The transient receptor potential vanilloid type 4 (TRPV4) channel, a Ca2+‐permeable nonselective cation channel, is widely distributed in the circulatory system, particularly in vascular endothelial ...cells (ECs) and smooth muscle cells (SMCs). The TRPV4 channel is activated by various endogenous and exogenous stimuli, including shear stress, low intravascular pressure, and arachidonic acid. TRPV4 has a role in mediating vascular tone and arterial blood pressure. The activation of the TRPV4 channel induces Ca2+ influx, thereby resulting in endothelium‐dependent hyperpolarization and SMC relaxation through SKCa and IKCa activation on ECs or through BKCa activation on SMCs. Ca2+ binds to calmodulin, which leads to the production of nitric oxide, causing vasodilation. Furthermore, the TRPV4 channel plays an important role in angiogenesis and arteriogenesis and is critical for tumor angiogenesis and growth, since it promotes or inhibits the development of various types of cancer. The TRPV4 channel is involved in the active growth of collateral arteries induced by flow shear stress, which makes it a promising therapeutic target in the occlusion or stenosis of the main arteries. In this review, we explore the role and the potential mechanism of action of the TRPV4 channel in the regulation of vascular tone and in the induction of neovascularization to provide a reference for future research.
Traditional distributed radar systems face challenges like limited localization precision and stringent time synchronization demands in implementing signal-level fusion algorithms. This paper ...presents a novel distributed radar localization method based on wideband signal synthesis technology to address these issues. In this method, each node of the distributed radar simultaneously transmits a set of narrowband stepped linear frequency-modulated signals. After de-chirping and filtering separation, the echo signals from each node are calibrated and synthesized into an equivalent wideband signal. This process improves the range resolution and localization accuracy of single nodes. However, wideband synthesis necessitates precise distance data, and the estimation error from narrowband echoes can be substantial, affecting the synthesis's efficiency. To overcome this, we propose a grid search wideband synthesis algorithm. The algorithm establishes a search area centered on the distance estimation derived from the narrowband signals, with a diameter determined by the resolution of these signals. Within this search area, the algorithm conducts a grid search, utilizing the peak magnitude of the synthesized signal's Fast Fourier Transform spectrum as a criterion to find the most accurate synthesis result. This method can be integrated with traditional fusion algorithms, enhancing localization precision further. Theoretical analysis and simulation results demonstrate that our method outperforms conventional techniques in terms of localization accuracy. Notably, the grid search algorithm reduces the requirement for precise time synchronization in signal-level fusion algorithms, improving the method's adaptability.
In this paper, a joint direction of arrival (DOA) and distance estimation (JDDE) method using a novel time-domain wideband synthesis signal system is proposed. In contrast to traditional time-domain ...synthesis methods, which transmit sub-pulses separately, a uniform linear array is used, and all stepped linear frequency modulated (SLFM) sub-pulses are transmitted simultaneously. The echo signal is mixed with each transmitted signal of the corresponding antenna and filtered to separate the single-frequency components from different targets and array elements for synthesis. Single-frequency components have different frequencies and discontinuous phases due to wave-way differences. To solve the problem that single-frequency components cannot be synthesized directly, the frequency and phase of single-frequency components need to be calibrated, including frequency conversion and phase shift, which require DOA information of the targets. Consequently, a high-precision DOA algorithm that employs phase difference fitting, along with the corresponding generic phase unwrapping algorithm, is designed for the characteristics of the arrays and signal system in this paper. After obtaining the DOA information, the wideband synthesis algorithm is applied to synthesize the single-frequency components to obtain high-resolution ranging results. The theoretical analysis and simulation results show that the method has high distance resolution and JDDE accuracy. In a multi-target environment, the number of targets is not limited by the number of antennas. In addition, unlike traditional wideband synthesis methods, the method utilizes multiple transmitting antennas to send SLFM signal pulses simultaneously rather than sequentially, which enhances the response speed of the radar.
Peroxisome proliferator-activated receptor gamma （PPARy） is a member of the PPARs, which are transcription factors of the steroid receptor superfamily. PPARy acts as an important molecule for ...regulating energy homeostasis, modulates the hypothalamic-pituitary-gonadal （HPG） axis, and is reciprocally regulated by HPG. In the human, PPARγprotein is highly expressed in ejaculated spermatozoa, implying a possible role of PPARγ signaling in regulating sperm energy dissipation. PPARγ protein is also expressed in Sertoli cells and germ cells （spermatocytes）. Its activation can be induced during capacitation and the acrosome reaction. This mini-review will focus on how PPARy signaling may affect fertility and sperm quality and the potential reversibility of these adverse effects.
The innate immune system is the first line of host defense against infection and involves several different cell types. Here we investigated the role of the phosphatidylinositol 3 kinase (PI3K) ...signaling pathway in innate immune cells. By blocking this pathway with pharmacological inhibitors, we found that the production of proinflammatory cytokines was drastically suppressed in monocytes and macrophages. Further study revealed that the suppression was mainly related to the mammalian target of rapamycin (mTOR)/p70(S6K) signaling. In addition, we found that the PI3K pathway was involved in macrophage motility and neovascularization. Our data provide a rationale that inhibition of the PI3K signaling pathway could be an attractive approach for the management of inflammatory disorders.
Identification of potential factors that can stratify a tumor's response to specific therapies will aid in the selection of cancer therapy. The aim was to highlight the role of programmed cell death ...1 ligand 1 (PD-L1) in bladder cancer. In this study, 92 of muscle-invasive bladder cancers and 28 of non-muscle invasive bladder cancers were selected for immunohistochemical staining analysis. Furthermore, human and murine bladder cancer cell lines were used to examine the correlation between PD-L1 and radiation response. Our data revealed that PD-L1 was overexpressed in the bladder tumor specimens compared with adjacent non-malignant specimens. Furthermore, the staining of PD-L1 was significantly linked to higher clinical stage, lower complete response rates and reduced disease-free survival rates. By in vitro and in vivo experiments, irradiation up-regulated the expression of PD-L1 in tumor cells, and its increase correlated with the irradiation dose. In immunocompetent mouse models, blocking PD-L1 induced a longer tumour growth delay following irradiation. The inhibition of T cell functions including proliferation and cytotoxicity against tumor cells was responsible to the effects of PD-L1 on radiation response. In conclusion, PD-L1 could be a significant clinical predictor for clinical stage and treatment response of bladder cancer.
Pulmonary neuroendocrine cells (PNECs) are proposed to be the first specialized cell type to appear in the lung, but their ontogeny remains obscure. Although studies of PNECs have suggested their ...involvement in a number of lung functions, neither their in vivo significance nor the molecular mechanisms underlying them have been elucidated. Importantly, PNECs have long been speculated to constitute the cells of origin of human small-cell lung cancer (SCLC) and recent mouse models support this hypothesis. However, a genetic system that permits tracing the early events of PNEC transformation has not been available. To address these key issues, we developed a genetic tool in mice by introducing a fusion protein of Cre recombinase and estrogen receptor (CreER) into the calcitonin gene-related peptide (CGRP) locus that encodes a major peptide in PNECs. The CGRP Cʳᵉᴱᴿ mouse line has enabled us to manipulate gene activity in PNECs. Lineage tracing using this tool revealed the plasticity of PNECs. PNECs can be colabeled with alveolar cells during lung development, and following lung injury, PNECs can contribute to Clara cells and ciliated cells. Contrary to the current model, we observed that elimination of PNECs has no apparent consequence on Clara cell recovery. We also created mouse models of SCLC in which CGRP Cʳᵉᴱᴿ was used to ablate multiple tumor suppressors in PNECs that were simultaneously labeled for following their fate. Our findings suggest that SCLC can originate from differentiated PNECs. Together, these studies provide unique insight into PNEC lineage and function and establish the foundation of investigating how PNECs contribute to lung homeostasis, injury/repair, and tumorigenesis.
Summary
Background
Liver fibrosis is the strongest histological risk factor for liver‐related complications and mortality in metabolic dysfunction‐associated fatty liver disease (MAFLD). Second ...harmonic generation/two‐photon excitation fluorescence (SHG/TPEF) is a powerful tool for label‐free two‐dimensional and three‐dimensional tissue visualisation that shows promise in liver fibrosis assessment.
Aim
To investigate combining multi‐photon microscopy (MPM) and deep learning techniques to develop and validate a new automated quantitative histological classification tool, named AutoFibroNet (Automated Liver Fibrosis Grading Network), for accurately staging liver fibrosis in MAFLD.
Methods
AutoFibroNet was developed in a training cohort that consisted of 203 Chinese adults with biopsy‐confirmed MAFLD. Three deep learning models (VGG16, ResNet34, and MobileNet V3) were used to train pre‐processed images and test data sets. Multi‐layer perceptrons were used to fuse data (deep learning features, clinical features, and manual features) to build a joint model. This model was then validated in two further independent cohorts.
Results
AutoFibroNet showed good discrimination in the training set. For F0, F1, F2 and F3‐4 fibrosis stages, the area under the receiver operating characteristic curves (AUROC) of AutoFibroNet were 1.00, 0.99, 0.98 and 0.98. The AUROCs of F0, F1, F2 and F3‐4 fibrosis stages for AutoFibroNet in the two validation cohorts were 0.99, 0.83, 0.80 and 0.90 and 1.00, 0.83, 0.80 and 0.94, respectively, showing a good discriminatory ability in different cohorts.
Conclusion
AutoFibroNet is an automated quantitative tool that accurately identifies histological stages of liver fibrosis in Chinese individuals with MAFLD.
Deep learning (DL) model and joint model (AutoFibroNet). Both deep learning models are used for automated classification and quantification of liver fibrosis stages, in which the AutoFibroNet uses multi‐layer perceptron (MLP) to integrate clinical features, manual features and DL features before classification.
Adverse maternal outcomes and perinatal complications are closely associated with overt maternal hypothyroidism, but whether these complications occur in women with subclinical hypothyroidism (SCH) ...during pregnancy remains controversial. The aim of this study was to evaluate the effects of SCH on maternal and perinatal outcomes during pregnancy.
A prospective study of data from 8012 pregnant women (371 women with SCH, 7641 euthyroid women) was performed. Maternal serum samples were collected in different trimesters to examine thyroid hormone concentrations. SCH was defined as a thyroid stimulating hormone concentration exceeding the trimester-specific reference value with a normal free thyroxine concentration. The occurrence of maternal outcomes, including gestational hypertension (GH), gestational diabetes mellitus, placenta previa, placental abruption, prelabor rupture of membranes (PROM), and premature delivery; and perinatal outcomes, including intrauterine growth restriction (IUGR), fetal distress, low birth weight (LBW; live birth weight ≤ 2500 g), stillbirth, and malformation, was recorded. Logistic regression with adjustment for confounding demographic and medical factors was used to determine the risks of adverse outcomes in patients with SCH.
Compared with euthyroid status, SCH was associated with higher rates of GH (1.819% vs. 3.504%, P = 0.020; χ2 = 7.345; odds ratio (OR), 2.243; 95% confidence interval (CI), 1.251-4.024), PROM (4.973% vs. 8.625%, P = 0.002; χ2 = 72.102; adjusted OR, 6.014; 95% CI, 3.975-9.099), IUGR (1.008% vs. 2.965%, <0.001; χ2 = 13.272; adjusted OR, 3.336; 95% CI, 1.745-6.377), and LBW (1.885% vs. 4.582%, P<0.001; χ2 = 13.558; adjusted OR, 2.919; 95% CI, 1.650-5.163).
The results of this study indicate that pregnant women with SCH had increased risks of GH and PROM, and their fetuses and infants had increased risks of IUGR and LBW. Thus, routine maternal thyroid function testing is necessary to improve maternal and perinatal outcomes.
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