Available evidence indicates voltage-gated Na
channels (VGSCs) in peripheral sensory neurons are essential for the pain and hypersensitivity associated with tissue injury. However, our understanding ...of the biophysical and pharmacological properties of the channels in sensory neurons is largely based on the study of heterologous systems or rodent tissue, despite evidence that both expression systems and species differences influence these properties. Therefore, we sought to determine the extent to which the biophysical and pharmacological properties of VGSCs were comparable in rat and human sensory neurons. Whole cell patch clamp techniques were used to study Na
currents in acutely dissociated neurons from human and rat. Our results indicate that while the two major current types, generally referred to as tetrodotoxin (TTX)-sensitive and TTX-resistant were qualitatively similar in neurons from rats and humans, there were several differences that have important implications for drug development as well as our understanding of pain mechanisms.
The activation of the transient receptor potential ankyrin 1 (TRPA1) channel has anti-fibrotic effects in the lung and intestine. Suburothelial myofibroblasts (subu-MyoFBs), a specialized subset of ...fibroblasts in the bladder, are known to express TRPA1. However, the role of the TRPA1 in the development of bladder fibrosis remains elusive. In this study, we use the transforming growth factor-β1 (TGF-β1) to induce fibrotic changes in subu-MyoFBs and assess the consequences of TRPA1 activation utilizing RT-qPCR, western blotting, and immunocytochemistry. TGF-β1 stimulation increased α-SMA, collagen type I alpha 1 chain(col1A1), collagen type III (col III), and fibronectin expression, while simultaneously suppressing TRPA1 in cultured human subu-MyoFBs. The activation of TRPA1, with its specific agonist allylisothiocyanate (AITC), inhibited TGF-β1-induced fibrotic changes, and part of these inhibition effects could be reversed by the TRPA1 antagonist, HC030031, or by reducing TRPA1 expression via RNA interference. Furthermore, AITC reduced spinal cord injury-induced fibrotic bladder changes in a rat model. The increased expression of TGF-β1, α-SMA, col1A1 and col III, and fibronectin, and the downregulation of TRPA1, were also detected in the mucosa of fibrotic human bladders. These findings suggest that TRPA1 plays a pivotal role in bladder fibrosis, and the negative cross talk between TRPA1 and TGF-β1 signaling may represent one of the mechanisms underlying fibrotic bladder lesions.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Approximately 60% of patients with autoimmune encephalitis (AE) exhibit secondary acute symptomatic seizures and showed highly sensitive to immunotherapy. However, it is difficult for many patients ...to receive early immunotherapy since the early identification of the cause in AE is more complex. This study aimed to investigate the early predictors of initial immune-related seizures and to guide the evaluation of treatment and prognosis.
One hundred and fifty-four patients with new-onset "unknown etiology" seizures with a course of disease less than 6 months were included. Serum and/or cerebrospinal fluid neuron-specific autoantibodies (NSAbs), including N-methyl-D-aspartate receptor (NMDAR), α-amino-3-hydroxy-5- Methyl-4-isoxazole propionic acid receptor 1 (AMPAR1), AMPAR2, anti-leucine rich glioma inactivated 1 antibody (LGI1), anti-gamma-aminobutyric acid type B receptor (GABABR), anti-contact protein-related protein-2 (CASPR2) were used to screen for immune etiology of the seizures. In addition, patients with epilepsy and encephalopathy were also examined via brain MRI, long-term video EEG, antibody prevalence in epilepsy and encephalopathy (APE2) score, and modified Rankin Scale (mRS). A logistic regression model was used to analyze the early predictors of immune etiology.
Thirty-four cases (22.1%) were positive for NSAbs. Among all 154 patients, 23 cases of autoimmune encephalitis (AE) (21 cases of NSAbs positive), 1 case of ganglionic glioma (NSAbs positive), 130 cases of epilepsy or seizures (12 cases of NSAbs positive) were recorded. Also, there were 17 patients (11.0%) with APE2 ≥ 4 points, and all of them met the clinical diagnosis of AE. The sensitivity and specificity of APE2 ≥ 4 points for predicting AE were 73.9% and 100%. The results of multivariate analysis showed that the NSAbs and APE2 scores independently influenced the early prediction of initial immune-related seizures (P < 0.05).
NSAbs and APE2 scores could act as early predictors of initial immune-related seizures.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Urothelial cells have been implicated in bladder mechanosensory transduction, and thus, initiation of the micturition reflex. Cell deformation caused by tension forces at an air-liquid interface ...(ALI) can induce an increase in intracellular Ca
2+
concentration (Ca
2+
i
) and ATP release in some epithelial cells. In this study, we aimed to examine the cellular mechanisms underlying ALI-induced Ca
2+
i
increase in cultured urothelial cells. The ALI was created by stopping the influx of the perfusion but maintaining efflux. The Ca
2+
i
increase was measured using the Ca
2+
imaging method. The ALI evoked a reversible Ca
2+
i
increase and ATP release in urothelial cells, which was almost abolished by GdCl
3
. The specific antagonist of the transient receptor potential vanilloid (TRPV4) channel (HC0674) and the antagonist of the pannexin 1 channel (
10
panx) both diminished the Ca
2+
i
increase. The blocker of Ca
2+
-ATPase pumps on the endoplasmic reticulum (thapsigargin), the IP3 receptor antagonist (Xest-C), and the ryanodine receptor antagonist (ryanodine) all attenuated the Ca
2+
i
increase. Degrading extracellular ATP with apyrase or blocking ATP receptors (P2X or P2Y) with pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS) significantly attenuated the Ca
2+
i
increase. Our results suggest that both Ca
2+
influx
via
TRPV4 or pannexin 1 and Ca
2+
release from intracellular Ca
2+
stores
via
IP3 or ryanodine receptors contribute to the mechanical responses of urothelial cells. The release of ATP further enhances the Ca
2+
i
increase by activating P2X and P2Y receptors
via
autocrine or paracrine mechanisms.
Debris flow, driven by natural events like heavy rainfall and snowmelt, involves sediment, rocks, and water, posing destructive threats to life and infrastructure. The accurate prediction of its ...activity range is crucial for prevention and mitigation efforts. Cellular automata circumvent is the cumbersome process of solving partial differential equations, thereby efficiently simulating complex dynamic systems. Given the anisotropic characteristics of square cells in the simulation of dynamic systems, this paper proposes a novel approach, utilizing a hexagonal cellular automaton for the numerical simulation of debris flows, where the direction judgment efficiency increased by 25%. Employing cubic interpolation, the model thereby determines the central elevation of each hexagonal cell. By modifying the flow direction function and stopping conditions, it achieves more accurate predictions of the debris flow run-out extent. This method was applied to the 2010 Yohutagawa debris flow event and the flume test. To evaluate the simulation’s accuracy, the Ω value and Fβ score were used. The Ω value is a comprehensive evaluation factor that takes into account missed or misjudgment areas. On this basis, the Fβ score emphasizes that the missed identification of debris flow areas will bring greater harm. Research indicates that the Ω value showed improvements of 6.47% and 3.96%, respectively, while the Fβ score improved by 3.10% and 4.61%.
Rockfall intrusion detection is crucial for the safety management of railway operations, and video detection methods help reduce deployment costs and improve detection efficiency. Mainstream neural ...network-based video detection methods have rapidly evolved in recent years but struggle to adapt to complex scenarios such as existing railway slope constructions due to weak generalization ability, low accuracy, and limited information acquisition. Therefore, this paper introduces a dynamic neural network detection model and establishes a dataset for rockfall intrusions in existing railway slope scenarios. The model initially relies on the YOLOv5 neural network, adopting an activation function suitable for the target scenario and addressing overfitting to achieve precise target recognition. Based on the neural network, the model dynamically detects rolling rockfalls by integrating a background subtraction algorithm based on the Gaussian Mixture Model and captures target dimensions using monocular vision technology, thus broadening the dimensions of detection information. Trials conducted on a railway in Shandong, China, demonstrate that the model accurately identifies moving rockfalls along the railway slopes and acquires the dimensions of moving rockfalls, successfully filtering out low-risk targets in the scene.
Convulsive status epilepticus (CSE) is a major subtype of status epilepticus that is known to be closely associated with systemic inflammation. Some important inflammatory biomarkers of this disorder ...include the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), systemic immune inflammation index (SII), and pan-immune inflammation value (PIV). This study aimed to determine the NLR, PLR, MLR, SII, and PIV levels before and after treatment in adult patients with CSE and investigated the relationship of these parameters with disease severity.
This retrospective study analyzed data from 103 adult patients with CSE and 103 healthy controls. The neutrophil, monocyte, platelet, and lymphocyte counts, as well as the NLR, PLR, MLR, SII, and PIV, were compared in adult patients with CSE during acute seizures (within 2 h of admission) and after treatment relief (1-2 weeks of complete seizure control). Furthermore, multivariate linear regression analysis investigated the relationship between NLR, PLR, MLR, SII, and PIV with the Status Epilepticus Severity Score (STESS).
The data revealed significant differences (
< 0.05) in neutrophils, monocytes, lymphocytes, NLR, PLR, MLR, SII, and PIV between adult patients with CSE during acute seizures and after treatment relief. The average neutrophil count was high during acute seizures in the patient group and decreased after remission. In contrast, the average lymphocyte count was lower after remission (
< 0.05). Furthermore, significant differences (
< 0.05) were observed in monocytes, lymphocytes, platelets, NLR, PLR, MLR, and PIV levels between adult patients with CSE after remission and the healthy control group. Multivariate linear regression analysis showed no significant correlation between NLR, PLR, MLR, SII, and PIV with STESS.
The results of this study indicated that adult patients with CSE experienced a transient systemic inflammatory response during acute seizures, which gradually returned to baseline levels after remission. However, there was a lack of robust clinical evidence correlating the severity of adult CSE and systemic inflammatory response.
Glutamine is the most abundant amino acid in the human and many other mammalian plasmas. Glutamine operates at multiple levels within intestinal cells, including intestinal epithelial cells, goblet ...cells, paneth cells, and immune cells in the intestinal mucosa, demonstrating its role in fostering both innate and adaptive immunity and its connections with the gut microbiome. This review introduces the potential mechanisms by which the glutamine functions as an intermediary between the gut microbiota and immune system, through changes in the intestinal microbiota and activation of toll-like receptors (TLRs) as well as the mTOR signaling pathway. Glutamine supplementation could increased proliferation and differentiation of T cells, as well as stimulation of secretory IgA (sIgA) secretion, thus contributing to a strengthened intestinal immune response. Studying the glutamine functions among the gut microbiota and immune system will provide ideas and perspectives for maintaining and maximizing intestinal health.
Helicobacter pylori
(
H. pylori, Hp
) has been designated a class I carcinogen and is closely associated with severe gastric diseases. During colonization in the gastric mucosa,
H. pylori
develops ...immune escape by inducing host immune tolerance. The gastric epithelium acts as the first line of defense against
H. pylori
, with Toll-like receptors (TLRs) in gastric epithelial cells being sensitive to
H. pylori
components and subsequently activating the innate immune system. However, the mechanism of immune tolerance induced by
H. pylori
through the TLR signalling pathway has not been fully elucidated. In this research, we detected the expression of TLRs and inflammatory cytokines in GES-1 cells upon sustained exposure to
H. pylori
or
H. pylori
lysate from 1 to 30 generations and in Mongolian gerbils infected with
H. pylori
for 5 to 90 weeks. We found that the levels of TLR6 and inflammatory cytokines first increased and then dropped during the course of
H. pylori
treatment in vitro and in vivo. The restoration of TLR6 potentiated the expression of IL-1β and IL-8 in GES-1 cells, which recruited neutrophils and reduced the colonization of
H. pylori
in the gastric mucosa of gerbils. Mechanistically, we found that persistent infection with
H. pylori
reduces the sensitivity of TLR6 to bacterial components and regulates the expression of inflammatory cytokines in GES-1 cells through TLR6/JNK signaling. The TLR6 agonist obviously alleviated inflammation in vitro and in vivo. Promising results suggest that TLR6 may be a potential candidate immunotherapy drug for
H. pylori
infection.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We aimed to investigate the expression and motor modulatory roles of several mechano-sensitive channels (MSCs) in human ureter. Human proximal ureters were obtained from eighty patients subjected to ...nephrectomy. Expression of MSCs at mRNA, protein and functional levels were examined. Contractions of longitudinal ureter strips were recorded in organ bath. A fluorescent probe Diaminofluoresceins was used to measure nitric oxide (NO). RT-PCR analyses revealed predominant expression of Piezo1 and TRPV2 mRNA in intact ureter and mucosa. Immunofluorescence assays indicate proteins of MSCs (Piezo1/Piezo2, TRPV2 and TRPV4) were mainly distributed in the urothelium. Ca2+ imaging confirmed functional expression of TRPV2, TRPV4 and Piezo1 in cultured urothelial cells. Specific agonists of Piezo1 (Yoda1, 3–300 μM) and TRPV2 (cannabidiol, 3–300 μM) attenuated the frequency of ureteral contractions in a dose-dependent manner while the TRPV4 agonist GSK1016790A (100 nM–1 μM) exerted no effect. The inhibitory effects of Piezo1 and TRPV2 agonists were significantly blocked by the selective antagonists (Dooku 1 for Piezo1, Tranilast for TRPV2), removal of the mucosa, and pretreatment with NO synthase inhibitor L-NAME (10 μM). Yoda1 (30 μM) and cannabidiol (50 μM) increased production of NO in cultured urothelial cells. Our results suggest that activation of Piezo1 or TRPV2 evokes NO production and release from mucosa that may mediate mechanical stimulus-induced reduction of ureter contractions. Our findings support the idea that targeting Piezo1 and TRPV2 channels may be a promising pharmacological strategy for ureter stone passage or colic pain relief.
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