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.

Ferroelectric compute-in-memory annealer for combinatorial optimization problems.

Computationally hard combinatorial optimization problems (COPs) are ubiquitous in many applications. Various digital annealers, dynamical Ising machines, and quantum/photonic systems have been developed for solving COPs, but they still suffer from the memory access issue, scalability, restricted applicability to certain types of COPs, and VLSI-incompatibility, respectively. Here we report a ferroelectric field effect transistor (FeFET) based compute-in-memory (CiM) annealer for solving larger-scale COPs efficiently. Our CiM annealer converts COPs into quadratic unconstrained binary optimization (QUBO) formulations, and uniquely accelerates in-situ the core vector-matrix-vector (VMV) multiplication operations of QUBO formulations in a single step. Specifically, the three-terminal FeFET structure allows for lossless compression of the stored QUBO matrix, achieving a remarkably 75% chip size saving when solving Max-Cut problems. A multi-epoch simulated annealing (MESA) algorithm is proposed for efficient annealing, achieving up to 27% better solution and ~ 2X speedup than conventional simulated annealing. Experimental validation is performed using the first integrated FeFET chip on 28nm HKMG CMOS technology, indicating great promise of FeFET CiM array in solving general COPs.

BitterDB database analysis plus cell stiffness screening identify flufenamic acid as the most potent TAS2R14-based relaxant of airway smooth muscle cells for therapeutic bronchodilation.

Rationale: Bitter taste receptors (TAS2Rs) are abundantly expressed in airway smooth muscle cells (ASMCs), which have been recognized as promising targets for bitter agonists to initiate relaxation and thereby prevent excessive airway constriction as the main characteristic of asthma. However, due to the current lack of tested safe and potent agonists functioning at low effective concentrations, there has been no clinically approved TAS2R-based drug for bronchodilation in asthma therapy. This study thus aimed at exploring TAS2R agonists with bronchodilator potential by BitterDB database analysis and cell stiffness screening. Methods: Bitter compounds in the BitterDB database were retrieved and analyzed for their working subtype of TAS2R and effective concentration. Compounds activating TAS2R5, 10, and 14 at < 100 µM effective concentration were identified and subsequently screened by cell stiffness assay using optical magnetic twisting cytometry (OMTC) to identify the most potent to relax ASMCs. Then the compound identified was further characterized for efficacy on various aspects related to relaxation of ASMCs, incl. but not limited to traction force by Fourier transform traction force microscopy (FTTFM), [Ca2+]i signaling by Fluo-4/AM intensity, cell migration by scratch wound healing, mRNA expression by qPCR, and protein expressing by ELISA. The compound identified was also compared to conventional ß-agonist (isoproterenol and salbutamol) for efficacy in reducing cell stiffness of cultured ASMCs and airway resistance of ovalbumin-treated mice. Results: BitterDB analysis found 18 compounds activating TAS2R5, 10, and 14 at < 100 µM effective concentration. Cell stiffness screening of these compounds eventually identified flufenamic acid (FFA) as the most potent compound to rapidly reduce cell stiffness at 1 µM. The efficacy of FFA to relax ASMCs in vitro and abrogate airway resistance in vivo was equivalent to that of conventional ß-agonists. The FFA-induced effect on ASMCs was mediated by TAS2R14 activation, endoplasmic reticulum Ca2+ release, and large-conductance Ca2+-activated K+ (BKCa) channel opening. FFA also attenuated lipopolysaccharide-induced inflammatory response in cultured ASMCs. Conclusions: FFA as a potent TAS2R14 agonist to relax ASMCs while suppressing cytokine release might be a favorite drug agent for further development of TAS2R-based novel dual functional medication for bronchodilation and anti-inflammation in asthma 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.

Ferroelectric FET-based context-switching FPGA enabling dynamic reconfiguration for adaptive deep learning machines.

Field programmable gate array (FPGA) is widely used in the acceleration of deep learning applications because of its reconfigurability, flexibility, and fast time-to-market. However, conventional FPGA suffers from the trade-off between chip area and reconfiguration latency, making efficient FPGA accelerations that require switching between multiple configurations still elusive. Here, we propose a ferroelectric field-effect transistor (FeFET)-based context-switching FPGA supporting dynamic reconfiguration to break this trade-off, enabling loading of arbitrary configuration without interrupting the active configuration execution. Leveraging the intrinsic structure and nonvolatility of FeFETs, compact FPGA primitives are proposed and experimentally verified. The evaluation results show our design shows a 63.0%/74.7% reduction in a look-up table (LUT)/connection block (CB) area and 82.7%/53.6% reduction in CB/switch box power consumption with a minimal penalty in the critical path delay (9.6%). Besides, our design yields significant time savings by 78.7 and 20.3% on average for context-switching and dynamic reconfiguration applications, respectively.

High Stretch Modulates cAMP/ATP Level in Association with Purine Metabolism via miRNA-mRNA Interactions in Cultured Human Airway Smooth Muscle Cells.

High stretch (>10% strain) of airway smooth muscle cells (ASMCs) due to mechanical ventilation (MV) is postulated to contribute to ventilator-induced lung injury (VILI), but the underlying mechanisms remain largely unknown. We hypothesized that ASMCs may respond to high stretch via regulatory miRNA-mRNA interactions, and thus we aimed to identify high stretch-responsive cellular events and related regulating miRNA-mRNA interactions in cultured human ASMCs with/without high stretch. RNA-Seq analysis of whole genome-wide miRNAs revealed 12 miRNAs differentially expressed (DE) in response to high stretch (7 up and 5 down, fold change >2), which target 283 DE-mRNAs as identified by a parallel mRNA sequencing and bioinformatics analysis. The KEGG and GO analysis further indicated that purine metabolism was the first enriched event in the cells during high stretch, which was linked to miR-370-5p-PDE4D/AK7. Since PDE4D/AK7 have been previously linked to cAMP/ATP metabolism in lung diseases and now to miR-370-5p in ASMCs, we thus evaluated the effect of high stretch on the cAMP/ATP level inside ASMCs. The results demonstrated that high stretch modulated the cAMP/ATP levels inside ASMCs, which could be largely abolished by miR-370-5p mimics. Together, these findings indicate that miR-370-5p-PDE4D/AK7 mediated high stretch-induced modulation of cAMP and ATP synthesis inside ASMCs. Furthermore, such interactive miRNA-mRNA pairs may provide new insights for the discovery of effective biomarkers/therapeutic targets for the diagnosis and treatment of VILI and other MV-associated respiratory diseases.

Metabolomics study reveals increased deoxycholic acid contributes to deoxynivalenol-mediated intestinal barrier injury.

AIMS: Deoxynivalenol (DON), namely vomitoxin, is one of the most prevalent fungal toxins in cereal crops worldwide. However, the underlying toxic mechanisms of DON remain largely unknown. MAIN METHODS: DON exposure-caused changes in the murine plasma metabolome and gut microbiome were investigated by an LC-MS/MS-based nontargeted metabolomics approach and sequencing of 16S rRNA in fecal samples, respectively. Cellular models were then used to validate the findings from the metabolomics study. KEY FINDINGS: DON exposure increased intestinal barrier permeability evidenced by its-mediated decrease in colonic Claudin 5 and E-cadherin, as well as increases in colonic Ifn-γ, Cxcl9, Cxcl10, and Cxcr3. Furthermore, DON exposure resulted in a significant increase in murine plasma levels of deoxycholic acid (DCA). Also, DON exposure led to gut microbiota dysbiosis, which was associated with DON exposure-caused increase in plasma DCA. In addition, we found not only DON but also DCA dose-dependently caused a significant increase in the levels of IFN-γ, CXCL9, CXCL10, and/or CXCR3, as well as a significant decrease in the expression levels of Claudin 5 and/or E-cadherin in the human colonic epithelial cells (NCM460). SIGNIFICANCE: DON-mediated increase in DCA contributes to DON-caused intestinal injury. DCA may be a potential therapeutic target for DON enterotoxicity.

Enhancing ion mobility spectrometry performance through a programmable ion swarm shaping method based on Bradbury-Nielsen gates.

The ion gate is a critical element in drift tube ion mobility spectrometry (IMS) as it directly influences the resolving power and sensitivity of the system. However, the conventional Bradbury-Nielsen gate (BNG) often leads to deformation of the ion swarm shape, resulting in reduced resolving power and significant discrimination effects. To address these limitations, we propose a novel method that incorporates a cutting phase following the gate opening. This approach effectively reduces trailing edge deformation, resulting in a maximum resolving power of over 100 and increased signal intensity. Additionally, this method maintains high resolving power even during longer gate opening times. Remarkably, this method not only significantly reduces the mobility discrimination effect but also enables the achievement of reverse discrimination by adjusting the duration of the cutting phase. Consequently, it demonstrates the potential to selectively amplify the peak height of target ions. Our method offers straightforward implementation across all IMS systems utilizing the BNG, thereby significantly improving system performance.

Embedding security into ferroelectric FET array via in situ memory operation.

Non-volatile memories (NVMs) have the potential to reshape next-generation memory systems because of their promising properties of near-zero leakage power consumption, high density and non-volatility. However, NVMs also face critical security threats that exploit the non-volatile property. Compared to volatile memory, the capability of retaining data even after power down makes NVM more vulnerable. Existing solutions to address the security issues of NVMs are mainly based on Advanced Encryption Standard (AES), which incurs significant performance and power overhead. In this paper, we propose a lightweight memory encryption/decryption scheme by exploiting in-situ memory operations with negligible overhead. To validate the feasibility of the encryption/decryption scheme, device-level and array-level experiments are performed using ferroelectric field effect transistor (FeFET) as an example NVM without loss of generality. Besides, a comprehensive evaluation is performed on a 128 × 128 FeFET AND-type memory array in terms of area, latency, power and throughput. Compared with the AES-based scheme, our scheme shows ~22.6×/~14.1× increase in encryption/decryption throughput with negligible power penalty. Furthermore, we evaluate the performance of our scheme over the AES-based scheme when deploying different neural network workloads. Our scheme yields significant latency reduction by 90% on average for encryption and decryption processes.

Powering Disturb-Free Reconfigurable Computing and Tunable Analog Electronics with Dual-Port Ferroelectric FET.

Single-port ferroelectric FET (FeFET) that performs write and read operations on the same electrical gate prevents its wide application in tunable analog electronics and suffers from read disturb, especially in the high-threshold voltage (VTH) state as the retention energy barrier is reduced by the applied read bias. To address both issues, we propose to adopt a read disturb-free dual-port FeFET where the write is performed on the gate featuring a ferroelectric layer and the read is done on a separate gate featuring a nonferroelectric dielectric. Combining the unique structure and the separate read gate, read disturb is eliminated as the applied field is aligned with polarization in the high-VTH state, thus improving its stability, while it is screened by the channel inversion charge and exerts no negative impact on the low-VTH state stability. Comprehensive theoretical and experimental validation has been performed on fully depleted silicon-on-insulator (FDSOI) FeFETs integrated on a 22 nm platform, which intrinsically has dual ports with its buried oxide layer acting as the nonferroelectric dielectric. Novel applications that can exploit the proposed dual-port FeFET are proposed and experimentally demonstrated for the first time, including FPGA that harnesses its read disturb-free feature and tunable analog electronics (e.g., frequency tunable ring oscillator in this work) leveraging the separated write and read paths.

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.

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.

Successful Retreatment with Crizotinib After Crizotinib-Induced Liver Failure in ALK-Positive Advanced Lung Adenocarcinoma: A Case Report.

Patients with non-small cell lung cancer (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangements are treated with crizotinib. However, treatment with crizotinib is often discontinued owing to hepatotoxicity. Herein, we report a case of crizotinib-induced liver failure that was successfully treated. A 70-year-old woman complained of a cough with blood in her sputum and presented to our hospital in September 2020. Imaging examination revealed a mass in the middle and lower lobes of the right lung invading the right pulmonary artery and metastases to the right hilar lymph nodes and pleura. A stage IVa (cT4N1M1a) lung adenocarcinoma with ALK fusion was diagnosed. The patient received crizotinib, an ALK tyrosine kinase inhibitor and achieved partial remission. However, she suffered from acute liver failure, which led to the cessation of treatment. The patient was started on a liver protection treatment, and the liver function subsequently recovered. One year later, crizotinib was readministered at a half-dose because of disease progression, and the patient achieved stable disease without hepatotoxicity for 9 months. Therefore, the patient benefited from crizotinib without hepatotoxicity one year after acute liver failure caused by crizotinib.

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.

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.

CMOS-compatible ising machines built using bistable latches coupled through ferroelectric transistor arrays.

Realizing compact and scalable Ising machines that are compatible with CMOS-process technology is crucial to the effectiveness and practicality of using such hardware platforms for accelerating computationally intractable problems. Besides the need for realizing compact Ising spins, the implementation of the coupling network, which describes the spin interaction, is also a potential bottleneck in the scalability of such platforms. Therefore, in this work, we propose an Ising machine platform that exploits the novel behavior of compact bi-stable CMOS-latches (cross-coupled inverters) as classical Ising spins interacting through highly scalable and CMOS-process compatible ferroelectric-HfO2-based Ferroelectric FETs (FeFETs) which act as coupling elements. We experimentally demonstrate the prototype building blocks of this system, and evaluate the scaling behavior of the system using simulations. Our work not only provides a pathway to realizing CMOS-compatible designs but also to overcoming their scaling challenges.

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.

Emerging toolset of three-dimensional pulmonary cell culture models for simulating lung pathophysiology towards mechanistic elucidation and therapeutic treatment of SARS-COV-2 infection.

The ongoing COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) poses a never before seen challenge to human health and the world economy. However, it is difficult to widely use conventional animal and cell culture models in understanding the underlying pathological mechanisms of COVID-19, which in turn hinders the development of relevant therapeutic treatments, including drugs. To overcome this challenge, various three-dimensional (3D) pulmonary cell culture models such as organoids are emerging as an innovative toolset for simulating the pathophysiology occurring in the respiratory system, including bronchial airways, alveoli, capillary network, and pulmonary interstitium, which provide a robust and powerful platform for studying the process and underlying mechanisms of SARS-CoV-2 infection among the potential primary targets in the lung. This review introduces the key features of some of these recently developed tools, including organoid, lung-on-a-chip, and 3D bioprinting, which can recapitulate different structural compartments of the lung and lung function, in particular, accurately resembling the human-relevant pathophysiology of SARS-CoV-2 infection in vivo. In addition, the recent progress in developing organoids for alveolar and airway disease modeling and their applications for discovering drugs against SARS-CoV-2 infection are highlighted. These innovative 3D cell culture models together may hold the promise to fully understand the pathogenesis and eventually eradicate the pandemic of COVID-19.

Modeling the modulation characteristics of the Bradbury-Nielsen gate in ion mobility spectrometers.

The Bradbury-Nelson gate (BNG) is a common device used for ion control in time-of-flight mass spectrometry and ion mobility spectrometry (IMS). A dual-location control model was employed in order to better understand the behavior of ions around a modulated BNG. This model illustrated that the ions are released from the starting location and truncated at the cutoff location. The shapes of the starting and cutoff locations are both curved with similar curvature, and the cutoff location is situated further back. Therefore, the distance between the two locations is a key parameter leading to the ion loss during modulation and is influenced by the gating voltage difference. Through simulations and experiments, the ion loss is verified to increase with the increase in the gating voltage difference. Taking a Fourier transform IMS as an example, by reducing the gating voltage difference from 150 to 50 V, the signal-to-noise ratio of the time domain result was improved from 91.7 to 386.5 and the resolving power was improved from 40.9 to 63.6. In addition, the superposition effect of multicycle modulation is shown and explained by the model. When the modulated frequency is too rapid and the closing time is insufficient for all the ions to be consumed, some ions continue to exist between the two locations, and the residual ions then enter the drift region during the next few cycles. This phenomenon needs to be avoided because the total number of ions entering the drift region will then increase uncontrollably.