Junctionless Structure Indium-Tin Oxide Thin-Film Transistors Enabling Enhanced Mechanical and Contact Stability.

In recent years, considerable attention has focused on high-performance and flexible crystalline metal oxide thin-film transistors (TFTs). However, achieving both high performance and flexibility in semiconductor devices is challenging due to the inherently conductive and brittle nature of crystalline metal oxide. In this study, we propose a facile way to overcome this limitation by employing a junctionless (JL) TFT structure via oxygen plasma treatment of the crystalline indium-tin oxide (ITO) films. The oxygen plasma treatment significantly reduced oxygen vacancies in the ITO films, contributing to the significant reduction in the carrier concentration from 4.67 × 1020 to 1.39 × 1016. Importantly, this reduction was achieved without inducing any noticeable structural changes in the ITO, enabling the successful realization of ITO JL TFTs with an adjustable threshold voltage. Furthermore, the ITO JL TFTs demonstrate good stability and reliability under various bias stress conditions, aging in the air atmosphere, and high-temperature processes. In addition, the ITO JL TFTs exhibit low light sensitivity due to the wide bandgap of ITO and further suppression of Vo defects, making them suitable for applications requiring stable performance under light exposure. To compare and analyze the flexibility of the JL structure and conventional structure with additional source/drain (S/D) junction in ITO TFTs with nonencapsulation, we utilized mechanical simulations and transmission line method (TLM). By employing the JL structure in ITO TFT through carefully optimized oxygen plasma treatment, we successfully mitigated stress concentration at the S/D-channel interface. This resulted in a JL ITO TFT that exhibited a change in contact resistance of less than 20% even after 20,000 bending cycles. Consequently, a stable and flexible ITO TFT with field-effect mobility (µFE) of 12.74 cm2/(V s) was realized, outperforming conventionally structured ITO TFTs with additional S/D junction, where the contact resistance nearly tripled.

Disparities in cause-specific mortality by health insurance type and premium: evidence from Korean NHIS-HEALS cohort study, 2002-2019.

BACKGROUND: Although one's socioeconomic status affects health outcomes, limited research explored how South Korea's National Health Insurance (NHI) system affects mortality rates. This study investigated whether health insurance type and insurance premiums are associated with mortality. METHODS: Based on the National Health Insurance Service-Health Screening cohort, 246,172 men and 206,534 women aged ≥ 40 years at baseline (2002-2003) were included and followed until 2019. Health insurance type was categorized as employee-insured (EI) or self-employed-insured (SI). To define low, medium, and high economic status groups, we used insurance premiums at baseline. Death was determined using the date and cause of death included in the cohort. Cox proportional hazard models were used to analyze the association between insurance factors and the overall and cause-specific mortality. RESULTS: The SI group had a significantly higher risk of overall death compared to the EI group (adjusted hazard ratio (HR) [95% confidence interval]: 1.13 [1.10-1.15] for men and 1.18 [1.15-1.22] for women), after adjusting for various factors. This trend extended to death from the five major causes of death in South Korea (cancer, cardiovascular disease, cerebrovascular disease, pneumonia, and intentional self-harm) and from external causes, with a higher risk of death in the SI group (vs. the EI group). Further analysis stratified by economic status revealed that individuals with lower economic status faced higher risk of overall death and cause-specific mortality in both sexes, compared to those with high economic status for both health insurance types. CONCLUSION: This nationwide study found that the SI group and those with lower economic status faced higher risk of overall mortality and death from the five major causes in South Korea. These findings highlight the potential disparities in health outcomes within the NHI system. To address these gaps, strategies should target risk factors for death at the individual level and governments should incorporate such strategies into public health policy development at the population level. TRIAL REGISTRATION: This study was approved by the Institutional Review Board of Chungbuk National University Hospital (CBNUH-202211-HR-0236) and adhered to the principles of the Declaration of Helsinki (1975).

Characterization of high Zn content Cd0.87Zn0.13Te0.98Se0.02 grown using Bridgman technique.

CdZnTe (CZT) is a promising commercial material used as a room-temperature operating semiconductor detector for gamma-ray detection. Recently, CdZnTeSe (CZTS) detectors improved upon the properties of CZT by improving homogeneity and reducing defect properties, thereby enabling higher production yield of high-quality crystals. However, addition of selenium to CZT will reduce the bandgap and increase the amount of thermally stimulated electrons, resulting in low resistivity of the crystal. In this study, the enhancement of zinc content was introduced to compensate the bandgap reduction owing to selenium addition, while maintaining the improved properties of selenium addition. The morphology and stoichiometry of CZTS were determined using scanning electron microscopy and electron probe micro-analyzer. Furthermore, the calculated bandgap with stoichiometry was compared with the measured bandgap using UV-Vis measurement and Tauc plot. The electrical, chemical, and other spectroscopic properties were characterized using an I-V curve, X-ray photoelectron spectroscopy, and gamma-spectroscopic techniques, respectively. Moreover, it was proven that the high zinc CZTS can exhibit superior properties owing to selenium addition without affecting the bandgap reduction.

Clinical machine learning predicting best stroke rehabilitation responders to exoskeletal robotic gait rehabilitation.

BACKGROUND: Although clinical machine learning (ML) algorithms offer promising potential in forecasting optimal stroke rehabilitation outcomes, their specific capacity to ascertain favorable outcomes and identify responders to robotic-assisted gait training (RAGT) in individuals with hemiparetic stroke undergoing such intervention remains unexplored. OBJECTIVE: We aimed to determine the best predictive model based on the international classification of functioning impairment domain features (Fugl- Meyer assessment (FMA), Modified Barthel index related-gait scale (MBI), Berg balance scale (BBS)) and reveal their responsiveness to robotic assisted gait training (RAGT) in patients with subacute stroke. METHODS: Data from 187 people with subacute stroke who underwent a 12-week Walkbot RAGT intervention were obtained and analyzed. Overall, 18 potential predictors encompassed demographic characteristics and the baseline score of functional and structural features. Five predictive ML models, including decision tree, random forest, eXtreme Gradient Boosting, light gradient boosting machine, and categorical boosting, were used. RESULTS: The initial and final BBS, initial BBS, final Modified Ashworth scale, and initial MBI scores were important features, predicting functional improvements. eXtreme Gradient Boosting demonstrated superior performance compared to other models in predicting functional recovery after RAGT in patients with subacute stroke. CONCLUSION: eXtreme Gradient Boosting may be an invaluable prognostic tool, providing clinicians and caregivers with a robust framework to make precise clinical decisions regarding the identification of optimal responders and effectively pinpoint those who are most likely to derive maximum benefits from RAGT interventions.

Autonomous Artificial Olfactory Sensor Systems with Homeostasis Recovery via a Seamless Neuromorphic Architecture.

Neuromorphic olfactory systems have been actively studied in recent years owing to their considerable potential in electronic noses, robotics, and neuromorphic data processing systems. However, conventional gas sensors typically have the ability to detect hazardous gas levels but lack synaptic functions such as memory and recognition of gas accumulation, which are essential for realizing human-like neuromorphic sensory system. In this study, a seamless architecture for a neuromorphic olfactory system capable of detecting and memorizing the present level and accumulation status of nitrogen dioxide (NO2) during continuous gas exposure, regulating a self-alarm implementation triggered after 147 and 85 s at a continuous gas exposure of 20 and 40 ppm, respectively. Thin-film-transistor type gas sensors utilizing carbon nanotube semiconductors detect NO2 gas molecules through carrier trapping and exhibit long-term retention properties, which are compatible with neuromorphic excitatory applications. Additionally, the neuromorphic inhibitory performance is also characterized via gas desorption with programmable ultraviolet light exposure, demonstrating homeostasis recovery. These results provide a promising strategy for developing a facile artificial olfactory system that demonstrates complicated biological synaptic functions with a seamless and simplified system architecture.

The secreted protein Amuc_1409 from Akkermansia muciniphila improves gut health through intestinal stem cell regulation.

Akkermansia muciniphila has received great attention because of its beneficial roles in gut health by regulating gut immunity, promoting intestinal epithelial development, and improving barrier integrity. However, A. muciniphila-derived functional molecules regulating gut health are not well understood. Microbiome-secreted proteins act as key arbitrators of host-microbiome crosstalk through interactions with host cells in the gut and are important for understanding host-microbiome relationships. Herein, we report the biological function of Amuc_1409, a previously uncharacterised A. muciniphila-secreted protein. Amuc_1409 increased intestinal stem cell (ISC) proliferation and regeneration in ex vivo intestinal organoids and in vivo models of radiation- or chemotherapeutic drug-induced intestinal injury and natural aging with male mice. Mechanistically, Amuc_1409 promoted E-cadherin/ß-catenin complex dissociation via interaction with E-cadherin, resulting in the activation of Wnt/ß-catenin signaling. Our results demonstrate that Amuc_1409 plays a crucial role in intestinal homeostasis by regulating ISC activity in an E-cadherin-dependent manner and is a promising biomolecule for improving and maintaining gut health.

Full integration of highly stretchable inorganic transistors and circuits within molecular-tailored elastic substrates on a large scale.

The emergence of high-form-factor electronics has led to a demand for high-density integration of inorganic thin-film devices and circuits with full stretchability. However, the intrinsic stiffness and brittleness of inorganic materials have impeded their utilization in free-form electronics. Here, we demonstrate highly integrated strain-insensitive stretchable metal-oxide transistors and circuitry (442 transistors/cm2) via a photolithography-based bottom-up approach, where transistors with fluidic liquid metal interconnection are embedded in large-area molecular-tailored heterogeneous elastic substrates (5 × 5 cm2). Amorphous indium-gallium-zinc-oxide transistor arrays (7 × 7), various logic gates, and ring-oscillator circuits exhibited strain-resilient properties with performance variation less than 20% when stretched up to 50% and 30% strain (10,000 cycles) for unit transistor and circuits, respectively. The transistors operate with an average mobility of 12.7 ( ± 1.7) cm2 V-1s-1, on/off current ratio of > 107, and the inverter, NAND, NOR circuits operate quite logically. Moreover, a ring oscillator comprising 14 cross-wired transistors validated the cascading of the multiple stages and device uniformity, indicating an oscillation frequency of ~70 kHz.

High-κ Dielectric (HfO2)/2D Semiconductor (HfSe2) Gate Stack for Low-Power Steep-Switching Computing Devices.

Herein, a high-quality gate stack (native HfO2 formed on 2D HfSe2) fabricated via plasma oxidation is reported, realizing an atomically sharp interface with a suppressed interface trap density (Dit ≈ 5 × 1010 cm-2 eV-1). The chemically converted HfO2 exhibits dielectric constant, κ ≈ 23, resulting in low gate leakage current (≈10-3 A cm-2) at equivalent oxide thickness ≈0.5 nm. Density functional calculations indicate that the atomistic mechanism for achieving a high-quality interface is the possibility of O atoms replacing the Se atoms of the interfacial HfSe2 layer without a substitution energy barrier, allowing layer-by-layer oxidation to proceed. The field-effect-transistor-fabricated HfO2/HfSe2 gate stack demonstrates an almost ideal subthreshold slope (SS) of ≈61 mV dec-1 (over four orders of IDS) at room temperature (300 K), along with a high Ion/Ioff ratio of ≈108 and a small hysteresis of ≈10 mV. Furthermore, by utilizing a device architecture with separately controlled HfO2/HfSe2 gate stack and channel structures, an impact ionization field-effect transistor is fabricated that exhibits n-type steep-switching characteristics with a SS value of 3.43 mV dec-1 at room temperature, overcoming the Boltzmann limit. These results provide a significant step toward the realization of post-Si semiconducting devices for future energy-efficient data-centric computing electronics.

ERRγ-inducible FGF23 promotes alcoholic liver injury through enhancing CYP2E1 mediated hepatic oxidative stress.

Fibroblast growth factor 23 (FGF23) is a member of endocrine FGF family, along with FGF15/19 and FGF21. Recent reports showed that under pathological conditions, liver produces FGF23, although the role of hepatic FGF23 remains nebulous. Here, we investigated the role of hepatic FGF23 in alcoholic liver disease (ALD) and delineated the underlying molecular mechanism. FGF23 expression was compared in livers from alcoholic hepatitis patients and healthy controls. The role of FGF23 was examined in hepatocyte-specific knock-out (LKO) mice of cannabinoid receptor type 1 (CB1R), estrogen related receptor γ (ERRγ), or FGF23. Animals were fed with an alcohol-containing liquid diet alone or in combination with ERRγ inverse agonist. FGF23 is mainly expressed in hepatocytes in the human liver, and it is upregulated in ALD patients. In mice, chronic alcohol feeding leads to liver damage and induced FGF23 in liver, but not in other organs. FGF23 is transcriptionally regulated by ERRγ in response to alcohol-mediated activation of the CB1R. Alcohol induced upregulation of hepatic FGF23 and plasma FGF23 levels is lost in ERRγ-LKO mice, and an inverse agonist mediated inhibition of ERRγ transactivation significantly improved alcoholic liver damage. Moreover, hepatic CYP2E1 induction in response to alcohol is FGF23 dependent. In line, FGF23-LKO mice display decreased hepatic CYP2E1 expression and improved ALD through reduced hepatocyte apoptosis and oxidative stress. We recognized CBIR-ERRγ-FGF23 axis in facilitating ALD pathology through hepatic CYP2E1 induction. Thus, we propose FGF23 as a potential therapeutic target to treat ALD.

Macrophage stimulating protein is a novel transcriptional target of estrogen related receptor gamma in alcohol-intoxicated mice.

Macrophage stimulating protein (MSP) is a multifunctional serum protein produced in the liver, belonging to the plasminogen-related kringle protein family. It exerts diverse biological functions by activating a transmembrane receptor protein-tyrosine kinase known as RON in humans and SKT in mice. MSP plays a pivotal role in innate immunity and is involved in various activities such as cell survival, migration, and phagocytosis. Elucidating the regulatory mechanisms governing MSP gene expression is of great importance. In this study, we comprehensively elucidate the molecular mechanism underlying hepatic MSP gene expression in response to alcoholism. Exposure to ethanol specifically upregulated the expression of ERRγ and MSP in the liver, while not in other organs. Liver-specific knockout of the cannabinoid receptor type 1 (CB1R), an upstream regulator of ERRγ, inhibited the alcohol-induced upregulation of MSP expression. Overexpression of ERRγ alone was sufficient to enhance MSP expression in hepatic cell lines and in mice. Conversely, knockdown of ERRγ in cell lines or liver-specific knockout of ERRγ in mice reversed ethanol-induced MSP gene expression. Promoter studies revealed the direct binding of ERRγ to the MSP gene promoter at the ERR response element (ERRE), resulting in the positive regulation of MSP gene expression in response to alcohol. This finding was further supported by ERRE-mutated MSP-luciferase reporter assays. Notably, treatment with GSK5182, an ERRγ-specific inverse agonist, significantly suppressed alcohol-induced hepatic MSP expression. Collectively, we exposed a novel mechanistic understanding of how alcohol-induced ERRγ controls the transcriptional regulation of MSP gene expression in the liver.

The Effectiveness of a Neurofeedback-Assisted Mindfulness Training Program Using a Mobile App on Stress Reduction in Employees: Randomized Controlled Trial.

BACKGROUND: Mindfulness-based training programs have consistently shown efficacy in stress reduction. However, questions regarding the optimal duration and most effective delivery methods remain. OBJECTIVE: This research explores a 4-week neurofeedback-assisted mindfulness training for employees via a mobile app. The study's core query is whether incorporating neurofeedback can amplify the benefits on stress reduction and related metrics compared with conventional mindfulness training. METHODS: A total of 92 full-time employees were randomized into 3 groups: group 1 received mobile mindfulness training with neurofeedback assistance (n=29, mean age 39.72 years); group 2 received mobile mindfulness training without neurofeedback (n=32, mean age 37.66 years); and group 3 were given self-learning paper materials on stress management during their first visit (n=31, mean age 38.65 years). The primary outcomes were perceived stress and resilience scales. The secondary outcomes were mindfulness awareness, emotional labor, occupational stress, insomnia, and depression. Heart rate variability and electroencephalography were measured for physiological outcomes. These measurements were collected at 3 different times, namely, at baseline, immediately after training, and at a 4-week follow-up. The generalized estimating equation model was used for data analysis. RESULTS: The 4-week program showed significant stress reduction (Wald χ22=107.167, P<.001) and improvements in psychological indices including resilience, emotional labor, insomnia, and depression. A significant interaction was observed in resilience (time × group, Wald χ42=10.846, P=.02). The post hoc analysis showed a statistically significant difference between groups 1 (least squares mean [LSM] 21.62, SE 0.55) and 3 (LSM 19.90, SE 0.61) at the posttraining assessment (P=.008). Group 1 showed a significant improvement (P<.001) at the posttraining assessment, with continued improvements through the 1-month follow-up assessment period (LSM 21.55, SE 0.61). Physiological indices were analyzed only for data of 67 participants (22 in group 1, 22 in group 2, and 23 in group 3) due to the data quality. The relaxation index (ratio of alpha to high beta power) from the right electroencephalography channel showed a significant interaction (time × group, Wald χ22=6.947, P=.03), with group 1 revealing the highest improvement (LSM 0.43, SE 0.15) compared with groups 2 (LSM -0.11, SE 0.10) and 3 (LSM 0.12, SE 0.10) at the 1-month follow-up assessment. CONCLUSIONS: The study demonstrated that the neurofeedback-assisted group achieved superior outcomes in resilience and relaxation during the 4-week mobile mindfulness program. Further research with larger samples and long-term follow-up is warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT03787407; https://clinicaltrials.gov/ct2/show/NCT03787407.

Humulus japonicus ameliorates irritant contact dermatitis by suppressing NF­κB p65­dependent inflammatory responses in mice.

As a type of contact dermatitis (CD), irritant CD (ICD) is an acute skin inflammation caused by external irritants, such as soap, water and chemicals. Humulus japonicus (HJ) is a herbal medicine widely distributed in Asian countries and has anti-inflammatory, antimicrobial and antioxidant effects. The current study aimed to investigate the anti-dermatitis effect of HJ on ICD and determine the molecular basis of this effect using 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced dermatitis mice models and lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Mice were orally administered HJ and luteolin, the major compound in HJ, and topically administered TPA on the right ear to induce dermatitis. Topical application of TPA induced ear redness, oedema and increased infiltration of neutrophils and macrophages, which ameliorated following HJ and luteolin administration. The gene expression levels of inflammatory cell migrating chemokines, chemokine ligand 3 (CCL3) and chemokine (C-X-C motif) ligand 2 (CXCL2), and pro-inflammatory cytokine, IL-1ß, were reduced in the ears of HJ- and luteolin-treated mice. HJ and luteolin also inhibited the gene expression of chemokines, CCL3 and CXCL2, and pro-inflammatory cytokines, IL-1ß, IL-6 and TNF-α, in LPS-stimulated RAW264.7 cells. Moreover, HJ and luteolin decreased the expression levels of two key inflammatory enzymes, cyclooxygenase-2 (COX2) and inducible nitric oxide synthase (iNOS), and total and active phosphorylation of NF-κB p65. These results suggest that HJ could have a protective effect against ICD by suppressing inflammatory responses; therefore, HJ is a promising therapeutic strategy for ICD treatment.

Phantom study of layered sensor module for photon-counting BMD detector.

In this study, we perform bone mineral density (BMD) calculation by designing a layered sensor module (LSM) that divides high- and low-energy spectra from a single shot of X-rays. Gamma-ray evaluation supports this mechanism; low-energy gamma rays are absorbed in the front detector, whereas high-energy gamma rays are absorbed in the rear detector. In this phantom study, LSM divides a single shot of X-ray into two spectra with different distributions of energy, thereby affording X-ray images with different properties, such as contrast and gray scale. The region of interest (ROI) is classified by the Prewitt operator to sort the pixels for BMD calculation or Rs value. The calculated final value is 1.2051 g/cm2 with a standard deviation (SD) of 0.3690 g/cm2, as obtained from our previous study. An improved SD results from the layered structure with two channels for signal processing, the introduction of Rs value, and the use of Prewitt filter to sort reliable data. Overall, this study displays the feasibility of LSM for BMD calculation with a small error, thereby enabling the diagnosis of osteoporosis with novel mechanism.

Localized coherent phonon generation in monolayer MoSe2 from ultrafast exciton trapping at shallow traps.

We report spectroscopic evidence for the ultrafast trapping of band edge excitons at defects and the subsequent generation of defect-localized coherent phonons (CPs) in monolayer MoSe2. While the photoluminescence measurement provides signals of exciton recombination at both shallow and deep traps, our time-resolved pump-probe spectroscopy on the sub-picosecond time scale detects localized CPs only from the ultrafast exciton trapping at shallow traps. Based on occupation-constrained density functional calculations, we identify the Se vacancy and the oxygen molecule adsorbed on a Se vacancy as the atomistic origins of deep and shallow traps, respectively. Establishing the correlations between the defect-induced ultrafast exciton trapping and the generation of defect-localized CPs, our work could open up new avenues to engineer photoexcited carriers through lattice defects in two-dimensional materials.

Metal-Oxide Heterojunction Optoelectronic Synapse and Multilevel Memory Devices Enabled by Broad Spectral Photocarrier Modulation.

Broad spectral response and high photoelectric conversion efficiency are key milestones for realizing multifunctional, low-power optoelectronic devices such as artificial synapse and reconfigurable memory devices. Nevertheless, the wide bandgap and narrow spectral response of metal-oxide semiconductors are problematic for efficient metal-oxide optoelectronic devices such as photonic synapse and optical memory devices. Here, a simple titania (TiO2 )/indium-gallium-zinc-oxide (IGZO) heterojunction structure is proposed for efficient multifunctional optoelectronic devices, enabling widen spectral response range and high photoresponsivity. By overlaying a TiO2 film on IGZO, the light absorption range extends to red light, along with enhanced photoresponsivity in the full visible light region. By implementing the TiO2 /IGZO heterojunction structure, various synaptic behaviors are successfully emulated such as short-term memory/long-term memory and paired pulse facilitation. Also, the TiO2 /IGZO synaptic transistor exhibits a recognition rate up to 90.3% in recognizing handwritten digit images. Moreover, by regulating the photocarrier dynamics and retention behavior using gate-bias modulation, a reconfigurable multilevel (≥8 states) memory is demonstrated using visible light.

Heterogeneous Structure Omnidirectional Strain Sensor Arrays With Cognitively Learned Neural Networks.

Mechanically stretchable strain sensors gain tremendous attention for bioinspired skin sensation systems and artificially intelligent tactile sensors. However, high-accuracy detection of both strain intensity and direction with simple device/array structures is still insufficient. To overcome this limitation, an omnidirectional strain perception platform utilizing a stretchable strain sensor array with triangular-sensor-assembly (three sensors tilted by 45°) coupled with machine learning (ML) -based neural network classification algorithm, is proposed. The strain sensor, which is constructed with strain-insensitive electrode regions and strain-sensitive channel region, can minimize the undesirable electrical intrusion from the electrodes by strain, leading to a heterogeneous surface structure for more reliable strain sensing characteristics. The strain sensor exhibits decent sensitivity with gauge factor (GF) of ≈8, a moderate sensing range (≈0-35%), and relatively good reliability (3000 stretching cycles). More importantly, by employing a multiclass-multioutput behavior-learned cognition algorithm, the stretchable sensor array with triangular-sensor-assembly exhibits highly accurate recognition of both direction and intensity of an arbitrary strain by interpretating the correlated signals from the three-unit sensors. The omnidirectional strain perception platform with its neural network algorithm exhibits overall strain intensity and direction accuracy around 98% ± 2% over a strain range of ≈0-30% in various surface stimuli environments.

Endothelial PTP4A1 mitigates vascular inflammation via USF1/A20 axis-mediated NF-κB inactivation.

AIMS: The nuclear factor-κB (NF-κB) signalling pathway plays a critical role in the pathogenesis of multiple vascular diseases. However, in endothelial cells (ECs), the molecular mechanisms responsible for the negative regulation of the NF-κB pathway are poorly understood. In this study, we investigated a novel role for protein tyrosine phosphatase type IVA1 (PTP4A1) in NF-κB signalling in ECs. METHODS AND RESULTS: In human tissues, human umbilical artery ECs, and mouse models for loss of function and gain of function of PTP4A1, we conducted histological analysis, immunostaining, laser-captured microdissection assay, lentiviral infection, small interfering RNA transfection, quantitative real-time PCR and reverse transcription-PCR, as well as luciferase reporter gene and chromatin immunoprecipitation assays. Short hairpin RNA-mediated knockdown of PTP4A1 and overexpression of PTP4A1 in ECs indicated that PTP4A1 is critical for inhibiting the expression of cell adhesion molecules (CAMs). PTP4A1 increased the transcriptional activity of upstream stimulatory factor 1 (USF1) by dephosphorylating its S309 residue and subsequently inducing the transcription of tumour necrosis factor-alpha-induced protein 3 (TNFAIP3/A20) and the inhibition of NF-κB activity. Studies on Ptp4a1 knockout or transgenic mice demonstrated that PTP4A1 potently regulates the interleukin 1ß-induced expression of CAMs in vivo. In addition, we verified that PTP4A1 deficiency in apolipoprotein E knockout mice exacerbated high-fat high-cholesterol diet-induced atherogenesis with upregulated expression of CAMs. CONCLUSION: Our data indicate that PTP4A1 is a novel negative regulator of vascular inflammation by inducing USF1/A20 axis-mediated NF-κB inactivation. Therefore, the expression and/or activation of PTP4A1 in ECs might be useful for the treatment of vascular inflammatory diseases.

KLK6/PAR1 Axis Promotes Tumor Growth and Metastasis by Regulating Cross-Talk between Tumor Cells and Macrophages.

Kallikrein-related peptidase (KLK)6 is associated with inflammatory diseases and neoplastic progression. KLK6 is aberrantly expressed in several solid tumors and regulates cancer development, metastatic progression, and drug resistance. However, the function of KLK6 in the tumor microenvironment remains unclear. This study aimed to determine the role of KLK6 in the tumor microenvironment. Here, we uncovered the mechanism underlying KLK6-mediated cross-talk between cancer cells and macrophages. Compared with wild-type mice, KLK6-/- mice showed less tumor growth and metastasis in the B16F10 melanoma and Lewis lung carcinoma (LLC) xenograft model. Mechanistically, KLK6 promoted the secretion of tumor necrosis factor-alpha (TNF-α) from macrophages via the activation of protease-activated receptor-1 (PAR1) in an autocrine manner. TNF-α secreted from macrophages induced the release of the C-X-C motif chemokine ligand 1 (CXCL1) from melanoma and lung carcinoma cells in a paracrine manner. The introduction of recombinant KLK6 protein in KLK6-/- mice rescued the production of TNF-α and CXCL1, tumor growth, and metastasis. Inhibition of PAR1 activity suppressed these malignant phenotypes rescued by rKLK6 in vitro and in vivo. Our findings suggest that KLK6 functions as an important molecular link between macrophages and cancer cells during malignant progression, thereby providing opportunities for therapeutic intervention.

Hepatocyte DAX1 Deletion Exacerbates Inflammatory Liver Injury by Inducing the Recruitment of CD4+ and CD8+ T Cells through NF-κB p65 Signaling Pathway in Mice.

Fulminant hepatitis is characterized by rapid and massive immune-mediated liver injury. Dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1 (DAX1; NR0B1) represses the transcription of various genes. Here, we determine whether DAX1 serves as a regulator of inflammatory liver injury induced by concanavalin A (ConA). C57BL/6J (WT), myeloid cell-specific Dax1 knockout (MKO), and hepatocyte-specific Dax1 knockout (LKO) mice received single intravenous administration of ConA. Histopathological changes in liver and plasma alanine aminotransferase and aspartate aminotransferase levels in Dax1 MKO mice were comparable with those in WT mice following ConA administration. Unlike Dax1 MKO mice, Dax1 LKO mice were greatly susceptible to ConA-induced liver injury, which was accompanied by enhanced infiltration of immune cells, particularly CD4+ and CD8+ T cells, in the liver. Factors related to T-cell recruitment, including chemokines and adhesion molecules, significantly increased following enhanced and prolonged phosphorylation of NF-κB p65 in the liver of ConA-administered Dax1 LKO mice. This is the first study to demonstrate that hepatocyte-specific DAX1 deficiency exacerbates inflammatory liver injury via NF-κB p65 activation, thereby causing T-cell infiltration by modulating inflammatory chemokines and adhesion molecules. Our results suggest DAX1 as a therapeutic target for fulminant hepatitis treatment.