Cuproptosis-related gene CDKN2A as a molecular target for IPF diagnosis and therapeutics.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive chronic interstitial lung disease with limited therapeutic options. Cuproptosis is a recently proposed novel form of programmed cell death, which has been strongly implicated in the development of various human diseases. However, the prognostic and therapeutic value of cuproptosis-related genes (CRGs) in IPF remains to be elucidated. METHODS: In the present study, weighted gene co-expression network analysis (WGCNA) was employed to identify the key CRGs associated with the development of IPF. The subsequent GSEA, immune cell correlation analysis, and single-cell RNA-Seq analysis were conducted to explore the potential role of the identified CRGs in IPF. In addition, ROC curves and survival analysis were used to assess the prognostic value of the key CRGs in IPF. Moreover, we explored the molecular mechanisms of participation of identified key CRGs in the development of pulmonary fibrogenesis through in vivo and in vitro experiments. RESULTS: The expression level of cyclin-dependent kinase inhibitor 2A (CDKN2A) is upregulated in the lung tissues of IPF patients and associated with disease severity. Notably, CDKN2A was constitutively expressed by fibrosis-promoting M2 macrophages. Decreased CDKN2A expression sensitizes M2 macrophages to elesclomol-induced cuproptosis in vitro. Inhibition of CDKN2A decreases the number of viable macrophages and attenuates bleomycin-induced pulmonary fibrosis in mice. CONCLUSION: These findings indicate that CDKN2A mediates the resistance of fibrosis-promoting M2 macrophages to cuproptosis and promotes pulmonary fibrosis in mice. Our work provides fresh insights into CRGs in IPF with potential value for research in the pathogenesis, diagnosis, and a new therapy strategy for IPF.

Bioorthogonal Reaction-Mediated Tumor-Selective Delivery of CRISPR/Cas9 System for Dual-Targeted Cancer Immunotherapy.

CRISPR system-assisted immunotherapy is an attractive option in cancer therapy. However, its efficacy is still less than expected due to the limitations in delivering the CRISPR system to target cancer cells. Here, we report a new CRISPR/Cas9 tumor-targeting delivery strategy based on bioorthogonal reactions for dual-targeted cancer immunotherapy. First, selective in vivo metabolic labeling of cancer and activation of the cGAS-STING pathway was achieved simultaneously through tumor microenvironment (TME)-biodegradable hollow manganese dioxide (H-MnO2 ) nano-platform. Subsequently, CRISPR/Cas9 system-loaded liposome was accumulated within the modified tumor tissue through in vivo click chemistry, resulting in the loss of protein tyrosine phosphatase N2 (PTPN2) and further sensitizing tumors to immunotherapy. Overall, our strategy provides a modular platform for precise gene editing in vivo and exhibits potent antitumor response by boosting innate and adaptive antitumor immunity.

Customizable trajectory of trapped particle in quadruple-beam optical trap.

We have presented and demonstrated a customizable trajectory of a trapped particle in the Quadruple-beam optical trap. The orbital motion of the trapped microsphere was realized by modulating the trapping power. The motion trajectories could be designed by adjusting the modulation frequency, amplitude, and phase. By using this method, we have realized the triangle, bowknot, ellipse, straight line, and hooklike trajectories. The motion frequencies and circumferences were also modulated. The customizable trajectory in the optical trap may result in more possibilities for directional movement, microfluidic mixing, driven machines, and even painting freely.

Dual-beam intracavity optical tweezers with all-optical independent axial and radial self-feedback control schemes.

The feedback control to optical tweezers is an obvious approach to improve the optical confinement. However, the electronic-based feedback controlling system in optical tweezers usually consists of complex software and hardware, and its performance is limited by the inevitable noise and time-delay from detecting and controlling devices. Here, we present and demonstrate the dual-beam intracavity optical tweezers enabling all-optical independent radial and axial self-feedback control of the trapped particle's radial and axial motions. We have achieved the highest optical confinement per unit intensity to date, to the best of our knowledge. Moreover, both the axial and radial confinements are adjustable in real-time, through tuning the foci offset of the clockwise and counter-clockwise beams. As a result, we realized three-dimensional self-feedback control of the trapped particle's motions with an equivalent level in the experiment. The dual-beam intracavity optical tweezers will significantly expand the range of optical manipulation in further studies of biology, physics and precise measurement, especially for the sample that is extremely sensitive to heat.

Hypoxia-Responsive Gene Editing to Reduce Tumor Thermal Tolerance for Mild-Photothermal Therapy.

Near-infrared (NIR)-light-triggered photothermal therapy (PTT) is usually associated with undesirable damage to healthy organs nearby due to the high temperatures (>50 °C) available for tumor ablation. Low-temperature PTT would therefore have tremendous value for clinical application. Here, we construct a hypoxia-responsive gold nanorods (AuNRs)-based nanocomposite of CRISPR-Cas9 for mild-photothermal therapy via tumor-targeted gene editing. AuNRs are modified with azobenzene-4,4'-dicarboxylic acid (p-AZO) to achieve on-demand release of CRISPR-Cas9 using hypoxia-responsive azo bonds. In the hypoxic tumor microenvironment, the azo groups of the hypoxia-activated CRISPR-Cas9 nanosystem based on gold nanorods (APACPs) are selectively reduced by the overexpression of reductases, leading to the release of Cas9 and subsequent gene editing. Owing to the knockout of HSP90α for reducing the thermal resistance of cancer cells, highly effective tumor ablation both in vitro and in vivo was achieved with APACPs under mild PTT.

Optical confinement efficiency in the single beam intracavity optical tweezers.

Single beam intracavity optical tweezers characterizes a novel optical trapping scheme where the laser operation is nonlinearly coupled to the motion of the trapped particle. Here, we first present and establish a physical model from a completely new perspective to describe this coupling mechanism, using transfer matrices to calculate the loss of the free-space optical path and then extracting the scattering loss that caused by the 3D motions of the particle. Based on this model, we discuss the equilibrium position in the single beam intracavity optical tweezers. The influences of the numerical aperture, pumping power, particle radius and refractive index on the optical confinement efficiency are fully investigated, compared with standard optical tweezers. Our work is highly relevant for guiding the experiments on the single beam intracavity optical tweezers to achieve higher optical confinement efficiency.

A 5.86 Million Quality Factor Cylindrical Resonator with Improved Structural Design Based on Thermoelastic Dissipation Analysis.

The cylindrical resonator is the core component of cylindrical resonator gyroscopes (CRGs). The quality factor (Q factor) of the resonator is one crucial parameter that determines the performance of the gyroscope. In this paper, the finite element method is used to theoretically investigate the influence of the thermoelastic dissipation (TED) of the cylindrical resonator. The improved structure of a fused silica cylindrical resonator is then demonstrated. Compared with the traditional structure, the thermoelastic Q (QTED) of the resonator is increased by 122%. In addition, the Q factor of the improved cylindrical resonator is measured, and results illustrate that, after annealing and chemical etching, the Q factor of the resonator is significantly higher than that of the cylindrical resonators reported previously. The Q factor of the cylindrical resonator in this paper reaches 5.86 million, which is the highest value for a cylindrical resonator to date.

Influence of Temperature Variation on the Vibrational Characteristics of Fused Silica Cylindrical Resonators for Coriolis Vibratory Gyroscopes.

The fused silica cylindrical resonator is a type of axisymmetric resonator that can be used for Coriolis vibratory gyroscopes. Although the resonant frequency, frequency mismatch, and Q factor are natural properties of the resonator, they can change with temperature. Therefore, the temperature drift severely limits the detection accuracy and bias stability of the gyroscope. In this paper, the influence of temperature variation on the vibrational characteristics of fused silica cylindrical resonators was investigated. Experiments were performed on a fused silica cylindrical resonator coated with Cr/Au films. It was shown that at the temperature range from 253.15 K to 353.15 K, the resonant frequency linearly increased with temperature, the frequency mismatch remained unchanged, and the Q factor gradually increased till about 333.15 K, when it began to decrease. Meanwhile, the change of thermoelastic damping with temperature may dominate the variation of Q factor at the temperature range from 253.15 K to 353.15 K. This phenomenon was theoretically analyzed and the variation trends of results were consistent with the theoretical analysis. This study indicates that, for the fused silica cylindrical resonator, to discover the influence of temperature variation on the resonant frequency, frequency mismatch, and Q factor, there are certain rules to follow and repeat. The relationship between temperature and frequency can be established, which provides the feasibility of using self-calibration based on temperature characteristics of the resonator for temperature drift compensations. Additionally, there is an optimum temperature that may improve the performance of the Coriolis vibratory gyroscope with the fused silica cylindrical resonator.

Influence of Electrostatic Forces on the Vibrational Characteristics of Resonators for Coriolis Vibratory Gyroscopes.

The Coriolis Vibratory Gyroscopes are a type of sensors that measure angular velocities through the Coriolis effect. The resonator is the critical component of the CVGs, the vibrational characteristics of which, including the resonant frequency, frequency mismatch, Q factor, and Q factor asymmetry, have a great influence on the performance of CVG. The frequency mismatch and Q factor of the resonator, in particular, directly determine the precision and drift characteristics of the gyroscope. Although the frequency mismatch and Q factor are natural properties of the resonator, they can change with external conditions, such as temperature, pressure, and external forces. In this paper, the influence of electrostatic forces on the vibrational characteristics of the fused silica cylindrical resonator is investigated. Experiments were performed on a fused silica cylindrical resonator coated with Cr/Au films. It was shown that the resonant frequency, frequency mismatch, and the decay time slightly decreased with electrostatic forces, while the decay time split increased. Lower capacitive gaps and larger applied voltages resulted in lower frequency mismatch and lower decay time. This phenomenon was theoretically analyzed, and the variation trends of results were consistent with the theoretical analysis. This study indicates that, for fused silica cylindrical resonator with electrostatic transduction, the electrostatic influence on the Q factor and frequency, although small, should be considered when designing the capacitive gap and choosing bias voltages.

All-fiber interferometer for displacement and velocity measurement of a levitated particle in fiber-optic traps.

We propose an all-fiber interferometer based on laser Doppler velocimetry in a dual-beam fiber-optic trap to measure the displacement and velocity of a trapped particle. ABCD matrices are used to compute the contrast ratio of the interference. The influence of the reflectivity of the fiber end face is discussed. We have designed an optimized reflectivity based on the parameters of our setup. The antireflective coatings on the fiber end face are employed to achieve the given reflectivity. The displacement and velocity of the trapped microparticle are successfully measured by the period and frequency of the interference signal, respectively. The sensitivity of the displacement detection is 368 nm. By describing the miniaturization of the detection system, this paper provides a simple and practical scheme to achieve the integration of the entire optical trapping setup.

Trimming of Imperfect Cylindrical Fused Silica Resonators by Chemical Etching.

The cylindrical resonator gyroscope (CRG) is a kind of solid-state gyroscope with a wide application market. The cylindrical resonator is the key component of CRG, whose quality factor and symmetry will directly affect the performance of the gyroscope. Due to the material properties and fabrication limitations, the actual resonator always has some defects. Therefore, frequency trimming, i.e., altering the local mass or stiffness distribution by certain methods, is needed to improve the overall symmetry of the resonator. In this paper, we made further derivation based on the chemical trimming theory proposed by Basarab et al. We built up the relation between the frequency split and the balanced mass to determine the mass to be removed. Chemical trimming experiments were conducted on three cylindrical fused silica resonators. The frequency splits of the three resonators were around 0.05 Hz after chemical trimming. The relation between frequency split and balanced mass established from experimental data was consistent with the theoretical calculation. Therefore, frequency split can be reduced to lower than 0.05 Hz under rigorous theoretical calculation and optimized chemical trimming parameters.

Optical and Electrical Method Characterizing the Dynamic Behavior of the Fused Silica Cylindrical Resonator.

Fused silica cylindrical resonant gyroscope (CRG) is a novel high-precision solid-wave gyroscope, whose performance is primarily determined by the cylindrical resonator's frequency split and quality factor (Q factor). The laser Doppler vibrometer (LDV) is extensively used to measure the dynamic behavior of fused silica cylindrical resonators. An electrical method was proposed to characterize the dynamic behavior of the cylindrical resonator to enhance the measurement efficiency and decrease the equipment cost. With the data acquisition system and the designed signal analysis program based on LabVIEW software, the dynamic behavior of the fused silica cylindrical resonator can be analyzed automatically and quickly. We compared all the electrical measurement results with the optical detection by LDV, demonstrating that the fast Fourier transform (FFT) result of the resonant frequency measured by the electrical method was 0.12 Hz higher than that with the optical method. Thus, the frequency split measured by the electrical and optical methods was the same in 0.18 Hz, and the measurement of the Q factor was basically the same in 730,000. We conducted all measurements under the same operation condition, and the optical method was used as a reference, demonstrating that the electrical method could characterize the dynamic behavior of the fused silica cylindrical resonator and enhance the measurement efficiency.

Decreasing Frequency Splits of Hemispherical Resonators by Chemical Etching.

The hemispherical resonator gyroscope (HRG) has attracted the interest of the world inertial navigation community because of its exceptional performance, ultra-high reliability and its potential to be miniaturized. These devices achieve their best performance when the differences in the frequencies of the two degenerate working modes are eliminated. Mechanical treatment, laser ablation, ion-beams etching, etc., have all been applied for the frequency tuning of resonators, however, they either require costly equipment and procedures, or alter the quality factors of the resonators significantly. In this paper, we experimentally investigated for the first time the use of a chemical etching procedure to decrease the frequency splits of hemispherical resonators. We provide a theoretical analysis of the chemical etching procedure, as well as the relation between frequency splits and mass errors. Then we demonstrate that the frequency split could be decreased to below 0.05 Hz by the proposed chemical etching procedure. Results also showed that the chemical etching method caused no damage to the quality factors. Compared with other tuning methods, the chemical etching method is convenient to implement, requiring less time and labor input. It can be regarded as an effective trimming method for obtaining medium accuracy hemispherical resonator gyroscopes.

Characteristics of the orbital rotation in dual-beam fiber-optic trap with transverse offset.

The orbital rotation is an important type of motion of trapped particles apart from translation and spin rotation. It could be realized by introducing a transverse offset to the dual-beam fiber-optic trap. The characteristics (e.g. rotation perimeter and frequency) of the orbital rotation have been analyzed in this article. We demonstrate the influences of offset distance, beam waist separation distance, light power, and radius of the microsphere by both experimental and numerical work. The experiment results, i.e. orbital rotation perimeter and frequency as functions of these parameters, are consistent with the theoretical model in the present work. The orbital rotation amplitude and frequency could be exactly controlled by varying these parameters. This controllable orbital rotation can be easily applied to the area where microfluidic mixing is required.

Dynamics analysis of microsphere in a dual-beam fiber-optic trap with transverse offset.

A comprehensive dynamics analysis of microsphere has been presented in a dual-beam fiber-optic trap with transverse offset. As the offset distance between two counterpropagating beams increases, the motion type of the microsphere starts with capture, then spiral motion, then orbital rotation, and ends with escape. We analyze the transformation process and mechanism of the four motion types based on ray optics approximation. Dynamic simulations show that the existence of critical offset distances at which different motion types transform. The result is an important step toward explaining physical phenomena in a dual-beam fiber-optic trap with transverse offset, and is generally applicable to achieving controllable motions of microspheres in integrated systems, such as microfluidic systems and lab-on-a-chip systems.

Quinolinic acid induces cell apoptosis in PC12 cells through HIF-1-dependent RTP801 activation.

Neurological disease comprises a series of disorders featuring brain dysfunction and neuronal cell death. Among the factors contributing to neuronal death, excitotoxicity induced by excitatory amino acids, such as glutamate, plays a critical role. However, the mechanisms about how the excitatory amino acids induce neuronal death remain elucidated. In this study, we investigated the role of HIF-1α (hypoxia inducible factor-1α) and RTP801 in cell apoptosis induced by quinolinic acid (QUIN), a glutamatergic agonist, in PC12 cells. We found that QUIN at 5 µM increased the expression of HIF-1α significantly with a peak at 24 h. After the treatment with QUIN (5-20 µM) for 24 h, the cells exhibited decreased viability and cell apoptosis with a concomitant increased expression of apoptosis related proteins. QUIN treatment also induced the generation of intracellular reactive oxygen species and RTP801 up-regulation in a HIF-1α-dependent manner that were inhibited by 2-methoxyestradiol, a HIF-1α inhibitor. Importantly, HIF-1 or RTP801 invalidation by siRNA rescued the cell apoptosis induced by QUIN or cobalt chloride, a chemical inducer of HIF-1. Taken together, these findings support the concept that neurotoxicity induced by QUIN is associated with HIF-1-dependent RTP801 activation and provide insight into the potential of RTP801 inhibitor in treatment of neurological disorders.

Monolithic Cylindrical Fused Silica Resonators with High Q Factors.

The cylindrical resonator gyroscope (CRG) is a typical Coriolis vibratory gyroscope whose performance is determined by the Q factor and frequency mismatch of the cylindrical resonator. Enhancing the Q factor is crucial for improving the rate sensitivity and noise performance of the CRG. In this paper, for the first time, a monolithic cylindrical fused silica resonator with a Q factor approaching 8 × 105 (ring-down time over 1 min) is reported. The resonator is made of fused silica with low internal friction and high isotropy, with a diameter of 25 mm and a center frequency of 3974.35 Hz. The structure of the resonator is first briefly introduced, and then the experimental non-contact characterization method is presented. In addition, the post-fabrication experimental procedure of Q factor improvement, including chemical and thermal treatment, is demonstrated. The Q factor improvement by both treatments is compared and the primary loss mechanism is analyzed. To the best of our knowledge, the work presented in this paper represents the highest reported Q factor for a cylindrical resonator. The proposed monolithic cylindrical fused silica resonator may enable high performance inertial sensing with standard manufacturing process and simple post-fabrication treatment.

Endovascular coiling vs. surgical clipping for unruptured intracranial aneurysm: A meta-analysis.

BACKGROUND: With increasing use of high-resolution imaging of brain, unruptured aneurysms are more and more frequently detected. With the advances in treatment techniques, an increasing number of aneurysms are now occluded using endovascular coiling instead of conventional surgical clipping. However, the better modality for unruptured intracranial aneurysm has been poorly understood. OBJECTIVE: The objective of this meta-analysis was to compare the outcomes between endovascular coiling and surgical clipping among patients with unruptured intracranial aneurysms. METHODS: PubMed, Embase, Web of Science, CENTRAL, and SIGLE were electronically searched from January 1, 1990 to March 13, 2012 with no language restriction for randomized or nonrandomized clinical controlled trials. Article screening and data extraction were conducted in duplicate. Results were statistically pooled through Review Manager 5 and StatsDirect 2.7.9. RESULTS: Seven studies met our inclusion criteria. The pooled risk ratios (coiling vs. clipping) were 0.59 (95% CI = 0.23-1.54) for death; 0.37 (95% CI = 0.10-1.41) for bleeding; 0.78 (95% CI = 0.38-1.58) for cerebral ischemia; 0.87 (95% CI = 0.70-1.08) for occlusion of aneurysm; 0.53 (95% CI = 0.18-1.52) for independence in daily activities. The pooled rates of death, bleeding, ischemia, occlusion of aneurysm, and mRS no less than 3 were 1% (95% CI = 0-2%), 2% (95% CI = 0-5%), 8% (95% CI = 4-13%), 82% (95% CI = 64-95%), and 5% (95% CI = 1-10%) for endovascular coiling, respectively, and 1% (95% CI = 0-2%), 6% (95% CI = 3-10%), 9% (95% CI = 5-15%), 95% (95% CI = 90-98%), and 8% (95% CI = 3-14%) for surgical clipping, respectively. We failed to evaluate quality of life and cognitive outcome due to insufficient data. Both meta-regression and sensitivity analysis showed consistent results. Furthermore, Begg's test and Egger's test failed to detect publication bias. CONCLUSION: We suggest that endovascular coiling and surgical clipping bear similar risk ratios of death, bleeding, cerebral ischemia, occlusion of aneurysm, and independence in daily activities and encourage further studies on quality of life and cognitive outcome. However, albeit the results in this meta-analysis are robust, due to great clinical heterogeneity and low quality of studies, the results in this meta-analysis should be interpreted with caution.

Spatial coating inhomogeneity of highly reflective mirrors determined by cavity ringdown measurements.

The inhomogeneity of high-reflectivity mirror coatings is a potential error source in the application of the cavity ringdown technique. Here, the ringdown times for different transverse modes were recorded. Together with the observed spatial distribution of these modes the ringdown times can be used to approximately locate the position of coating defects. A simple model based on a weighted sum of Hermite-Gaussian mode functions is used to explain the experimental results.

[Clinical classification and selection of surgical approaches for cervical spinal dumbbell tumors].

OBJECTIVE: To explore the clinical classification and selection of surgical approaches for cervical spinal dumbbell tumors. METHODS: The clinical data of 87 patients with cervical spinal dumbbell tumors undergoing surgical operations from January 2005 to December 2012 at our hospital were analyzed retrospectively. According to the size of inner and outer parts of tumors and the presence or absence of spinal bone damage, the cervical spinal dumbbell tumors were divided into 4 types of intraspinal predominant (I, n = 48), extraspinal predominant (II, n = 1), intrapinal and extraspinal without damage of spinal bone (III, n = 15) and intrapinal and extraspinal type with damage of spinal bone (IV, n = 7). Different surgical approaches were selected on the basis of tumor classification: posterior median-hemilamina approaches for type I tumors, lateral-muscle gap approaches for type II tumors, ateral-muscle gap-hemilamina or lateral-muscle gap-posterior median-hemilamina approaches for type III tumors, posterior far lateral-muscle gap-hemilamina or posterior median-muscle gap-hemilamina approaches plus posterior occipital cervical or cervical spinal bone graft fusion and internal fixation for type IV tumors. RESULTS: Among them, 83 cases underwent total resection and another 4 subtotal resection in one-stage operation. The postoperative follow-up period had a range of 9 months to 6 years (mean, 3.2 years). There was no recurrence of tumors for total resection and 1 case of tumor recurrence for subtotal resection. During the follow-up period, the clinical manifestations of 85 patients improved while another 2 deteriorated. And there was no occurrence of spinal deformity. CONCLUSION: Clinical classification of cervical spinal dumbbell tumor plays an important guiding role in the selection of surgical approaches. Adopting appropriate surgical approaches based on tumor type can not only improve the rate of total resection of tumor but also reduce the incidence of postoperative spinal deformity.