High Performance Indium-Tin-Oxide Schottky Diodes for Terahertz Band Operation.

Schottky diode, capable of ultrahigh frequency operation, plays a critical role in modern communication systems. To develop cost-effective and widely applicable high-speed diodes, researchers have delved into thin-film semiconductors. However, a performance gap persists between thin-film diodes and conventional bulk semiconductor-based ones. Featuring high mobility and low permittivity, indium-tin-oxide has emerged to bridge this gap. Nevertheless, due to its high carrier concentration, indium-tin-oxide has predominantly been utilized as electrode rather than semiconductor. In this study, a remarkable quantum confinement induced dedoping phenomenon was discovered during the aggressive indium-tin-oxide thickness downscaling. By leveraging such a feature to change indium-tin-oxide from metal-like into semiconductor-like, in conjunction with a novel heterogeneous lateral design facilitated by an innovative digital etch, we demonstrated an indium-tin-oxide Schottky diode with a cutoff frequency reaching terahertz band. By pushing the boundaries of thin-film Schottky diodes, our research offers a potential enabler for future fifth-generation/sixth-generation networks, empowering diverse applications.

Tumor immune dysfunction and exclusion subtypes in bladder cancer and pan-cancer: a novel molecular subtyping strategy and immunotherapeutic prediction model.

BACKGROUND: Molecular subtyping is expected to enable precise treatment. However, reliable subtyping strategies for clinical application remains defective and controversial. Given the significance of tumor immune dysfunction and exclusion (TIDE), we aimed to develop a novel TIDE-based subtyping strategy to guide personalized immunotherapy in the bladder cancer (BC). METHODS: Transcriptome data of BC was used to evaluate the heterogeneity and the status of TIDE patterns. Subsequently, consensus clustering was applied to classify BC patients based on TIDE marker-genes. Patients' clinicopathological, molecular features and signaling pathways of the different TIDE subtypes were well characterized. We also utilize the deconvolution algorithms to analyze the tumor microenvironment, and further explore the sensitivity and mechanisms of each subtype to immunotherapy. Furthermore, BC patient clinical information, real-world BC samples and urine samples were collected for the validation of our findings, which were used for RNA-seq analysis, H&E staining, immunohistochemistry and immunofluorescence staining, and enzyme-linked immunosorbent assay. Finally, we also explored the conservation of our novel TIDE subtypes in pan-cancers. RESULTS: We identified 69 TIDE biomarker genes and classified BC samples into three subtypes using consensus clustering. Subtype I showed the lowest TIDE status and malignancy with the best prognosis and highest sensitivity to immune checkpoint blockade (ICB) treatment, which was enriched of metabolic related signaling pathways. Subtype III represented the highest TIDE status and malignancy with the poorest prognosis and resistance to ICB treatment, resulting from its inhibitory immune microenvironment and T cell terminal exhaustion. Subtype II was in a transitional state with intermediate TIDE level, malignancy, and prognosis. We further confirmed the existence and characteristics of our novel TIDE subtypes using real-world BC samples and collected patient clinical data. This subtyping method was proved to be more efficient than previous known methods in identifying non-responders to immunotherapy. We also propose that combining our TIDE subtypes with known biomarkers can potentially improve the sensitivity and specificity of these biomarkers. Moreover, besides guiding ICB treatment, this classification approach can assist in selecting the frontline or recommended drugs. Finally, we confirmed that the TIDE subtypes are conserved across the pan-tumors. CONCLUSIONS: Our novel TIDE-based subtyping method can serve as a powerful clinical tool for BC and pan-cancer patients, and potentially guiding personalized therapy decisions for selecting potential beneficiaries and excluding resistant patients of ICB therapy.

A Novel Joint Denoising Method for Hydrophone Signal Based on Improved SGMD and WT.

Underwater acoustic technology as an important means of exploring the oceans is receiving more attention. Denoising for underwater acoustic information in complex marine environments has become a hot research topic. In order to realize the hydrophone signal denoising, this paper proposes a joint denoising method based on improved symplectic geometry modal decomposition (ISGMD) and wavelet threshold (WT). Firstly, the energy contribution (EC) is introduced into the SGMD as an iterative termination condition, which efficiently improves the denoising capability of SGMD and generates a reasonable number of symplectic geometry components (SGCs). Then spectral clustering (SC) is used to accurately aggregate SGCs into information clusters mixed-clusters, and noise clusters. Spectrum entropy (SE) is used to distinguish clusters quickly. Finally, the mixed clusters achieve the signal denoising by wavelet threshold. The useful information is reconstructed to achieve the original signal denoising. In the simulation experiment, the denoising effect of different denoising algorithms in the time domain and frequency domain is compared, and SNR and RMSE are used as evaluation indexes. The results show that the proposed algorithm has better performance. In the experiment of hydrophone, the denoising ability of the proposed algorithm is also verified.

High Stretch Associated with Mechanical Ventilation Promotes Piezo1-Mediated Migration of Airway Smooth Muscle Cells.

Ventilator-induced lung injury (VILI) during mechanical ventilation (MV) has been attributed to airway remodeling involving increased airway smooth muscle cells (ASMCs), but the underlying mechanism is not fully understood. Thus, we aimed to investigate whether MV-associated high stretch (>10% strain) could modulate mechanosensitive Piezo1 expression and thereby alter cell migration of ASMCs as a potential pathway to increased ASMCs in VILI. C57BL/6 mice and ASMCs were subjected to MV at high tidal volume (VT, 18 mL/kg, 3 h) and high stretch (13% strain, 0.5 Hz, 72 h), respectively. Subsequently, the mice or cells were evaluated for Piezo1 and integrin mRNA expression by immunohistochemical staining and quantitative PCR (qPCR), and cell migration and adhesion by transwell and cell adhesion assays. Cells were either treated or not with Piezo1 siRNA, Piezo1-eGFP, Piezo1 knockin, Y27632, or blebbistatin to regulate Piezo1 mRNA expression or inhibit Rho-associated kinase (ROCK) signaling prior to migration or adhesion assessment. We found that expression of Piezo1 in in situ lung tissue, mRNA expression of Piezo1 and integrin αVß1 and cell adhesion of ASMCs isolated from mice with MV were all reduced but the cell migration of primary ASMCs (pASMCs) isolated from mice with MV was greatly enhanced. Similarly, cell line mouse ASMCs (mASMCs) cultured in vitro with high stretch showed that mRNA expression of Piezo1 and integrin αVß1 and cell adhesion were all reduced but cell migration was greatly enhanced. Interestingly, such effects of MV or high stretch on ASMCs could be either induced or abolished/reversed by down/up-regulation of Piezo1 mRNA expression and inhibition of ROCK signaling. High stretch associated with MV appears to be a mechanical modulator of Piezo1 mRNA expression and can, thus, promote cell migration of ASMCs during therapeutic MV. This may be a novel mechanism of detrimental airway remodeling associated with MV, and, therefore, a potential intervention target to treat VILI.

Hemolymph Node - An Immunomorphlogical Organ: Modeling the Hemolymph Node by Allografting Renal Tissue in the Rat.

There is no authoritative characterization of the attributes of the hemolymph node (HLN) since Gibbes' first description in 1884. Early reports showed that HLN are found near the kidney in human and animals with the feature of numerous erythrocytes in sinuses. Subsequent studies mainly focused on anatomy and histology, such as the source, distribution, and quantity of erythrocytes in sinuses. Recent articles mentioned that the emergence of HLN was related to immunity, but there was no strong evidence to support this hypothesis. Therefore, it is still uncertain whether the HLN is an organ of anatomy, histology, or immunology. It has been found that the development of HLN could be elicited in the parathymic area by stimuli such as Escherichia coli, allogeneic breast cancer cells, and renal tissue that were injected/transplanted into the tail of rats in our pilot studies. In this study, the model of the HLN was established by transferring allogeneic renal tissue in the rat. Intrasinusoidal erythrocytes of the node were the component for producing a red macroscopic appearance, while macrophage-erythrocyte-lymphocyte rosettes were the major immunomorphological changes, reflecting the immune activity against the invasion of the allogeneic tissue within the node. Therefore, the HLN is an immunomorphological organ.

Chemical Activation of Piezo1 Alters Biomechanical Behaviors toward Relaxation of Cultured Airway Smooth Muscle Cells.

Inspired by the well-known phenomenon of stretch-induced airway dilation in normal lungs and the emerging stretch-responsive Piezo1 channels that can be chemically activated by specific agonists such as Yoda1, we attempted to investigate whether chemical activation of Piezo1 by Yoda1 can modulate the biomechanical behaviors of airway smooth muscle cells (ASMCs) so that it may be exploited as a novel approach for bronchodilation. Thus, we treated in vitro cultured rat ASMCs with Yoda1, and examined the cells for calcium signaling, cell stiffness, traction force, cell migration, and the mRNA expression and distribution of molecules relevant to cell biomechanics. The data show that ASMCs expressed abundant mRNA of Piezo1. ASMCs exposed to 1 µM Yoda1 exhibited a potent but transient Ca2+ signaling, and treatment with 1 µM Yoda1 for 24 h led to decreased cell stiffness and traction force, all of which were partially reversed by Piezo1 inhibitor GsMTx4 and Piezo1 knockdown, respectively. In addition, ASMCs treated with 1 µM Yoda1 for 24 h exhibited impaired horizontal but enhanced vertical cell migration, as well as significant changes in key components of cells' contractile machinery including the structure and distribution of stress fibers and alpha-smooth muscle actin (α-SMA) fibrils, the mRNA expression of molecules associated with cell biomechanics. These results provide the first evidence that chemical activation of Piezo1 by Yoda1 resulted in marked pro-relaxation alterations of biomechanical behaviors and contractile machinery of the ASMCs. These findings suggest that Piezo1-specific agonists may indeed have great potential as alternative drug agents for relaxing ASMCs.

LSH catalyzes ATP-driven exchange of histone variants macroH2A1 and macroH2A2.

LSH, a homologue of the ISWI/SNF2 family of chromatin remodelers, is required in vivo for deposition of the histone variants macroH2A1 and macroH2A2 at specific genomic locations. However, it remains unknown whether LSH is directly involved in this process or promotes other factors. Here we show that recombinant LSH interacts in vitro with macroH2A1-H2B and macroH2A2-H2B dimers, but not with H2A.Z-H2B dimers. Moreover, LSH catalyzes the transfer of macroH2A into mono-nucleosomes reconstituted with canonical core histones in an ATP dependent manner. LSH requires the ATP binding site and the replacement process is unidirectional leading to heterotypic and homotypic nucleosomes. Both variants macroH2A1 and macroH2A2 are equally well incorporated into the nucleosome. The histone exchange reaction is specific for histone variant macroH2A, since LSH is not capable to incorporate H2A.Z. These findings define a previously unknown role for LSH in chromatin remodeling and identify a novel molecular mechanism for deposition of the histone variant macroH2A.

Lsh/HELLS is required for B lymphocyte development and immunoglobulin class switch recombination.

Mutation of HELLS (Helicase, Lymphoid-Specific)/Lsh in human DNA causes a severe immunodeficiency syndrome, but the nature of the defect remains unknown. We assessed here the role of Lsh in hematopoiesis using conditional Lsh knockout mice with expression of Mx1 or Vav Cre-recombinase. Bone marrow transplantation studies revealed that Lsh depletion in hematopoietic stem cells severely reduced B cell numbers and impaired B cell development in a hematopoietic cell-autonomous manner. Lsh-deficient mice without bone marrow transplantation exhibited lower Ig levels in vivo compared to controls despite normal peripheral B cell numbers. Purified B lymphocytes proliferated normally but produced less immunoglobulins in response to in vitro stimulation, indicating a reduced capacity to undergo class switch recombination (CSR). Analysis of germline transcripts, examination of double-stranded breaks using biotin-labeling DNA break assay, and End-seq analysis indicated that the initiation of the recombination process was unscathed. In contrast, digestion-circularization PCR analysis and high-throughput sequencing analyses of CSR junctions and a chromosomal break repair assay indicated an impaired ability of the canonical end-joining pathway in Lsh-deficient B cells. Our data suggest a hematopoietic cell-intrinsic role of Lsh in B cell development and in CSR providing a potential target for immunodeficiency therapy.

Formononetin improves the inflammatory response and bone destruction in knee joint lesions by regulating the NF-kB and MAPK signaling pathways.

Formononetin (FMN) is a phytoestrogen that belongs to the isoflavone family. It has antioxidant and anti-inflammatory effects, as well as, many other biological activities. Existing evidence has aroused interest in its ability to protect against osteoarthritis (OA) and promote bone remodeling. To date, research on this topic has not been thorough and many issues remain controversial. Therefore, the purpose of our study was to explore the protective effect of FMN against knee injury and clarify the possible molecular mechanisms. We found that FMN inhibited osteoclast formation induced by receptor activator of NF-κB ligand (RANKL). Inhibition of the phosphorylation and nuclear translocation of p65 in the NF-κB signaling pathway plays a role in this effect. Similarly, during the inflammatory response of primary knee cartilage cells activated by IL-1ß, FMN inhibited the NF-κB signaling pathway and the phosphorylation of the ERK and JNK proteins in the MAPK signaling pathway to suppress the inflammatory response. In addition, in vivo experiments showed that both low- and high-dose FMN had a clear protective effect against knee injury in the DMM (destabilization of the medial meniscus) model, and the therapeutic effect of high-dose FMN was stronger. In conclusion, these studies provide evidence of the protective effect of FMN against knee injury.

Improved Artificial Potential Field Algorithm Assisted by Multisource Data for AUV Path Planning.

With the development of ocean exploration technology, the exploration of the ocean has become a hot research field involving the use of autonomous underwater vehicles (AUVs). In complex underwater environments, the fast, safe, and smooth arrival of target points is key for AUVs to conduct underwater exploration missions. Most path-planning algorithms combine deep reinforcement learning (DRL) and path-planning algorithms to achieve obstacle avoidance and path shortening. In this paper, we propose a method to improve the local minimum in the artificial potential field (APF) to make AUVs out of the local minimum by constructing a traction force. The improved artificial potential field (IAPF) method is combined with DRL for path planning while optimizing the reward function in the DRL algorithm and using the generated path to optimize the future path. By comparing our results with the experimental data of various algorithms, we found that the proposed method has positive effects and advantages in path planning. It is an efficient and safe path-planning method with obvious potential in underwater navigation devices.

Mechanical Ventilation-Related High Stretch Mainly Induces Endoplasmic Reticulum Stress and Thus Mediates Inflammation Response in Cultured Human Primary Airway Smooth Muscle Cells.

Ventilator-induced lung injury (VILI) occurs in mechanically ventilated patients of respiratory disease and is typically characterized by airway inflammation. However, recent studies increasingly indicate that a major cause of VILI may be the excessive mechanical loading such as high stretch (>10% strain) on airway smooth muscle cells (ASMCs) due to mechanical ventilation (MV). Although ASMCs are the primary mechanosensitive cells in airways and contribute to various airway inflammation diseases, it is still unclear how they respond to high stretch and what mediates such a response. Therefore, we used whole genome-wide mRNA-sequencing (mRNA-Seq), bioinformatics, and functional identification to systematically analyze the mRNA expression profiles and signaling pathway enrichment of cultured human ASMCs exposed to high stretch (13% strain), aiming to screen the susceptible signaling pathway through which cells respond to high stretch. The data revealed that in response to high stretch, 111 mRNAs with count ≥100 in ASMCs were significantly differentially expressed (defined as DE-mRNAs). These DE-mRNAs are mainly enriched in endoplasmic reticulum (ER) stress-related signaling pathways. ER stress inhibitor (TUDCA) abolished high-stretch-enhanced mRNA expression of genes associated with ER stress, downstream inflammation signaling, and major inflammatory cytokines. These results demonstrate in a data-driven approach that in ASMCs, high stretch mainly induced ER stress and activated ER stress-related signaling and downstream inflammation response. Therefore, it suggests that ER stress and related signaling pathways in ASMCs may be potential targets for timely diagnosis and intervention of MV-related pulmonary airway diseases such as VILI.

Angular velocity measurement with wide range based on dual-comb Sagnac interferometer.

Interferometric fiber optic gyroscopes are widely used in spacecraft, navigation, and autopilot and missile systems due to their high accuracy and fast speed. However, the dynamic measurement range is generally limited to a small value. In this paper, an angular velocity measurement system based on a dual-comb Sagnac interferometer is proposed. The theoretical dynamic range can reach the order of 108 deg/s, which is remarkably superior to that of the conventional fiber optic gyroscopes. To the best of our knowledge, this is the first demonstration of a dual-comb-based passive fiber optic gyroscope system, offering an attractive tool for measuring angular velocity with large dynamic range.

Three-dimensional morphology measurement of underwater objects based on the photoacoustic effect.

Complexities of the underwater environment can seriously affect many underwater detection means, especially the influence of light scattering by water. To solve this problem, a three-dimensional (3D) morphology measurement method is proposed based on the photoacoustic effect. In this method, a measurement object is irradiated with pulsed laser light to produce ultrasonic waves via the photoacoustic effect. A probe collects the ultrasonic signal and subsequent data processing can yield complete object detection. This approach can make full use of the advantages of high precision and good directivity of laser ranging and completely avoid the influence on the laser of backscattering from water. The results yield a displacement measurement accuracy of less than 0.5 mm and an average error of 3D reconstruction of 0.21 mm, demonstrating great application potential.

Extending Non-Ambiguity Range of Dual-Comb Ranging for a Mobile Target Based on FPGA.

Dual-comb ranging (DCR) is an important method in absolute distance ranging because of its high precision, fast acquisition rate, and large measuring range. DCR needs to obtain precise results during distance measurements for a mobile target. However, the non-ambiguity range (NAR) is a challenge when pushing the dual-comb ranging to the industry field. This paper presents a solution for extending NAR by designing an algorithm and realizing it on a field-programmable gate array (FPGA). The algorithm is robust when facing the timing jitter in the optical frequency comb. Without averaging, the Allan deviation of the results in 1 ms is ∼3.89 µm and the Allan deviation of the results is ∼0.37 µm at an averaging time of 100 ms when the target object is standstill near the NAR. In addition, several ranging experiments were conducted on a mobile target whose speed was from ∼5 mm/s to ∼10 mm/s. The experimental results verify the effectiveness and robustness of our design. The implemented design is an online and real-time data processing unit that shows great industrial potential for using the DCR system.

Method for fabricating large-area gratings with a uniform duty cycle without a spatial beam modulator.

A fabrication method for large-area gratings with uniform duty without using a spatial beam modulator is introduced in this study. The inhomogeneity of gratings caused by flaws of the lens and stray light was solved by controlling exposure time within an appropriate range and selecting a suitable beam expansion aperture in the optical path. A model for representing this process was established by analyzing the effects of exposure and development time length, and experimental results exhibited good agreement with the simulation results. Finally, a grating with a period of 550 nm, a uniform duty cycle, and a diameter larger than 30 mm was achieved using a Mach-Zehnder interferometer optical path without a spatial beam modulator. The uniformity of this grating was observed via atomic force microscopy, and the results were highly desirable.

Mode-resolved dual-comb spectroscopy using error correction based on single optical intermedium.

Dual-comb spectroscopy (DCS) is an emerging and promising spectrometric technique with high resolution, high sensitivity, broad spectral range, and fast acquisition speed. For the recovery of the information encoded on comb modes without resolution loss, two continuous wave lasers are commonly utilized as optical intermedia to track the real-time jitter of dual-comb interferograms. This paper presents a simplified error correction method based on single optical intermedium for quasi-free-running fiber DCS. This method combines the strengths of conventional optical referencing and self-referencing error correction. We acquired whole P branch H13C14N transmittance spectra in the near infrared as a demonstration. In contrast to that of conventional dual intermedium error correction, the standard deviation of our method was merely 0.01 over the 4 THz spectral range. Our method provides a balanced and practical postprocessing routine for high-performance mode-resolved DCS applications.

Phase-stable repetition rate multiplication of dual-comb spectroscopy based on a cascaded Mach-Zehnder interferometer.

In this Letter, we demonstrate a passive all-fiber pulse delay method for repetition rate multiplication of dual-comb spectroscopy. By combining a cascaded Mach-Zehnder interferometer and digital error correction, a mode-resolved spectrum with improved acquisition speed and sensitivity can be obtained. This technique has the strengths of compact, broadband, high energetic efficiency, and low complexity. Due to the use of an adaptive post-processing algorithm, sophisticated closed-loop feedback electronics are not required, which provides a simple and effective scheme to break through the physical limitation of the repetition frequency of the frequency comb for phase-stable dual-comb applications.

Improving Resolution of Dual-Comb Gas Detection Using Periodic Spectrum Alignment Method.

Dual-comb spectroscopy has been an infusive spectroscopic tool for gas detection due to its high resolution, high sensitivity, and fast acquisition speed over a broad spectral range without any mechanical scanning components. However, the complexity and cost of high-performance dual-comb spectroscopy are still high for field-deployed applications. To solve this problem, we propose a simple frequency domain post-processing method by extracting the accurate position of a specific absorption line frame by frame. After aligning real-time spectra and averaging for one second, the absorbance spectrum of H13C14N gas in the near-infrared is obtained over 1.1 THz spectral range. By using this method, the standard deviation of residual error is only ~0.002, showing great agreement with the conventional correction method. In addition, the spectral resolution is improved from 13.4 GHz to 4.3 GHz compared to direct spectrum averaging. Our method does not require a specially designed common-mode suppression comb, rigorous frequency control system, or complicated computational algorithm, providing a cost-effective scheme for field-deployed Doppler-limited spectroscopy applications.

Patterning nanoscale crossed grating with high uniformity by using two-axis Lloyd's mirrors based interference lithography.

A two-axis Lloyd's mirrors interferometer based optical fabrication system was theoretically investigated and constructed for patterning high-uniformity nanoscale crossed grating structures over a large area with a high throughput. The current interferometer was configured with two reflected mirrors and a grating holder, which are placed edge by edge and orthogonal with each other. In such a manner, the two beams reflected from the two mirrors interfere with the incident beam, respectively, forming a crossed grating patterns with only one exposure. Differing from the conventional solution for elimination of unexpected interference between the two reflected beams, a systematical analysis, that is based on the proposed index indicating the non-orthogonality between the two beams at different incident angles, was conducted by using a spatial full polarization tracing method. Without polarization modulation to eliminate the additional interference, an optimal exposure condition with small non-orthogonality between reflected beams was found at a certain incident angle range, while the two required interferences to construct cross grating still remain high. A pattern period of ∼1 µm-level crossed grating structure could be obtained through balancing the structure area and the non-orthogonality. Finally, the exposure setup with orthogonal two-axis Lloyd's mirrors interferometer is established, and the crossed grating structure with the periods of 1076 nm along X-direction and 1091 nm along Y-direction was successfully fabricated on a silicon substrate via microfabrication technology over a large area of 400 mm2. The uniformity of crossed grating array over the whole area was evaluated by an atomic force microscope, and the standard deviations of structure periods along X- and Y-directions smaller than 0.3% are achieved. It is demonstrated that the orthogonal two-axis Lloyd's mirrors interferometer based on single-beam single-exposure scheme with non-orthogonality systematic analysis is an effective approach to fabricate crossed grating patterns of 1 µm-level period with high uniformity over a large area.

Sanguinarine Rapidly Relaxes Rat Airway Smooth Muscle Cells Dependent on TAS2R Signaling.

Excessive contraction of airway smooth muscle cells (ASMCs) is a hallmark feature of asthma. Intriguing, the activation of bitter taste receptor (TAS2R) in ASMCs can relax ASMCs. However, there is a lack of potent TAS2R agonists that can be used in asthma therapies since those tested agonists cannot relax ASMCs at the dose below a few hundred micromolar. Considering that sanguinarine (SA) is a bitter substance often used in small doses for the treatment of asthma in folk medicine, the present study was to determine the rapid relaxation effect of SA on ASMCs and to reveal the underlying mechanisms associated with TAS2R signaling. Here, cell stiffness, traction force, calcium signaling, cAMP levels, and the mRNA expression were evaluated by using optical magnetic twisting cytometry, traction force microscopy, Fluo-4/AM labeling, enzyme-linked immunosorbent assay (ELISA), and quantitative (q)RT-PCR, respectively. We found that 0.5 µM SA immediately decreased cell stiffness and traction force, which is comparable with the effect of 5 µM isoproterenol. In addition, 0.5 µM SA immediately increased intracellular free calcium concentration ([Ca2+]i) and decreased the mRNA expression of contractile proteins such as calponin and α-smooth muscle actin after the treatment for 24 h. Furthermore, SA-mediated decrease in cell stiffness/traction force and increase in [Ca2+]i were significantly blunted by inhibiting the TAS2Rs signaling. These findings establish the rapid relaxation effect of SA at low concentration (<1 µM) on cultured ASMCs depending on TAS2R signaling, indicating that SA might be developed as a useful bronchodilator in asthma therapy.