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Purpose This study aimed to assess the survival rate (SR) and death risk for associated pulmonary arterial hypertension (aPAH; 10th revision of the International Statistical Classification of Diseases [ICD-10], I27.2) in Koreans. Methods The data were collected from the Korean National Health Insurance Service from 2006 through 2017 (n= 15,448). We analyzed the SR using the Kaplan-Meier method and carried out Cox proportional hazards analyses. Results Patients’ mean age upon aPAH diagnosis was 60.1±24.0 years, and 60.7% of the patients were female. The 10-year SR of aPAH was 46.3% (95% confidence interval, 45.0 to 47.6). The factors associated with an increase in the adjusted death risk included age of 0 to 9 years, advancing age, male sex, lower income level, and comorbidities including diabetes mellitus, myocardial infarction, heart failure, hemorrhagic stroke, chronic kidney disease, malignant neoplasm, hereditary hemorrhagic telangiectasia, and systemic lupus erythematosus. Conclusion The 10-year SR of aPAH was over 46%. The risk of death from aPAH was significantly higher with advancing age, sex, lower income level, and comorbidities.

Abstract Background Data regarding the clinical effects of bacteremia on severe community-acquired pneumonia (CAP) are limited. Thus, we investigated clinical characteristics and outcomes of severe CAP patients with bacteremia compared with those of subjects without bacteremia. In addition, we evaluated clinical factors associated with bacteremia at the time of sepsis awareness. Methods We enrolled sepsis patients diagnosed with CAP at emergency departments (EDs) from an ongoing nationwide multicenter observational registry, the Korean Sepsis Alliance, between September 2019 and December 2020. For evaluation of clinical factors associated with bacteremia, we divided eligible patients into bacteremia and non-bacteremia groups, and logistic regression analysis was performed using the clinical characteristics at the time of sepsis awareness. Result During the study period, 1,510 (47.9%) sepsis patients were caused by CAP, and bacteremia was identified in 212 (14.0%) patients. Septic shock occurred more frequently in the bacteremia group than in the non-bacteremia group (27.4% vs. 14.8%; p

Abstract Idiopathic pulmonary fibrosis (IPF) is a chronic, fatal, fibrotic, interstitial lung disease of unknown cause. Despite extensive studies, the underlying mechanisms of IPF development remain unknown. Here, we found that p300 was upregulated in multiple epithelial cells in lung samples from patients with IPF and mouse models of lung fibrosis. Lung fibrosis was significantly diminished by the alveolar type II (ATII) cell–specific deletion of the p300 gene. Moreover, we found that ubiquitin C-terminal hydrolase L3 (UCHL3)-mediated deubiquitination of p300 led to the transcriptional activation of the chemokines Ccl2, Ccl7, and Ccl12 through the cooperative action of p300 and C/EBPβ, which consequently promoted M2 macrophage polarization. Selective blockade of p300 activity in ATII cells resulted in the reprogramming of M2 macrophages into antifibrotic macrophages. These findings demonstrate a pivotal role for p300 in the development of lung fibrosis and suggest that p300 could serve as a promising target for IPF treatment.

Chd8+/N2373K mice with a human C-terminal-truncating mutation (N2373K) display autistic-like behaviors in juvenile and adult males but not in females. In contrast, Chd8+/S62X mice with a human N-terminal-truncating mutation (S62X) display behavioral deficits in juvenile males (not females) and adult males and females, indicative of age-differential sexually dimorphic behaviors. Excitatory synaptic transmission is suppressed and enhanced in male and female Chd8+/S62X juveniles, respectively, but similarly enhanced in adult male and female mutants. ASD-like transcriptomic changes are stronger in newborn and juvenile (but not adult) Chd8+/S62X males but in newborn and adult (not juvenile) Chd8+/S62X females. These results point to age-differential sexual dimorphisms in Chd8+/S62X mice at synaptic and transcriptomic levels, in addition to the behavioral level.

Autism spectrum disorders (ASD) are ~4-times more common in males than females, and CHD8 (a chromatin remodeler)-related ASD shows a strong male bias (~4:1), although the underlying mechanism remains unclear. Chd8-mutant mice with a C-terminal protein-truncating mutation (N2373K) display male-preponderant behavioral deficits as juveniles and adults, although whether this also applies to other Chd8 mutations remains unknown. In addition, it remains unclear whether sexually dimorphic phenotypes in Chd8-mutant mice are differentially observed in males and females across different ages. We here generated new Chd8-mutant (knock-in) mice carrying a patient-derived mutation causing an N-terminal and stronger protein truncation (Chd8+/S62X mice) and characterized the mice by behavioral analyses. Juvenile Chd8+/S62X mice displayed male-preponderant autistic-like behaviors; hypoactivity and enhanced mother-seeking/attachment behavior in males but not in females. Adult male and female Chd8+/S62X mice showed largely similar deficits in repetitive and anxiety-like behavioral domains. Therefore, the CHD8-S62X mutation induces ASD-like behaviors in juvenile male mice and adult male and female mice, pointing to an age-differential sexual dimorphism and also distinct sexual dimorphisms in different Chd8 mutations (N2373K and S62X).

Autism spectrum disorders (ASD) are ~4-times more common in males than females, and CHD8 (a chromatin remodeler)-related ASD shows a strong male bias (~4:1), although the underlying mechanism remains unclear. Chd8-mutant mice with a C-terminal protein-truncating mutation (N2373K) display male-preponderant behavioral deficits as juveniles and adults, although whether this also applies to other Chd8 mutations remains unknown. In addition, it remains unclear whether sexually dimorphic phenotypes in Chd8-mutant mice are differentially observed in males and females across different ages. We here generated new Chd8-mutant (knock-in) mice carrying a patient-derived mutation causing an N-terminal and stronger protein truncation (Chd8+/S62X mice) and characterized the mice by behavioral analyses. Juvenile Chd8+/S62X mice displayed male-preponderant autistic-like behaviors; hypoactivity and enhanced mother-seeking/attachment behavior in males but not in females. Adult male and female Chd8+/S62X mice showed largely similar deficits in repetitive and anxiety-like behavioral domains. Therefore, the CHD8-S62X mutation induces ASD-like behaviors in juvenile male mice and adult male and female mice, pointing to an age-differential sexual dimorphism and also distinct sexual dimorphisms in different Chd8 mutations (N2373K and S62X). [ABSTRACT FROM AUTHOR]

Abstract RAS proteins are peripheral membrane GTPases that activate multiple downstream effectors for cell proliferation and differentiation. The formation of a signaling RAS–RAF complex at the plasma membrane is implicated in a quarter of all human cancers; however, the underlying mechanism remains unclear. In this work, nanodisc platforms and paramagnetic relaxation enhancement (PRE) analyses to determine the structure of a hetero‐tetrameric complex comprising KRAS and the RAS‐binding domain (RBD) and cysteine‐rich domain (CRD) of activated RAF1 are employed. The binding of the RBD or RBD–CRD differentially alters the dimerization modes of KRAS on both anionic and neutral membranes, validated by interface‐specific mutagenesis. Notably, the RBD binding allosterically generated two distinct KRAS dimer interfaces in equilibrium, favored by KRAS free and in complex with the RBD–CRD, respectively. Additional interactions of the CRD with both KRAS protomers are mutually cooperative to stabilize a new dimer configuration of KRAS bound to the RBD–CRD. The RAF binding sequentially alters KRAS dimerization, providing new insights into RAF activation, including a configurational transition of the KRAS dimer to provide an interaction site for the CRD and release the autoinhibited RAF complex. These methods are applicable to many other signaling protein complexes on the membrane.

Abstract The implications of administration of mRNA vaccines to individuals with chronic inflammatory diseases, including myocarditis, rheumatoid arthritis (RA), and inflammatory bowel disease (IBD), are unclear. We investigated mRNA vaccine effects in a chronic inflammation mouse model implanted with an LPS pump, focusing on toxicity and immunogenicity. Under chronic inflammation, mRNA vaccines exacerbated cardiac damage and myocarditis, inducing mild heart inflammation with heightened pro-inflammatory cytokine production and inflammatory cell infiltration in the heart. Concurrently, significant muscle damage occurred, with disturbances in mitochondrial fusion and fission factors signaling impaired muscle repair. However, chronic inflammation did not adversely affect muscles at the vaccination site or humoral immune responses; nevertheless, it partially reduced the cell-mediated immune response, particularly T-cell activation. These findings underscore the importance of addressing mRNA vaccine toxicity and immunogenicity in the context of chronic inflammation, ensuring their safe and effective utilization, particularly among vulnerable populations with immune-mediated inflammatory diseases.

In this paper, a new pixel circuit for active matrix organic light-emitting diode (AMOLED) display that can achieve high uniformity in low gray levels and its driving method are proposed. The proposed circuit compensates for threshold voltage variation of thin-film-transistors (TFTs), with the structure that minimizes the loss of sensed threshold voltage. However, the high current error rate in extremely low gray level is unavoidable, as the driving TFT (DRT) operates in subthreshold region, where the current difference caused by the threshold voltage variation can be severe. To suppress high error rates in low gray levels, the operation region of DRT is restricted to the saturation region, by adopting duty ratio modulation (DRM) method. With the DRM method, low gray is expressed with high current value and short emission time. The viability of the proposed circuit and its operation are analyzed with HSPICE. Compared to the conventional driving method, DRM significantly reduces the current error rate in low gray area. The proposed circuit is fabricated within 220 $\mu {\mathrm {m}} \times 440 \mu {\mathrm {m}}$ . The measurement of the circuit also verified the capability of the proposed circuit and the DRM method.

In this paper, we proposed a new low-temperature polycrystalline oxide (LTPO) thin-film transistor (TFT) pixel circuit for micro light-emitting diode (μ LED) displays that produces a highly stable and uniform driving current. The proposed pixel circuit suppresses the current level change along with the sweep signal due to the parasitic capacitances and compensates for the TFT's threshold voltage (VTH) variation-induced current error, including even falling shape. In addition, the proposed circuit produces a constant current regardless of the data voltage. As a result, a relative current error rate of less than 2% was achieved across all gray levels under the ±0.5 V VTH fluctuation. The proposed circuit was verified using HSPICE with a low-temperature polycrystalline silicon (LTPS) TFT and amorphous indium-galliumzinc- oxide (a-IGZO) TFT model based on the measured data. The simulation analysis confirmed that the optimal sweep signal input position and pulse width modulation (PWM) and constant current generation (CCG) parts connecting method were key design points for stable and uniform performance.

In this paper, we conducted a simulation of an indium-gallium-zinc oxide (IGZO)-based neuromorphic system and proposed layer-by-layer membrane capacitor (Cmem) optimization for integrate-and-fire (I&F) neuron circuits to minimize the accuracy drop in spiking neural network (SNN). The fabricated synaptic transistor exhibited linear 32 synaptic weights with a large dynamic range $(\sim 846$ ), and an n-type-only IGZO I&F neuron circuit was proposed and verified by HSPICE simulation. The network, consisting of three fully connected layers, was evaluated with an offline learning method employing synaptic transistor and I&F circuit models for three datasets: MNIST, Fashion-MNIST, and CIFAR-10. For offline learning, accuracy drop can occur due to information loss caused by overflow or underflow in neurons, which is largely affected by Cmem. To address this problem, we introduced a layer-by-layer ${\mathrm{ C}}_{\mathrm{ mem}}$ optimization method that adjusts appropriate ${\mathrm{ C}}_{\mathrm{ mem}}$ for each layer to minimize the information loss. As a result, high SNN accuracy was achieved for MNIST, Fashion-MNIST, and CIFAR-10 at 98.42%, 89.16%, and 48.06%, respectively. Furthermore, the optimized system showed minimal accuracy degradation under device-to-device variation.

In this paper, we propose a new active-matrix organic light-emitting diode (AMOLED) pixel circuit using amorphous indium-gallium-zinc oxide (a-IGZO) thin film transistors (TFTs). The proposed pixel circuit consists of seven TFTs and two capacitors, compensating for both threshold voltage (VTH) and mobility variations. The simulation results show that the proposed pixel circuit can successfully compensate for mobility variation. Also, the mobility compensation stage positively affects a significant ${\mathrm{ V}}_{\mathrm{ TH}}$ fluctuation. The proposed circuit is fabricated within an area of $19.95\,\,\boldsymbol{\mu }\text{m}\,\,\times 39.9\,\,\boldsymbol{\mu }\text{m}$ that can achieve 635 pixels per inch (PPI), and the experimental results show relatively consistent current levels even under severe TFT variations.

Abstract We developed a promising mRNA vaccine against severe fever with thrombocytopenia syndrome (SFTS), an infectious disease caused by the SFTS virus that is primarily transmitted through tick bites. Administration of lipid nanoparticle-encapsulated mRNA-Gn successfully induced neutralizing antibodies and T-cell responses in mice. The vaccinated mice were protected against a lethal SFTS virus challenge, suggesting that this mRNA vaccine may be an effective and successful SFTS vaccine candidate.

Synaptic transistors using an indium–gallium–zinc oxide (IGZO) charge trap layer (CTL) have great potential for high-performance neuromorphic applications due to their excellent stability and high linearity in conductance modulation. Since the high conductivity of the IGZO CTL enhances charge de-trapping performance, the post-annealing process, which directly affects the conductivity of the film, should be carefully conducted. In this study, we investigated the effect of post-annealing temperature (TPA) on the charge de-trapping performance of synaptic transistors. The synaptic transistor showed superior charge de-trapping performance at a TPA of 250 °C, resulting from the increased conductivity of the CTL. Through various electrical and chemical analysis methods, it was revealed that the hydrogen decrease within the CTL and the oxidation–reduction reaction at the interface between the tunneling layer and the CTL contributed to the significant increase in the conductivity of the CTL. The synaptic transistor with the optimal TPA exhibited high linearity of potentiation (αp: 0.56) and depression (αd: −0.65) with 64 conductance levels, enabling the spiking neural network simulation to achieve a high accuracy of 88.75% using a Fashion-MNIST dataset. This work shows that TPA is one of the critical process strategies for the high charge de-trapping performance of the synaptic transistor by inducing the chemical reaction at the CTL interface and hydrogen content change within the CTL.

In this paper, we present a novel pulse width modulation (PWM) operational scheme for micro-light-emitting-diode ( $\mu$ LED) displays using inverter and dynamic SWEEP signal slope. In the proposed PWM operational scheme, the slope of the SWEEP signal steepens as the gray level decreases. This adjustable SWEEP signal slope further shortens the falling time compared to the inverter-only strategy, leading to an exceptional capability to express extremely low gray levels. We implement the proposed scheme with a low-temperature poly-Si oxide (LTPO) thin-film transistor (TFT) pixel circuit and verify the operation through HSPICE based on measured TFT data. The simulation results show that the proposed scheme can significantly shorten the falling time to under $\mu$ s level. The gray level of 14 G is accurately expressed without wavelength shift or pulse distortion, achieving a falling time of $\mu$ s. In addition, we also verify the compensation accuracy of the pixel circuit, and the results indicate that the proposed pixel circuit can reliably compensate for TFT variations.