in cladding-mode resonance for the TFBGs obtained was wider than 170 nm with an intensity exceeding 20 dB. Combined with microscope images, the formation of these localized TFBGs and their spectral performance are discussed. The effect of an inscription offset along the $y$-axis direction was further investigated. With increasing offset, the intensity of the cladding-mode resonance dropped rapidly. The refractive index response sensitivity of the 7° TFBG was measured at 507.54 nm/RIU.

Effect of Polystyrene Microplastics of Different Sizes to Escherichia coli and Bacillus cereus.

The toxicity of polystyrene (PS) particles of different sizes was investigated using Gram-negative Escherichia coli and Gram-positive Bacillus cereus. PS particles could inhibit the cell growth of E. coli but promote the cell growth of B. cereus, and this difference might be attributed to different composition in their cell walls and the different interactions between the two bacteria and PS particles. Direct adhesion of E. coli cells on the surface of 5 µm PS microbeads by flagella was observed, indicating the putative role of E. coli on biofilm formation of plastisphere. The regulations of malondialdehyde, lactate dehydrogenase and glutathione were similar between the two bacteria, so the difference in the toxicity effect of PS between the two bacteria was not caused by the antioxidant activity. The overall results of the present study could help to understand the responses of different bacteria to microplastic exposure.

Optimal Frequency and Amplitude of Vertical Viewpoint Oscillation for Improving Vection Strength and Reducing Neural Constrains on Gait.

Inducing self-motion illusions referred as vection are critical for improving the sensation of walking in virtual environments (VE). Adding viewpoint oscillations to a constant forward velocity in VE is effective for improving vection strength under static conditions. However, the effects of oscillation frequency and amplitude on vection strength under treadmill walking conditions are still unclear. Besides, due to the visuomotor entrainment mechanism, these visual oscillations would affect gait patterns and be detrimental for achieving natural walking if not properly designed. This study was aimed at determining the optimal frequency and amplitude of vertical viewpoint oscillations for improving vection strength and reducing gait constraints. Seven subjects walked on a treadmill while watching a visual scene. The visual scene presented a constant forward velocity equal to the treadmill velocity with different vertical viewpoint oscillations added. Five oscillation patterns with different combinations of frequency and amplitude were tested. Subjects gave verbal ratings of vection strength. The mediolateral (M-L) center of pressure (CoP) complexity was calculated to indicate gait constraints. After the experiment, subjects were asked to give the best and the worst oscillation pattern based on their walking experience. The oscillation frequency and amplitude had strong positive correlations with vection strength. The M-L CoP complexity was reduced under oscillations with low frequency. The medium oscillation amplitude had greater M-L CoP complexity than the small and large amplitude. Besides, subjects preferred those oscillation patterns with large gait complexity. We suggested that the oscillation amplitude with largest M-L CoP complexity should first be chosen to reduce gait constraints. Then, increasing the oscillation frequency to improve vection strength until individual preference or the boundary of motion sickness. These findings provide important guidelines to promote the sensation of natural walking in VE.

A novel method to detect wafer-bonding energy using function fitting.

The bonding energy is an important parameter to evaluate the quality of bonded wafers in the semiconductor industry. The most important currently used method to measure the bonding energy is the so-called crack opening method. Unfortunately, the infrared cameras used for the wafer inspection with this method have limiting resolutions, and the derived direct crack length reading error is relatively large. To solve the reading error and adaptability problems, in this study, we improve upon the conventional image processing method and propose a crack length identification method that uses function fitting. The effectiveness and feasibility of the method are verified through experiments.

High purity optical vortex generation in a fiber Bragg grating inscribed by a femtosecond laser.

In this Letter, a method for orbital angular momentum (OAM) mode generation is proposed and experimentally demonstrated using a fiber Bragg grating (FBG) and off-axis incidence. The FBG fabricated by a femtosecond laser was used to couple the incidence beam into backward high-order modes. The generated modes were then reformed into ring-shaped OAM modes by adjusting the off-axis displacement of the input beam. The intensity distribution, phase vortex, and mode purity of the output light were experimentally investigated. Results indicates that the order of the generated OAM modes is dependent on the resonant wavelength of the FBG, and the sign of the OAM topological charge is determined by the displacement value of the off-axis incident light. In the experiment, ±1- and ±2-order OAM modes were achieved and confirmed, with purities as high as 90%, 91%, 89%, and 88%, respectively.

Acute and chronic combined effect of polystyrene microplastics and dibutyl phthalate on the marine copepod Tigriopus japonicus.

Dibutyl phthalate (DBP) is a commonly used additive in plastic products, so it may potentially coexist with microplastics (MPs) in marine environment. The ingestion of MPs might affect the accumulation of DBP in marine organisms. In this study, the marine copepod Tigriopus japonicus was applied to study the combined effect of DBP and polystyrene microplastics (mPS) on the copepod through both acute mortality tests and chronic reproduction tests. The LC50 of DBP was 1.23 mg L-1 (95% CI: 1.11-1.35 mg L-1), while exposure to mPS didn't have significant lethal effect on the copepods. Adsorption to MPs led to decreased bioavailability of DBP, resulting in decreased toxicity of DBP. In contrast to the results of acute toxicity tests, DBP didn't affect the reproduction of the copepods at lower exposure concentrations, while mPS reduced the number of nauplii and extended the time to hatch. Similar as acute toxicity tests, antagonistic interaction was observed for mPS and DBP in chronic reproduction tests, which might be attributed to promoted aggregation of mPS at presence of DBP. Overall, antagonistic toxicity effect between the two pollutants was observed for both acute and chronic tests, but the mechanisms of the interaction between DBP and mPS were different. Results of the present study highlighted the importance of long-term exposure when evaluating the toxic effect of MPs and their combined effect with other chemicals.

Combined effect of polystyrene microplastics and dibutyl phthalate on the microalgae Chlorella pyrenoidosa.

The combined effect of polystyrene microplastics (mPS) and dibutyl phthalate (DBP), a common plastic additive, on the microalgae Chlorella pyrenoidosa was investigated in the present study. The 96 h-IC50 value of DBP was 2.41 mg L-1. Polystyrene microplastics exhibited size-dependent inhibitory effect to C. pyrenoidosa, with the 96 h-IC50 at 6.90 and 7.19 mg L-1 for 0.1 and 0.55 µm mPS respectively, but little toxicity was observed for 5 µm mPS. The interaction parameter ρ based on the response additive response surface (RARS) model varied from -0.309 to 5.845, indicating the interaction pattern varying with exposure concentrations of chemical mixtures. A modified RARS model (taking ρ as a function of exposure concentration) was constructed and could well predict the combined toxicity of mPS and DBP. More than 20% reduction of DBP was observed at 20 mg L-1 mPS, while 1 mg L-1 mPS had no significant effect on the bioavailability of DBP at different sampling time points. Volume, morphological complexity and chlorophyll fluorescence intensity of microalgal cells were disturbed by both DBP and mPS. The antagonistic effect of high concentrations of mPS might be partially attributed to the combination of hetero- and homo-aggregation and the reduced bioavailability of DBP. The overall findings of the present study profiled the combined toxic effects of mPS and DBP on marine phytoplankton species which will be helpful for further evaluation of ecological risks of mPS and DBP in marine environment.

Local Dynamic Stability of Self-Paced Treadmill Walking Versus Fixed-Speed Treadmill Walking.

The purpose of this study was to assess the influence of gait stability induced by treadmill accelerations during self-paced treadmill walking (SPW). Local dynamic stability of three-dimensional (3D) upper body accelerations and hip angles were quantified. The results demonstrated that SPW was more unstable and had higher risk of falling than fixed-speed treadmill walking (FSW) under the impact of treadmill accelerations. The frequency domain analysis of treadmill speed indicated that intrastride treadmill speed variation was the dominating cause of the instability, and self-paced control strategies which can reduce the intrastride variation may achieve higher gait stability during SPW.