Suppression Of Activity Research Articles

Influence of presentation duration on filtering of irrelevant stimuli in visual working memory

In environments teeming with distractions, the ability to selectively focus on relevant information is crucial for advanced cognitive processing. Existing research using event-related potential (ERP) technology has shown active suppression of irrelevant stimuli during the consolidation phase of visual working memory (VWM). In previous studies, participants have always been given sufficient time to consolidate VWM, while suppressing distracting information. However, it remains unclear whether the suppression of irrelevant distractors requires continuous effort throughout their presence or whether this suppression is only necessary after the consolidation of task-relevant information. To address this question, our study examines whether distractor suppression is necessary in scenarios where consolidation time is limited. This research investigates the effect of varying presentation durations on the filtering of distractors in VWM. We tasked participants with memorizing two color stimuli and ignoring four distractors, presented for either 50 ms or 200 ms. Using ERP technology, we discovered that the distractor-induced distractor positivity (PD) amplitude is larger during longer presentation durations compared to shorter ones. These findings underscore the significant impact of presentation duration on the efficacy of distractor suppression in VWM, as prolonged exposure results in a stronger suppression effect on distractors. This study sheds light on the temporal dynamics of attention and memory, emphasizing the critical role of stimulus timing in cognitive tasks. These findings provide valuable insights into the mechanisms underlying VWM and have significant implications for models of attention and memory.

Potassium nitrate suppresses hyperactivities of Vc neurons of the model with dentin hypersensitivity

ObjectivePotassium nitrate (KNO3) suppresses nociception induced by dental hypersensitivity (HYS). We aimed to examine the effects of KNO3 on the neural activity of the trigeminal spinal subnucleus caudalis (Vc) in HYS model rats. MethodsKNO3 or vehicle was applied to the exposed dentin of HYS rats for 3 days. c-Fos expression and neuronal activity in the Vc after acetone treatment for cold stimulation were examined to evaluate the effects of KNO3 application on dentin. ResultsThe number of c-Fos-immunoreactive cells in the Vc was lower in the group that received KNO3 (KNO3 group) than in the group that received vehicle (control group). Spike firing of Vc neurons in response to cold stimulation of the dentin was recorded before and after KNO3 application to the cavity, and the increased neural activity was effectively suppressed by KNO3 application. Scanning electron microscopy revealed that the dentin tubules were not occluded by deposits in any of the groups. ConclusionsKNO3-induced suppression of Vc neuronal activity does not involve physical occlusion of the dentin tubules but likely involves suppression of Aδ or C-fiber activities in the tooth pulp, resulting in the suppression of Vc neuronal activities.

Domain-selective and sex-dependent regulation of learning and memory in mice by GIRK channel activity in CA1 pyramidal neurons of the dorsal hippocampus.

G protein-gated inwardly rectifying K+ (GIRK) channels mediate the postsynaptic inhibitory effect of many neurotransmitters in the hippocampus and are implicated in neurological disorders characterized by cognitive deficits. Here, we show that enhancement or suppression of GIRK channel activity in dorsal CA1 pyramidal neurons disrupted novel object recognition in mice, without impacting open field activity or avoidance behavior. Contextual fear learning was also unaffected, but extinction of contextual fear was disrupted by suppression of GIRK channel activity in male mice. Thus, the strength of GIRK channel activity in dorsal CA1 pyramidal neurons regulates select cognitive task performance in mice.

An Invasive Predator Substantially Alters Energy Flux Without Changing Food Web Functional State or Stability

ABSTRACTUnderstanding how invasive species affect the stability and function of ecosystems is critical for conservation. Here, we quantified the effect of an actively suppressed invasive species on the Yellowstone Lake ecosystem using a food web energetics approach. We compared energy flux, functional state, and stability of four food web states: a pre‐invasion network and three post‐invasion networks undergoing active invasive species suppression, namely, initial invasion, expansion, and decline. Invasion caused ≥ 25% change (±) in energy flux for most consumers, and total flux increased twofold post‐invasion. Flux to the species of conservation concern, Yellowstone cutthroat trout (Oncorhynchus virginalis bouvieri), was 2.8 times less post‐invasion versus pre‐invasion, whereas invasive lake trout (Salvelinus namaycush) flux was up to 17.3 times higher compared to the initial invasion network. The dominant functional state and food web stability did not change post‐invasion, likely due to introduction of a generalist predator and the stabilizing effect of suppression. Lake trout invasion in Yellowstone Lake caused large changes to energy flux, shifting dominant fluxes away from the species of conservation concern, despite not changing functional state or stability. We demonstrate that changes in energy flux may signal invasions in ecosystems, but functional state or stability may not necessarily reflect the magnitude of invasion influences. For invaded fish communities, a better understanding of how the invasive species control the food web beyond just the direct influence on prey can be achieved by investigating energy flux, functional state, and food web stability. Furthermore, evaluating the effect of suppression beyond the invasive species can demonstrate the far‐reaching value of suppression management actions for conservation.

Activity in the dorsal hippocampus-mPFC circuit modulates stress-coping strategies during inescapable stress

Anatomical connectivity and lesion-deficit studies have shown that the dorsal and ventral hippocampi contribute to cognitive and emotional processes, respectively. However, the role of the dorsal hippocampus (dHP) in emotional or stress-related behaviors remains unclear. Here, we showed that neuronal activity in the dHP affects stress-coping behaviors in mice via excitatory projections to the medial prefrontal cortex (mPFC). The antidepressant ketamine rapidly induced c-Fos expression in both the dorsal and ventral hippocampi. The suppression of GABAergic transmission in the dHP-induced molecular changes similar to those induced by ketamine administration, including eukaryotic elongation factor 2 (eEF2) dephosphorylation, brain-derived neurotrophic factor (BDNF) elevation, and extracellular signal-regulated kinase (ERK) phosphorylation. These synaptic and molecular changes in the dHP induced a reduction in the immobility time of the mice in the tail-suspension and forced swim tests without affecting anxiety-related behavior. Conversely, pharmacological and chemogenetic potentiation of inhibitory neurotransmission in the dHP CA1 region induced passive coping behaviors during the tests. Transneuronal tracing and electrophysiology revealed monosynaptic excitatory connections between dHP CA1 neurons and mPFC neurons. Optogenetic stimulation of dHP CA1 neurons in freely behaving mice produced c-Fos induction and spike firing in the mPFC neurons. Chemogenetic activation of the dHP-recipient mPFC neurons reversed the passive coping behaviors induced by suppression of dHP CA1 neuronal activity. Collectively, these results indicate that neuronal activity in the dHP modulates stress-coping strategies to inescapable stress and contributes to the antidepressant effects of ketamine via the dHP-mPFC circuit.

MTA-cooperative PRMT5 inhibitors enhance T cell-mediated antitumor activity in MTAP-loss tumors

BackgroundHyperactivated protein arginine methyltransferases (PRMTs) are implicated in human cancers. Inhibiting tumor intrinsic PRMT5 was reported to potentiate antitumor immune responses, highlighting the possibility of combining PRMT5 inhibitors (PRMT5i) with...

Diabetes Mellitus Inhibits Hair Follicle Regeneration by Inducing Macrophage Reprogramming-Mediated Pyroptosis.

Diabetes mellitus (DM) is known to inhibit skin self-renewal and hair follicle stem cell (HFSC) activation, which may be key in the formation of chronic diabetic wounds. This study aimed to investigate the reasons behind the suppression of HFSC activation in DM mice. Type 1 DM (T1DM) was induced in 6-week-old mice via streptozotocin, and hair follicle growth was subsequently monitored. RNA sequencing, bioinformatics analyses, qRT‒PCR, immunostaining, and cellular experiments were carried out to investigate the underlying mechanisms involved. T1DM inhibited HFSC activation, which correlated with an increase in caspase-dependent programmed cell death. Additionally, T1DM triggered apoptosis and pyroptosis, predominantly in HFSCs and epidermal regions, with pyroptosis being more pronounced in the inner root sheath of hair follicles. Notably, significant cutaneous immune imbalances were observed, particularly in macrophages. Cellular experiments demonstrated that M1 macrophages inhibited HaCaT cell proliferation and induced cell death, whereas high-glucose environments alone did not have the same effect. T1DM inhibits HFSC activation via macrophage reprogramming-mediated caspase-dependent pyroptosis, and there is a significant regional characterization of cell death. Moreover, T1DM-induced programmed cell death in the skin may be more closely related to immune homeostasis imbalance than to hyperglycemia itself. These findings shed light on the pathogenesis of diabetic ulcers and provide a theoretical basis for the use of hair follicle grafts in wound repair.

A CD25×TIGIT bispecific antibody induces anti-tumor activity through selective intratumoral Treg cell depletion

Intratumoral regulatory T cells (Tregs) express high levels of CD25 and TIGIT, which are also recognized as markers of effector T cell (Teff) activation. Targeting these molecules each alone with monoclonal antibodies (mAbs) poses a risk of concurrently depleting both Teffs and peripheral Tregs, thereby compromising the effectiveness and selectivity of intratumoral Treg depletion. Here, leveraging the increased abundance of CD25+ TIGIT+ double positive Tregs in the solid tumor microenvironment (but not in peripheral tissues), we explored the feasibility of using a CD25×TIGIT bispecific antibody (bsAb) to selectively deplete intratumoral Tregs. We initially constructed a bsAb co-targeting mouse CD25 and TIGIT, NSWm7210, and found that NSWm7210 conferred enhanced intratumoral Treg depletion, Teff activation, and tumor suppression as compared to the parental monotherapies in mouse models. We subsequently constructed a bsAb co-targeting human CD25 and TIGIT (NSWh7216), which preferentially eliminated CD25+ TIGIT+ double positive cells over single positive cells in vitro. NSWh7216 exhibited enhanced anti-tumor activity without toxicity of peripheral Tregs in CD25 humanized mice compared to the parental monotherapies. Our study illustrates the use of CD25×TIGIT bsAbs as effective agents against solid tumors based on selective depletion of intratumoral Tregs.

Total Phenolics, Flavonoids, and ɑ-Glucosidase Inhibitory Activity of Red Betel (Piper crocatum) Extract in Various Solvents

Alpha-glucosidase enzyme activity needs to be inhibited to avoid increasing blood sugar levels in diabetics. Red betel leaf extract is reported to have active compounds such as phenolics and flavonoids that have alpha-glucosidase enzyme inhibition activity. Previous research showed that 70% betel leaf extract has an ɑ-glucosidase enzyme inhibition activity of 69.84%, but it is not yet known how the effect of extracts with different levels of polarity on the inhibition activity of alpha-glucosidase enzyme. This study aimed to determine extracts that have optimal levels of phenolic and flavonoid content and the highest suppression of α-glucosidase activity. The multistage maceration method was used to extract red betel leaf simplicia using solvents with different levels of polarity (n-hexane, ethyl acetate, methanol). Tests were conducted on overall phenolic concentration, flavonoids, and ɑ-glucosidase inhibition ability. Data were analyzed using one-way ANOVA test with Tukey's further test (p<0.05). The results of the assessment of phenolic concentration, flavonoids, and α-glucosidase inhibitory activity as a whole showed statistically significant differences (p<0.05) in all extracts with the highest total phenolic and flavonoid content found in the n-hexane extract of 25.68 ± 0.29 mg GAE/g and 65.84 ± 0.96 mg QE/g respectively. Meanwhile, methanol extract of red betel leaf became the best extract in this study with the greatest inhibition among all extracts with a percent α-glucosidase inhibition value of 43.87 ± 1.83%.

Magnetic biochar conjugated quaternary ammonium salt-constructed hemoperfusion adsorbent for viral removal with rapid and high-performance

Due to variations in virus structures and their high variability, treating viral infections remains challenging. Moreover, developing vaccines and medications for newly emerged viruses demands a significant time investment. Efficient methods are required to prevent dangerous infections caused by unknown pathogens. Hemoperfusion, with its low cost, can effectively remove toxins from the blood quickly, thus achieving therapeutic effects. The core of the hemoperfusion technology lies in the adsorbent. Therefore, the development of a viral adsorbent aiming to combat viruses through hemoperfusion was envisioned, following general principles to effectively save lives and buy time for the research and development of vaccines and medications. Towards this goal, a facile, green, and low-priced magnetic biochar/quaternary ammonium salt (Fe3O4/C-2) was constructed using the hydrothermal carbonization (HTC) method. HIV lentiviruses were used as a model pathogen to quantify the adsorption capacity and elucidate the adsorption mechanism. Benefiting from a macroporous structure and electrostatic interactions, fabricated Fe3O4/C-2 has a high adsorption capacity (965 ng g−1) and strong suppression of infectious activity (99.99%). Moreover, a low hemolysis ratio (<2%), high cell viability (>100%), high activated partial thromboplastin time (APTT) (67.29 s), and low protein adsorption (<5%) indicate outstanding biocompatibility and good anticoagulant activity. Therefore, Fe3O4/C-2 is expected to serve as a simple and efficient pathogen sorbent for viral diseases treatment.

Recent Visual Experience Reshapes V4 Neuronal Activity and Improves Perceptual Performance.

Recent visual experience heavily influences our visual perception, but how neuronal activity is reshaped to alter and improve perceptual discrimination remains unknown. We recorded from populations of neurons in visual cortical area V4 while two male rhesus macaque monkeys performed a natural image change detection task under different experience conditions. We found that maximizing the recent experience with a particular image led to an improvement in the ability to detect a change in that image. This improvement was associated with decreased neural responses to the image, consistent with neuronal changes previously seen in studies of adaptation and expectation. We found that the magnitude of behavioral improvement was correlated with the magnitude of response suppression. Furthermore, this suppression of activity led to an increase in signal separation, providing evidence that a reduction in activity can improve stimulus encoding. Within populations of neurons, greater recent experience was associated with decreased trial-to-trial shared variability, indicating that a reduction in variability is a key means by which experience influences perception. Taken together, the results of our study contribute to an understanding of how recent visual experience can shape our perception and behavior through modulating activity patterns in the mid-level visual cortex.

The GBA1 K198E Variant Is Associated with Suppression of Glucocerebrosidase Activity, Autophagy Impairment, Oxidative Stress, Mitochondrial Damage, and Apoptosis in Skin Fibroblasts.

Parkinson's disease (PD) is a multifactorial, chronic, and progressive neurodegenerative disorder inducing movement alterations as a result of the loss of dopaminergic (DAergic) neurons of the pars compacta in the substantia nigra and protein aggregates of alpha synuclein (α-Syn). Although its etiopathology agent has not yet been clearly established, environmental and genetic factors have been suggested as the major contributors to the disease. Mutations in the glucosidase beta acid 1 (GBA1) gene, which encodes the lysosomal glucosylceramidase (GCase) enzyme, are one of the major genetic risks for PD. We found that the GBA1 K198E fibroblasts but not WT fibroblasts showed reduced catalytic activity of heterozygous mutant GCase by -70% but its expression levels increased by 3.68-fold; increased the acidification of autophagy vacuoles (e.g., autophagosomes, lysosomes, and autolysosomes) by +1600%; augmented the expression of autophagosome protein Beclin-1 (+133%) and LC3-II (+750%), and lysosomal-autophagosome fusion protein LAMP-2 (+107%); increased the accumulation of lysosomes (+400%); decreased the mitochondrial membrane potential (∆Ψm) by -19% but the expression of Parkin protein remained unperturbed; increased the oxidized DJ-1Cys106-SOH by +900%, as evidence of oxidative stress; increased phosphorylated LRRK2 at Ser935 (+1050%) along with phosphorylated α-synuclein (α-Syn) at pathological residue Ser129 (+1200%); increased the executer apoptotic protein caspase 3 (cleaved caspase 3) by +733%. Although exposure of WT fibroblasts to environmental neutoxin rotenone (ROT, 1 μM) exacerbated the autophagy-lysosomal system, oxidative stress, and apoptosis markers, ROT moderately increased those markers in GBA1 K198E fibroblasts. We concluded that the K198E mutation endogenously primes skin fibroblasts toward autophagy dysfunction, OS, and apoptosis. Our findings suggest that the GBA1 K198E fibroblasts are biochemically and molecularly equivalent to the response of WT GBA1 fibroblasts exposed to ROT.

Vincamine exerts hepato-protective activity during colon ligation puncture-induced sepsis by modulating oxidative stress, apoptosis, and TNFα/Nrf-2/Keap-1 signaling pathways

Sepsis is a pathological and biochemical disorder induced by numerous infections, leading to critical illness and a high mortality rate worldwide. Vincamine is an indole alkaloid compound obtained from the leaves of Vinca minor. The present study aims to investigate the hepato-protective activity of vincamine during colon ligation puncture (CLP)-induced sepsis at the molecular level. Sepsis was induced using the CLP model. Liver function enzymes such as ALT and AST were analyzed. The hepatic antioxidant status (SOD and GSH), lipid peroxidation (MDA), the pro-inflammatory cytokines (TNFα, IL-6, and IL-1β), bax, bcl2, and cleaved caspase 3 proteins were estimated. Nrf-2 and Keap-1 protein expression was evaluated using western blotting. Histopathological investigation of liver tissues was also performed. CLP-induced sepsis led to liver injury through the elevation of ALT and AST liver enzymes. Oxidative stress was initiated during CLP via the suppression of hepatic GSH content and SOD activity and the elevation of MDA. The inflammatory condition was activated by the upregulation of TNFα, IL-6, IL-1β, and Keap-1 and the downregulation of Nrf-2 proteins. The apoptosis was initiated through the activation of bax and cleaved caspase 3 protein expression and inhibition of bcl2 protein expression. However, vincamine significantly improved the hepatic histological abnormalities and decreased liver enzymes (ALT and AST). It ameliorated oxidative stress, as evidenced by reducing the hepatic MDA content and increasing the SOD activity and GSH content. Moreover, vincamine reduced the hepatic content of TNFα, IL-6, IL-1β, and Keap-1 and increased Nrf-2 protein expression. Additionally, it upregulated bcl2 protein expression and downregulated bax and cleaved caspase 3 protein expression. Vincamine exhibited hepato-protective potential during CLP-induced sepsis via the cross-connection of antioxidant, anti-inflammatory, and anti-apoptotic activities by modulating TNFα/IL-6/IL-1β/Nrf-2/Keap-1 and regulating bax/bcl2/cleaved caspase 3 signaling pathways.

An active-passive integrated actuator based on macro fiber composite for on-orbit micro-vibration isolation

Micro-vibration suppression is crucial for satellites to ensure high imaging performance of optical loads. Herein, an active-passive integrated actuator based on macro fiber composite for micro-vibration isolation is proposed and investigated. Integrated passive and active vibration suppression is achieved by arraying a composite laminated beam consisting of the stiffness layer, damping layer and macro fiber composite layer. A dominant-frequency-correction hysteresis modeling strategy is devised to describe the asymmetric and rate-dependent voltage-force hysteresis of the proposed actuator. By treating the correction as a disturbance, the voltage-force hysteresis is compensated in combination with an extended state observer. In order to achieve resonance suppression, a full-estimation-feedback controller featuring merely displacement response feedback is developed exploiting the estimation of the extended state observer as feedback. Simulation results verify that the full-estimation-feedback controller is capable of suppressing the resonance peak with weak adverse effects on the transmissibility in the isolation band. Finally, experiments are performed to identify the voltage-force hysteresis model and evaluate the vibration isolation performance. Periodic and sweep excitation test results demonstrate that in passive mode, the actuator has a small resonance frequency of 2.3 Hz and a wide isolation band starting from 3.5 Hz. With the full-estimation-feedback controller, the resonance peak is effectively suppressed using a single signal feedback, while maintaining excellent vibration attenuation within the isolation band. The proposed actuator provides a paradigm for the design of active-passive integration vibration isolators for broadband micro-vibration suppression, which holds significant promise in enhancing the effectiveness of current observation missions.

Exploring antithrombotic mechanisms and effective constituents of Lagopsis supina using an integrated strategy based on network pharmacology, molecular docking, metabolomics, and experimental verification in rats

Ethnopharmacological relevanceThrombosis is a common cause of morbidity and mortality worldwide. Lagopsis supina (Stephan ex Willd.) Ikonn.-Gal. ex Knorring is an ancient Chinese herbal medicine used for treating thrombotic diseases. Nevertheless, the antithrombotic mechanisms and effective constituents of this plant have not been clarified. Aim of the studyThis work aimed to elucidate the pharmacodynamics and mechanism of L. supina against thrombosis. Materials and methodsSystematic network pharmacology was used to explore candidate effective constituents and hub targets of L. supina against thrombosis. Subsequently, the binding affinities of major constituents with core targets were verified by molecular docking analysis. Afterward, the therapeutic effect and mechanism were evaluated in an arteriovenous bypass thrombosis rat model. In addition, the serum metabolomics analysis was conducted using ultra-high performance liquid chromatography coupled with Q-Exactive mass spectrometry. ResultsA total of 124 intersected targets of L. supina against thrombosis were predicted. Among them, 24 hub targets were obtained and their mainly associated with inflammation, angiogenesis, and thrombosis approaches. Furthermore, 9 candidate effective constituents, including (22E,24R)-5α,8α-epidioxyergosta-6,22-dien-3β-ol, aurantiamide, (22E,24R)-5α,8α-epidioxyergosta-6,9 (11),22-trien-3β-ol, lagopsinA, lagopsin C, 15-epi-lagopsin C, lagopsin D, 15-epi-lagopsin D, and lagopsin G in L. supina and 6 potential core targets (TLR-4, TNF-α, HIF-1α, VEGF-A, VEGFR-2, and CLEC1B) were acquired. Then, these 9 constituents demonstrated strong binding affinities with the 6 targets, with their lowest binding energies were all less than −5.0 kcal/mol. The antithrombotic effect and potential mechanisms of L. supina were verified, showing a positively associated with the inhibition of inflammation (TNF-α, IL-1β, IL-6, IL-8, and IL-10) and coagulation cascade (TT, APTT, PT, FIB, AT-III), promotion of angiogenesis (VEGF), suppression of platelet activation (TXB2, 6-keto-PGF1α, and TXB2/6-keto-PGF1α), and prevention of fibrinolysis (t-PA, u-PA, PAI-1, PAI-1/t-PA, PAI-1/u-PA, and PLG). Finally, 14 endogenous differential metabolites from serum samples of rats were intervened by L. supina based on untargeted metabolomics analysis, which were closely related to amino acid metabolism, inflammatory and angiogenic pathways. ConclusionOur integrated strategy based on network pharmacology, molecular docking, metabolomics, and in vivo experiments revealed for the first time that L. supina exerts a significant antithrombotic effect through the inhibition of inflammation and coagulation cascade, promotion of angiogenesis, and suppression of platelet activation. This paper provides novel insight into the potential of L. supina as a candidate agent to treat thrombosis.

Angiotensin II depends on hippo/YAP signaling to reprogram angiogenesis and promote liver fibrosis

Liver fibrosis is a chronic pathological process in which the abnormal proliferation of connective tissue is induced by various pathogenic factors. During the process of fibrosis, excessive angiogenesis is observed. Physiological angiogenesis has the potential to impede the progression of liver fibrosis through augmenting matrix metalloenzyme activity; however, pathological angiogenesis can exacerbate liver fibrosis by promoting collagen accumulation. Therefore, a key scientific research focus in the treatment of liver diseases is to search for the “on-off” mechanism that regulates angiogenesis from normal proliferation to pathological proliferation. In this study, we found that excessive angiogenesis appeared during the initial phase of hepatic fibrosis without mesenchymal characteristics. In addition, angiogenesis accompanied by significant endothelial-to-mesenchymal transition (EndMT) was observed in mice after the intraperitoneal injection of angiotensin II (Ang II). Interestingly, the changes in Yes-associated protein (YAP) activity in endothelial cells (ECs) can affect the regulation of angiogenesis by Ang II. The results of in vitro experiments revealed that the regulatory influence of Ang II on ECs was significantly attenuated upon suppression of YAP activity. Furthermore, the function of Ang II in regulating angiogenesis during fibrosis was investigated in liver-specific transgenic mice. The results revealed that Ang II gene deletion could restrain liver fibrosis and EndMT. Meanwhile, Ang II deletion downregulated the profibrotic YAP signaling pathway in ECs. The small molecule AT1R agonist olmesartan targeting Ang II-YAP signaling could also alleviate liver fibrosis. In conclusion, this study identified Ang II as a pivotal regulator of EndMT during the progression of liver fibrosis and evaluated the therapeutic effect of the Ang II-targeted drug olmesartan on liver fibrosis.

Nociceptive transient receptor potential ankyrin 1 (TRPA1) in sensory neurons are targets of the antifungal drug econazole

BackgroundEconazole is a widely used imidazole derivative antifungal for treating skin infections. The molecular targets for its frequent adverse effects of skin irritation symptoms, such as pruritus, burning sensation, and pain, have not been clarified. Transient receptor potential (TRP) channels, non-selective cation channels, are mainly expressed in peripheral sensory neurons and serve as sensors for various irritants.MethodsWe investigated the effect of econazole on TRP channel activation by measuring intracellular calcium concentration ([Ca2+]i) through fluorescent ratio imaging in mouse dorsal root ganglion (DRG) neurons isolated from wild-type, TRPA1(−/−) and TRPV1(−/−) mice, as well as in heterologously TRP channel-expressed cells. A cheek injection model was employed to assess econazole-induced itch and pain in vivo.ResultsEconazole evoked an increase in [Ca2+]i, which was abolished by the removal of extracellular Ca2+ in mouse DRG neurons. The [Ca2+]i responses to econazole were suppressed by a TRPA1 blocker but not by a TRPV1 blocker. Attenuation of the econazole-induced [Ca2+]i responses was observed in the TRPA1(−/−) mouse DRG neurons but was not significant in the TRPV1(−/−) neurons. Econazole increased the [Ca2+]i in HEK293 cells expressing TRPA1 (TRPA1-HEK) but not in those expressing TRPV1, although at higher concentrations, it induced Ca2+ mobilization from intracellular stores in untransfected naïve HEK293 cells. Miconazole, which is a structural analog of econazole, also increased the [Ca2+]i in mouse DRG neurons and TRPA1-HEK, and its nonspecific action was larger than econazole. Fluconazole, a triazole drug failed to activate TRPA1 and TRPV1 in mouse DRG neurons and TRPA1-HEK. Econazole induced itch and pain in wild-type mice, with reduced responses in TRPA1(−/−) mice.ConclusionsThese findings suggested that the imidazole derivatives econazole and miconazole may induce skin irritation by activating nociceptive TRPA1 in the sensory neurons. Suppression of TRPA1 activation may mitigate the adverse effects of econazole.

ANXA5 predicts prognosis and immune response and mediates proliferation and migration in head and neck squamous cell carcinoma

BackgroundHead and neck squamous cell carcinoma (HNSCC) is a common malignancy that often develops unnoticed. Typically, these tumors are identified at advanced stages, resulting in a relatively low chance of successful treatment. Anoikis serves as a natural defense against the spread of tumor cells, meaning circumventing anoikis can effectively inhibit tumor metastasis. Nonetheless, studies focusing on anoikis in the context of HNSCC remain scarce. MethodsAnoikis-related genes (ARGs) were identified by using the GeneCards and Harmonizome databases. Expression data of these genes and relevant clinical features were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. A LASSO regression and a prognostic risk score model were developed to determine their prognostic significance. The analysis included the use of the CIBERSORT algorithm to quantify immune and stromal cell presence. Furthermore, in vitro and in vivo, we confirmed the expression and functional roles of proteins and mRNA of genes independently predictive of prognosis. ResultsThe study identified eight genes linked to prognosis (ANXA5, BAK1, CDKN2A, PPARG, CCR7, MAPK11, CRYAB, CRYBA1) and developed a prognostic model that effectively forecasts the survival outcomes for patients with HNSCC. A higher survival likelihood is associated with lower risk scores. In addition, a significant relationship was found between immune and risk score, and ANXA5 deletion promoted the killing of HNSCC cells by activated CD8+ T cells. During the screening process, 65 different chemotherapeutic drugs were found to have significant differences in IC50 values when comparing high- and low-risk categories. ANXA5 emerged as a gene with independent prognostic significance, exhibiting notably elevated protein and mRNA levels in HNSCC tissue compared to non-tumorous tissue. The suppression of ANXA5 gene activity resulted in a substantial decrease in both the growth and mobility of HNSCC cells. Animal model experiments demonstrated that inhibiting ANXA5 suppressed HNSCC growth and migration in vivo. ConclusionThrough bioinformatics, a prognostic risk model of high precision was developed, offering valuable insights into the survival rates and immune responses in patients with HNSCC. ANXA5 is highlighted as a significant prognostic factor among the identified genes, indicating its promise as a potential therapeutic target for those with HNSCC.

Discovery of a Covalent Inhibitor of Pro-Caspase-1 Zymogen Blocking NLRP3 Inflammasome Activation and Pyroptosis.

Caspase-1 plays a central role in innate immunity, as its activation by inflammasomes induces the production of proinflammatory cytokines and pyroptosis. However, specific inhibition of the enzymatic activity of this protease is not effective in suppressing inflammation, owing to its enzyme-independent function. Herein, we identified a cyclohexenyl isothiocyanate compound (CIB-1476) that potently inhibited caspase-1 activity and suppressed the assembly and activation of the NLRP3 inflammasome and gasdermin-D-mediated pyroptosis. Mechanistically, CIB-1476 directly targeted pro-caspase-1 as an irreversible covalent inhibitor by binding to Cys285 and Cys397, resulting in more durable anti-inflammatory effects in the suppression of enzyme-dependent IL-1β production and enzyme-independent nuclear factor κB activation. Chemoproteomic profiling demonstrated the engagement of CIB-1476 with caspase-1. CIB-1476 showed potent therapeutic effects by suppressing inflammasome activation in mice, which was abolished in Casp1-/- mice. These results warrant further development of CIB-1476 along with its analogues as a novel strategy for caspase-1 inhibitors.

Active disturbance rejection control for piezoelectric cantilever beam with time delay

This Letter presents an active control method for the vibration of piezoelectric structures. First, a controller based on nonlinear extended state observer is designed to improve the disturbance rejection capability of the vibration structure. Additionally, an improved nonlinear active disturbance rejection control (IMNADRC) method is combined with Smith predictor for time delay compensation, resulting in Smith predictor-based IMNADRC. Finally, numerical simulations and experiments are carried out for active vibration suppression of piezoelectric beam under fixed harmonic excitation and variable harmonic excitation, respectively. The results show that the proposed method has good control effect on structural vibration suppression and is highly adaptable to various external excitations.