Adjacent Cells Research Articles

A thermal management design using phase change material in embedded finned shells for lithium-ion batteries

Phase change material (PCM) has recently been regarded as a promising thermal management means for lithium-ion (Li-ion) batteries. However, solid-liquid phase change of many current PCMs occurs in a narrow temperature range, and the cooling performance of their liquid phase is rather poor. To tackle these issues, this article presents a battery thermal management (BTM) design which injects PCM into an aluminum shell around each cell, and machines the shell inner surfaces into a row of straight rectangular fins immersed into the PCM and its outer surfaces into a plain-fin shape exposed in the air. In the mild thermal conditions, the finned shells of two adjacent cells can be embedded and passive PCM cooling is employed. Once the PCM completely melts, the shells will move apart and an airflow will be driven through the gap between them. The BTM design can also protect Li-ion batteries in a freezing environment, by taking advantage of PCM solidification when the finned shells return to their embedded configuration. A series of experiments were conducted to examine its effectiveness on two 50Ah lithium nickel cobalt manganese oxide (NCM) prismatic batteries, which were discharged at a capacity-rate of 2C and at room temperatures of T0=25∘C, 40∘C and −10∘C. It is shown that in the battery discharge at T0=25∘C, PCM in the embedded finned shells effectively reduced the average battery-surface temperature (T¯) and the maximum temperature difference (ΔTmax) by 21% and 36.7%, respectively, compared to bare batteries. At T0=40∘C, this BTM design successfully limited the growth of T¯ to 9.0∘C and led to ΔTmax no more than 1.5∘C. As to the low-temperature scenario, it maintained the batteries at temperatures above T0 for 55.2% longer than those without any BTM protections. Its cooling performance was also compared with that of the conventional liquid-cooling scheme using a bottom serpentine-channel cooling plate. All these results clearly demonstrate that the BTM design in this article can compensate for the deficiencies of conventional PCM-based BTM schemes. Regardless of whether the PCM phase change is available, it has well coped with different thermal management demands of Li-ion batteries.

Design of 2.5-D Miniaturized Frequency Selective Surface with Enhanced Oblique Stability

Abstract This paper presents a miniaturized 2.5-D frequency selective surface (FSS) that exhibits a band stop response at frequency of 1.5 GHz. In the unit cell, the meander patterns on both sides of the substrate are connected in series by four vias. Moreover, the meandered pattern in each quadrant is also connected with one of the meander patterns of the adjacent unit cell. In this manner, a 2.5-D closed loop is created with large perimeter. The enlarged perimeter amplifies the effective inductance and leads to a decrease in both the resonant frequency and the dimensions of unit cell. Subsequently, the proposed FSS demonstrates excellent miniaturization with an overall size of 0.038 λ0 × 0.038 λ0. Moreover, the frequency response is highly stable up to 86° for both TE and TM polarization. The resonance mechanism of the designed FSS is explicated through distribution of surface current and electric field. The testing board of the proposed FSS has been fabricated for the verification of the design. The measured frequency response of the prototype are congruent with the simulation results. The distinguished features of the constructed structure are enhanced angular stability, miniaturized unit cell, low profile, simple geometry and easy fabrication.

Intracellular Calcium Dynamics in Primary Human Adrenocortical Cells Deciphered with a Novel Pipeline.

The fluctuations of the intracellular Ca2+ concentration ([Ca2+]i) are key physiological signals for cell function under normal conditions and can undergo profound alterations in disease states, as high blood pressure due to endocrine disorders like primary aldosteronism (PA). However, when assessing such fluctuations several parameters in the Ca2+ signal dynamics need to be considered, which renders their assessmentchallenging. Aimto develop an observer-independent custom-made pipeline to analyze Ca2+ dynamics in terms of frequency and peak parameters, as amplitude, full width at half maximum (FWHM) and area under the curve (AUC). We applied a custom-made methodology to aldosterone-producing adenoma (APA) and APA adjacent cells (AAC) and found this pipeline to be suitable for monitoring and processing a wide-range of [Ca2+]i events in these cell types delivering reproducible results. The designed pipeline can provide a useful tool for [Ca2+]i signal analysis that allows comparisons of Ca2+ dynamics not only in PA, but in other cell phenotypes that are relevant for the regulation of blood pressure.

Single-cell transcriptomic landscape and the microenvironment of normal adjacent tissues in hypopharyngeal carcinoma.

The cellular origin of hypopharyngeal diseases is crucial for further diagnosis and treatment, and the microenvironment in tissues may also be associated with specific cell types at the same time. Normal adjacent tissues (NATs) of hypopharyngeal carcinoma differ from non-tumor-bearing tissues, and can influenced by the tumor. However, the heterogeneity in kinds of disease samples remains little known, and the transcriptomic profile about biological information associated with disease occurrence and clinical outcome contained in it has yet to be fully evaluated. For these reasons, we should quickly investigate the taxonomic and transcriptomic information of NATs in human hypopharynx. Single-cell suspensions of normal adjacent tissues (NATs) of hypopharyngeal carcinoma were obtained and single-cell RNA sequencing (scRNA-seq) was performed. We present scRNA-seq data from 39,315 high-quality cells in the hypopharyngeal from five human donors, nine clusters of normal adjacent human hypopharyngeal cells were presented, including epithelial cells, endothelial cells (ECs), mononuclear phagocyte system cells (MPs), fibroblasts, T cells, plasma cells, B cells, mural cells and mast cells. Nonimmune components in the microenvironment, including epithelial cells, endothelial cells, fibroblasts and the subpopulations of them were performed. Our data provide a solid basis for the study of single-cell landscape in human normal adjacent hypopharyngeal tissues biology and related diseases.

A mathematical model on the propagation of tau pathology in neurodegenerative diseases.

A system of partial differential equations is developed to study the spreading of tau pathology in the brain for Alzheimer's and other neurodegenerative diseases. Two cases are considered with one assuming intracellular diffusion through synaptic activities or the nanotubes that connect the adjacent cells. The other, in addition to intracellular spreading, takes into account of the secretion of the tau species which are able to diffuse, move with the interstitial fluid flow and subsequently taken up by the surrounding cells providing an alternative pathway for disease spreading. Cross membrane transport of the tau species are considered enabling us to examine the role of extracellular clearance of tau protein on the disease status. Bifurcation analysis is carried out for the steady states of the spatially homogeneous system yielding the results that fast cross-membrane transport combined with effective extracellular clearance is key to maintain the brain's healthy status. Numerical simulations of the first case exhibit solutions of travelling wave form describing the gradual outward spreading of the pathology; whereas the second case shows faster spreading with the buildup of neurofibrillary tangles quickly elevated throughout. Our investigation thus indicates that the gradual progression of the intracellular spreading case is more consistent with the clinical observations of the development of Alzheimer's disease.

Dual sources of melatonin and evidence for different primary functions.

This article discusses data showing that mammals, including humans, have two sources of melatonin that exhibit different functions. The best-known source of melatonin, herein referred to as Source #1, is the pineal gland. In this organ, melatonin production is circadian with maximal synthesis and release into the blood and cerebrospinal fluid occurring during the night. Of the total amount of melatonin produced in mammals, we speculate that less than 5% is synthesized by the pineal gland. The melatonin rhythm has the primary function of influencing the circadian clock at the level of the suprachiasmatic nucleus (the CSF melatonin) and the clockwork in all peripheral organs (the blood melatonin) via receptor-mediated actions. A second source of melatonin (Source # 2) is from multiple tissues throughout the body, probably being synthesized in the mitochondria of these cells. This constitutes the bulk of the melatonin produced in mammals and is concerned with metabolic regulation. This review emphasizes the action of melatonin from peripheral sources in determining re-dox homeostasis, but it has other critical metabolic effects as well. Extrapineal melatonin synthesis does not exhibit a circadian rhythm and it is not released into the blood but acts locally in its cell of origin and possibly in a paracrine matter on adjacent cells. The factors that control/influence melatonin synthesis at extrapineal sites are unknown. We propose that the concentration of melatonin in these cells is determined by the subcellular redox state and that melatonin synthesis may be inducible under stressful conditions as in plant cells.

From genetic mosaicism to tumorigenesis through indirect genetic effects.

Genetic mosaicism has long been linked to aging, and several hypotheses have been proposed to explain the potential connections between mosaicism and susceptibility to cancer. It has been proposed that mosaicism may disrupt tissue homeostasis by affecting intercellular communications and releasing microenvironmental constraints within tissues. The underlying mechanisms driving these tissue-level influences remain unidentified, however. Here, we present an evolutionary perspective on the interplay between mosaicism and cancer, suggesting that the tissue-level impacts of genetic mosaicism can be attributed to Indirect Genetic Effects (IGEs). IGEs can increase the level of cellular stochasticity and phenotypic instability among adjacent cells, thereby elevating the risk of cancer development within the tissue. Moreover, as cells experience phenotypic changes in response to challenging microenvironmental conditions, these changes can initiate a cascade of nongenetic alterations, referred to as Indirect non-Genetic Effects (InGEs), which in turn catalyze IGEs among surrounding cells. We argue that incorporating both InGEs and IGEs into our understanding of the process of oncogenic transformation could trigger a major paradigm shift in cancer research with far-reaching implications for practical applications.

Physical insight into turn‐on transient of silicon carbide gate turn‐off thyristor

AbstractSilicon Carbide (SiC) Gate Turn‐off (GTO) thyristor is regarded as a promising option for pulsed power applications; however, the formation of high di/dt has been constrained by the slow current rise transient phase and the turn‐on current heterogeneity over the chip device. In this paper, a practical integrated multi‐cell simulation is performed to physically characterize the turn‐on transient of SiC GTO thyristor. Through examining electrical coupling between adjacent cells caused by both parasitics of electrode metallization and carrier travelling via SiC, the current distributions are observed, and the carrier transport dynamics are analyzed in detail. Furthermore, physical mechanisms dominating the current heterogeneity among multi‐cells are discovered in depth. It is revealed that the current heterogeneity during the turn‐on transient is primarily resulted from the Gate signal delay caused by the Gate Runner metallization, and the lateral interaction from adjacent semiconductor regions adds to this inhomogeneity; however, this situation can be improved once the electrical distance between each Anode contact and the Anode electrode gets lowered. Design method for turn‐on performance improvement is also proposed accordingly. Besides, based on the analysis conducted on the multi‐cell simulation results, the possible reason of the extremely slow current rise transient phase is speculated and experimentally verified. The improvement in the comprehension of SiC GTO's turn‐on transient, which cannot be obtained from the traditional investigation from the viewpoint of one elementary cell, will provide guiding principles helping in directing future efforts to advance the improvement of device design technology.

Abstract PO1-15-05: Gene expression signature as a predictor of pathological complete response to neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab treatment in locally advanced HER2-positive breast cancer

Abstract Background: Neoadjuvant pertuzumab and trastuzumab in combination with chemotherapy can achieve pathological complete response (pCR, defined as ypT0/is ypN0) in approximately 40–60% of patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC). Patients who achieve pCR have significantly improved survival. Therefore, the prediction of pCR is crucial for optimizing neoadjuvant therapy. Methods: To identify a gene expression signature that could predict pCR in patients with HER2+ BC, we used the nCounter Breast Cancer 360TM V2 panel to quantify the expression of 758 genes in 104 HER2+ BC samples from patients who received neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) chemotherapy and subsequent curative breast surgery. Data normalization, differentially expressed gene (DEG) analysis, and gene set enrichment analysis (GSEA) were performed using the NanoTube Bioconductor package. Using the elastic net logistic regression model with optimal hyperparameters determined by 5-fold cross-validation (5-CV), we developed a chemosensitivity score based on the expression of significant DEGs (genes with absolute log2-fold-change ≥0.5 and q-value < 0.1). We tested its predictive value for pCR using multivariable logistic regression analysis. Results: The median age at diagnosis was 49.5 years. The clinical stage was II in 53 (51%) patients and III in 51 (49%) patients at diagnosis. Ninety (86.5%) patients had a HER2 immunohistochemistry (IHC) score of 3+, while the remaining 14 (13.5%) patients had HER2 IHC 2+ but HER2 amplification detected by in situ hybridization. Pathological evaluation of surgical specimens revealed that 55 (52.9%) patients achieved pCR. Menopausal status (p = 0.01), PAM50 intrinsic subtype (p = 0.002), hormone receptor (HR) status (p < 0.001), and HER2 IHC score (p = 0.019) were significantly correlated with the pCR rate. DEG analysis using the PAM50 intrinsic subtype, HR status, and HER2 IHC score as covariates revealed 6 downregulated DEGs and 33 upregulated DEGs in patients who achieved pCR compared to patients who did not (Table 1). The 39 DEGs were significantly enriched in nine preselected MSigDB hallmark gene sets representing immunological processes (p < 0.001). The optimal elastic net logistic regression model containing 39 DEGs achieved the mean 5-CV area under the receiver operating characteristic curve of 0.81. The chemosensitivity score calculated using the optimal model parameters was significantly correlated with pCR after adjustment for the PAM50 intrinsic subtype, HR status, and HER2 IHC score (p < 0.001). GSEA revealed eight hallmark gene sets that were significantly up- or downregulated in samples with pCR, including epithelial-mesenchymal transition (normalized enrichment score [NES] = -2.16; q < 0.001), late estrogen response (NES = -2.01; q = 0.004), early estrogen response (NES = -1.972; q = 0.005), and inflammatory response (NES = 1.53; q = 0.06). Conclusion: Our findings demonstrate that gene expression patterns can predict the response to neoadjuvant TCHP chemotherapy in HER2+ BC. The functional characterization of 39 DEGs suggests that the tumor microenvironment, including adjacent immune cells, plays a significant role in modulating the response to neoadjuvant chemotherapy in HER2+ BC. Table 1. Significant DEGs Citation Format: Junghoon Shin, Ji-Yeon Kim, Eun Yoon Cho, Seok Won Kim, Jeong Eon Lee, Hyunwoo Lee, Yeon Hee Park, Jin Seok Ahn, Young-Hyuck Im. Gene expression signature as a predictor of pathological complete response to neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab treatment in locally advanced HER2-positive breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-15-05.

Abstract PO2-28-08: A spatial transcriptomic study of a triple-negative breast cancer (TNBC) patient-derived xenograft (PDX) model of residual disease refractory to conventional chemotherapy

Abstract TNBC is one of the most aggressive subtypes of breast cancer. Combating chemotherapy resistance is critical to improving quality of care and reducing fatality among TNBC patients. In order to understand the mechanisms of chemoresistance in TNBC tumors, it has been proposed that the spatial interactions between cell types in the tumor microenvironment (TME) could offer insights into the differential response to therapy among tumors, and metastatic potential of certain tumors over others. Thus, this study utilizes spatially resolved transcriptomic (SRT) technology to profile the spatial interactions in the TNBC TME. With the goal of better understanding chemoresistance in TNBC and providing a proof-of-concept for new technology, we have launched a longitudinal SRT study of a TNBC PDX of residual disease before, during, and after adriamycin and cyclophosphamide (AC) treatment (Tx). SRT by 10X Genomics Visium was performed on vehicle, AC-treated residual tumor (21 days post-Tx), and AC-treated regrown tumor (50 days post-Tx when tumors regrew to starting tumor volume). This study is divided into two parts: 1) development of a computational pipeline; 2) spatial colocalization analysis of residual and regrown tumors to understand chemoresistance. PART 1: Due to the lack of specialized tools for processing and sorting xenograft reads from SRT data, we developed the Xenomake pipeline, which combines a xenograft sorting algorithm (Xengsort) and spatial barcode demultiplexing pipeline to assign reads into the host and graft organisms for each spatial spot. RESULTS: Xenomake permits clustering the spatial spots into stroma-rich (enriched for mouse mRNAs), and epithelial-rich (enriched for human mRNAs) regions. We show that Xenomake can find differential cytokine production in the stroma and epithelium. Since PDX data separate the tumor into stroma and epithelium by organism, the pipeline enables fine-tuned downstream analysis such as stromal-stromal and stromal-epithelial interactions. Xenomake is thus generally applicable for SRT involving PDX samples. PART 2: Previously we detailed patterns of tumor regression into a residual tumor state, followed by uncontrolled regrowth in the absence of treatment in multiple PDX models of TNBC. Although using PDX models necessitates immune-compromised mice, several types of stromal populations are present and analyzable in these models. Thus, using organism-assigned reads processed by Xenomake, we computationally inferred the localization pattern of stromal cell types in Visium spots including cancer associated fibroblasts (CAF), macrophages (MP), endothelial cells (ENDO), monocytes, and perivascular-like cells. We compared the spatial localization profiles (SLP) of stromal cell types across samples. With human reads, we computed the spatial pathway activity map (SPAM) for the ~30 HALLMARK pathways across samples. We correlated the patterns of SPAM with stroma cell-type SLP to survey the stroma-epithelial interactions across samples. RESULTS: Stroma cells are generally distributed in the tumor periphery in vehicle and AC50, while in AC21 there is a notable increase in stroma abundance and stroma infiltration within tumor mass. SLP of MP (Cd68+ and Csf1r+) is correlated with ENDO (Pecam1+), and with CAF (Acta2+ and Pdgfrb+). Additionally, all 3 cell types are correlated with Vim and Cd44 expression. Although all samples show enrichment of MP, ENDO, and CAF, they interact differently with pathway activities of adjacent epithelial cells. In vehicle and AC50, the 3 cell types are colocalized with OXPHOS, MYC targets, E2F pathway, while in AC21, a switch to colocalization with EMT is observed. Furthermore, hypoxia response and glycolysis display anti-correlation with stroma cell types, meaning that these pathway activities are further away from stroma and occupy distinct territories. The results suggest stroma-tumor metabolic crosstalk and ways of targeting residual disease. Citation Format: Benjamin Strope, Katherine Pendleton, William Bowie, Gloria Echeverria, Qian Zhu. A spatial transcriptomic study of a triple-negative breast cancer (TNBC) patient-derived xenograft (PDX) model of residual disease refractory to conventional chemotherapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-28-08.

Simulation of Conducted Responses in Microvascular Networks: Role of Current Rectification by Endothelial Cell Gap Junctions

Neuronal activity in the brain stimulates local increases in blood flow. Such flow increases require dilation of feeding arterioles, which can be initiated by upstream conducted responses in the form of electrical currents transmitted along the endothelial lining of the vessels. One potential trigger for this response is hyperpolarization of capillary endothelial cells in active regions resulting from local elevation of extracellular K+ concentration. The conducted hyperpolarization causes arteriolar dilation. For this mechanism to be effective in delivering increased flow to a specific location, the conducted response must travel in the upstream direction only, without reentry into adjacent parallel flow pathways. Such specificity in the response to activation has been observed in skeletal muscle, and may result from partial rectification of current in gap junctions connecting adjacent endothelial cells. The goal of this work is to simulate the spread of hyperpolarizing currents along vessel walls in microvascular networks of the cerebral circulation, including the effects of rectification in gap junctions. A theoretical model was developed for the spread of electrical current in the endothelial cells of a network of microvessels in response to local K+- induced hyperpolarization. Transmembrane currents are represented in the model by a KIR-channel conductance, a non-voltage-dependent K+ conductance, and a background conductance. Currents along vessel walls are represented assuming asymmetric gap junction conductance between adjacent endothelial cells, with higher conductance for downstream currents (causing upstream hyperpolarization) than for upstream currents. The model was applied to a synthetic network of 45 segments, assuming 20 nS conductance for upstream propagation, while a range of values was used for downstream propagation. The model shows effective upstream propagation of conducted responses when the gap junction conductance for downstream propagation is 1 nS or less. This result was confirmed in a simulation of a reconstructed murine cerebral cortex network with 4881 segments. In conclusion, partial current rectification by endothelial gap junctions can result in preferential upstream propagation of conducted responses, consistent with experimental observations of local flow regulation. Supported by NIH grant U01 HL133362. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Regulation of cardiac fibroblasts reprogramming into cardiomyocyte-like cells with a cocktail of small molecule compounds.

Myocardial infarction results in extensive cardiomyocyte apoptosis, leading to the formation of noncontractile scar tissue. Given the limited regenerative capacity of adult mammalian cardiomyocytes, direct reprogramming of cardiac fibroblasts (CFs) into cardiomyocytes represents a promising therapeutic strategy for myocardial repair, and small molecule drugs might offer a more attractive alternative to gene editing approaches in terms of safety and clinical feasibility. This study aimed to reprogram rat CFs into cardiomyocytes using a small molecular chemical mixture comprising CHIR99021, Valproic acid, Dorsomorphin, SB431542, and Forskolin. Immunofluorescence analysis revealed a significant increase in the expression of cardiomyocyte-specific markers, including cardiac troponin T (cTnT), Connexin 43 (Cx43), α-actinin, and Tbx5. Changes in intracellular calcium ion levels and Ca2+ signal transfer between adjacent cells were monitored using a calcium ion fluorescence probe. mRNA sequencing analysis demonstrated the upregulation of genes associated with cardiac morphogenesis, myocardial differentiation, and muscle fiber contraction during CF differentiation induced by the small-molecule compounds. Conversely, the expression of fibroblast-related genes was downregulated. These findings suggest that chemical-induced cell fate conversion of rat CFs into cardiomyocyte-like cells is feasible, offering a potential therapeutic solution for myocardial injury.

Multiphysics integrated model of NMC111 battery module for micro-mobility applications using PCM as intercell material

The widespread use of e-bikes and e-scooters powered by lithium-ion batteries in urban settings has heightened safety concerns, particularly the risk of thermal runaway, which can result in dangerous incidents. The surge in battery-related fire incidents highlights the critical need for a deep understanding of thermal runaway phenomena. This study addresses this imperative by introducing a Multiphysics model combining pseudo-bidimensional electrochemical for simulating electrical performance, lumped thermal model for simulating the heat transfer behavior inside the module, and a thermal runaway kinetic model for propagation evaluation. This approach facilitates precise predictions of battery performance and proactively addresses safety concerns by incorporating thermal behavior simulations and predicting potential thermal runaway events. The model proposed allows the evaluation of different strategies for improving battery safety and performance, such as phase change materials and thermal insulators. Simulations reveal that implementing sodium hydrogen phosphate dodecahydrate (Na2HPO4··12H2O) as an intercell material substantially enhances thermal management. This material reduced the maximum temperature of the battery module by up to 30% during critical thermal runaway events. Additionally, it slowed the rate of temperature increase by 50%, significantly decreasing the possibility of adjacent cells reaching thermal runaway conditions. The research findings demonstrate the effectiveness of advanced thermal management strategies using PCMs to prevent potentially catastrophic thermal events in battery modules typical of micro-mobility devices.

Reinforcement mechanism and the stress-strain behaviors of geocells made by non-woven geotextile

Geocell is one of the most widely employed geosynthetics for reinforcing soil beds across diverse applications, including base layer pavement and various structures such as embankments, foundations, and retaining walls. Its reinforcement mechanisms encompass both vertical and lateral cellular confinement, enhancing load distribution. Geocells are commonly made from polymer networks like high-density polyethylene (HDPE), non-woven geotextiles, and geogrids. Each type of geocell offers special advantages and effects on the reinforcement mechanism for the soil bed, dependent on material stiffness and effective opening size. This paper aims to assess both the reinforcement mechanism and stress–strain behavior of geocells (made by non-woven geotextile). To this end, three series of plate-loading tests were conducted on reinforced sand beds. The reinforcement configurations included single cells as well as multi-cells arranged in predetermined patterns. The experiments enabled us to determine bearing capacity, vertical surface displacement and axial strain of cell wall for different pocket sizes and numbers of cells. The results suggest that cells with pocket sizes matching the diameter of the loading plate exhibit superior performance. Furthermore, a comparative analysis between performance of single cells and multi-cells revealed that incorporating adjacent cells, particularly for geocells with smaller pocket sizes, significantly mitigates loading plate settlement. In addition, the results showed that the axial strain and deformation applied on non-woven geotextiles were more pronounced for smaller pocket sizes than for cells with larger pocket sizes.

Single-cell RNA-seq analysis of cell-cell communications in human lung reveals a novel role of VEGF-D in acute lung injury

BACKGROUND: Vascular disorders are a prominent pathological feature across many pulmonary diseases, such as acute lung injury (ALI) or acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and COVID-19. Paracrine signals are enriched throughout the lung tissue and are critical in maintaining functional microvascular homeostasis. In this study, we applied comprehensive computational tools to analyze single-cell RNA-seq (scRNAseq) datasets in healthy and diseased lungs and identified a local component in human lung microvascular niche VEGF-D exhibiting barrier protective property in ALI/ARDS animal models. METHODS: Leveraging scRNAseq-based ligand-receptor analysis, we studied the cell-cell crosstalk signals in the human lung microvascular niche among healthy adults and in IPF and COPD individuals. The impact of identified ligands on vascular barrier function and anti-inflammation was further assessed in vitro assays and lipopolysaccharide (LPS)-induced lung injury models. RESULTS: scRNAseq datasets reveal over 24 cell populations in the human lung microvascular niche. We applied Connectome to map the averaged gene expression per cell type to known ligand-receptor interactions cataloged in the NicheNet database. Using microvascular ECs, such as EC Aerocyte and EC General Capillary, as signal receivers (Senders) and the putative adjacent cell types (alveolar fibroblast, ATI, ATII, pericyte, plasma cell, etc.) in the microvascular niche as signal senders (Ligands), we identified several specific and abundant ligand-receptor pairs based on their expression levels in the niche, including SLIT2-ROBO4, ANGPT1-TEK, ADM-RAMP2, VEGFD-VEGFR2, BMP5-BMPR2, etc. Interestingly, these highly produced ligands were significantly reduced in patients with IPF or COPD. Upon treatment with these ligands on human lung endothelial cells, we found that VEGF-D could significantly increase the barrier function, unlike its analogs, VEGF-A and VEGF-C. Additionally, VEGF-D exerts barrier-protective properties against tumor necrosis factor-α, interleukin 1-β, and thrombin challenges. The blockage of VEGFR2 through either siRNA or pharmacological inhibitor SU5614 attenuates the impact of VEGF-D. Furthermore, intravenous administration of VEGF-D significantly reduced vascular permeability and immune cell infiltration in the LPS-induced lung injury model. CONCLUSIONS: This study highlights the cell-cell crosstalk signals in lung microvascular niche between healthy and diseased individuals and determines a novel and potentially therapeutic role of VEGF-D in improving lung vascular integrity during acute lung injury. NIH K99HL159261 (Y.Y.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Mitochondrial genome transfer drives metabolic reprogramming in adjacent colonic epithelial cells promoting TGFβ1-mediated tumor progression.

Although nontumor components play an essential role in colon cancer (CC) progression, the intercellular communication between CC cells and adjacent colonic epithelial cells (CECs) remains poorly understood. Here, we show that intact mitochondrial genome (mitochondrial DNA, mtDNA) is enriched in serum extracellular vesicles (EVs) from CC patients and positively correlated with tumor stage. Intriguingly, circular mtDNA transferred via tumor cell-derived EVs (EV-mtDNA) enhances mitochondrial respiration and reactive oxygen species (ROS) production in CECs. Moreover, the EV-mtDNA increases TGFβ1 expression in CECs, which in turn promotes tumor progression. Mechanistically, the intercellular mtDNA transfer activates the mitochondrial respiratory chain to induce the ROS-driven RelA nuclear translocation in CECs, thereby transcriptionally regulating TGFβ1 expression and promoting tumor progression via the TGFβ/Smad pathway. Hence, this study highlights EV-mtDNA as a major driver of paracrine metabolic crosstalk between CC cells and adjacent CECs, possibly identifying it as a potential biomarker and therapeutic target for CC.

Photonic Crystal-Integrated Semitransparent Solar Cell for Solar Greenhouse Application

Solar greenhouse technology emerges as a solution that intensifies crop yields and allows utilities to generate energy from photovoltaic cells. Here, we demonstrate a photonic crystal-integrated solar cell that selectively transmits photosynthetic light for plant cultivation and reflects the remaining light to the adjacent solar cells to generate electricity. The photonic crystal is fabricated using an e-beam evaporation method by nonperiodic stacking of TiO2 and SiO2 layers to transmit light at 400–500 nm (blue) and 600–700 nm (red) and reflect green (500–600 nm), ultraviolet, and infrared light. The photonic crystal-integrated solar cell is constructed with the vertically arranged copper indium gallium diselenide (CIGS) solar cell and the tilted photonic crystal with respect to the CIGS cell. By controlling the tilting angle of the photonic crystal film, it achieves the generated electric power of 40.2 W m-2 and the irradiance of 124.6 W m-2 for transmitted photosynthetic lights (400–500 and 600–700 nm). In contrast, a conventional horizontal CIGS cell shows a power generation of 55.6 W m-2 without any light transmission. This work provides a new optical strategy and design principle for the development of a wavelength-selective semitransparent solar cell.

Identification of PANoptosis-related subtypes, construction of a prognosis signature, and tumor microenvironment landscape of hepatocellular carcinoma using bioinformatic analysis and experimental verification.

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide. PANoptosis is a recently unveiled programmed cell death pathway, Nonetheless, the precise implications of PANoptosis within the context of HCC remain incompletely elucidated. We conducted a comprehensive bioinformatics analysis to evaluate both the expression and mutation patterns of PANoptosis-related genes (PRGs). We categorized HCC into two clusters and identified differentially expressed PANoptosis-related genes (DEPRGs). Next, a PANoptosis risk model was constructed using LASSO and multivariate Cox regression analyses. The relationship between PRGs, risk genes, the risk model, and the immune microenvironment was studies. In addition, drug sensitivity between high- and low-risk groups was examined. The expression profiles of these four risk genes were elucidate by qRT-PCR or immunohistochemical (IHC). Furthermore, the effect of CTSC knock down on HCC cell behavior was verified using in vitro experiments. We constructed a prognostic signature of four DEPRGs (CTSC, CDCA8, G6PD, and CXCL9). Receiver operating characteristic curve analyses underscored the superior prognostic capacity of this signature in assessing the outcomes of HCC patients. Subsequently, patients were stratified based on their risk scores, which revealed that the low-risk group had better prognosis than those in the high-risk group. High-risk group displayed a lower Stromal Score, Immune Score, ESTIMATE score, and higher cancer stem cell content, tumor mutation burden (TMB) values. Furthermore, a correlation was noted between the risk model and the sensitivity to 56 chemotherapeutic agents, as well as immunotherapy efficacy, in patient with. These findings provide valuable guidance for personalized clinical treatment strategies. The qRT-PCR analysis revealed that upregulated expression of CTSC, CDCA8, and G6PD, whereas downregulated expression of CXCL9 in HCC compared with adjacent tumor tissue and normal liver cell lines. The knockdown of CTSC significantly reduced both HCC cell proliferation and migration. Our study underscores the promise of PANoptosis-based molecular clustering and prognostic signatures in predicting patient survival and discerning the intricacies of the tumor microenvironment within the context of HCC. These insights hold the potential to advance our comprehension of the therapeutic contribution of PANoptosis plays in HCC and pave the way for generating more efficacious treatment strategies.

Umbravirus-like RNA viruses are capable of independent systemic plant infection in the absence of encoded movement proteins.

The signature feature of all plant viruses is the encoding of movement proteins (MPs) that supports the movement of the viral genome into adjacent cells and through the vascular system. The recent discovery of umbravirus-like viruses (ULVs), some of which only encode replication-associated proteins, suggested that they, as with umbraviruses that lack encoded capsid proteins (CPs) and silencing suppressors, would require association with a helper virus to complete an infection cycle. We examined the infection properties of 2 ULVs: citrus yellow vein associated virus 1 (CY1), which only encodes replication proteins, and closely related CY2 from hemp, which encodes an additional protein (ORF5CY2) that was assumed to be an MP. We report that both CY1 and CY2 can independently infect the model plant Nicotiana benthamiana in a phloem-limited fashion when delivered by agroinfiltration. Unlike encoded MPs, ORF5CY2 was dispensable for infection of CY2, but was associated with faster symptom development. Examination of ORF5CY2 revealed features more similar to luteoviruses/poleroviruses/sobemovirus CPs than to 30K class MPs, which all share a similar single jelly-roll domain. In addition, only CY2-infected plants contained virus-like particles (VLPs) associated with CY2 RNA and ORF5CY2. CY1 RNA and a defective (D)-RNA that arises during infection interacted with host protein phloem protein 2 (PP2) in vitro and in vivo, and formed a high molecular weight complex with sap proteins in vitro that was partially resistant to RNase treatment. When CY1 was used as a virus-induced gene silencing (VIGS) vector to target PP2 transcripts, CY1 accumulation was reduced in systemic leaves, supporting the usage of PP2 for systemic movement. ULVs are therefore the first plant viruses encoding replication and CPs but no MPs, and whose systemic movement relies on a host MP. This explains the lack of discernable helper viruses in many ULV-infected plants and evokes comparisons with the initial viruses transferred into plants that must have similarly required host proteins for movement.

Pushing boundaries: mechanisms enabling bacterial pathogens to spread between cells.

For multiple intracellular bacterial pathogens, the ability to spread directly into adjacent epithelial cells is an essential step for disease in humans. For pathogens such as Shigella, Listeria, Rickettsia, and Burkholderia, this intercellular movement frequently requires the pathogens to manipulate the host actin cytoskeleton and deform the plasma membrane into structures known as protrusions, which extend into neighboring cells. The protrusion is then typically resolved into a double-membrane vacuole (DMV) from which the pathogen quickly escapes into the cytosol, where additional rounds of intercellular spread occur. Significant progress over the last few years has begun to define the mechanisms by which intracellular bacterial pathogens spread. This review highlights the interactions of bacterial and host factors that drive mechanisms required for intercellular spread with a focus on how protrusion structures form and resolve.