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During Hedgehog (Hh) signal transduction in development and disease, the atypical G protein-coupled receptor (GPCR) SMOOTHENED (SMO) communicates with GLI transcription factors by binding the protein kinase A catalytic subunit (PKA-C) and physically blocking its enzymatic activity. Here, we show that GPCR kinase 2 (GRK2) orchestrates this process during endogenous mouse and zebrafish Hh pathway activation in the primary cilium. Upon SMO activation, GRK2 rapidly relocalizes from the ciliary base to the shaft, triggering SMO phosphorylation and PKA-C interaction. Reconstitution studies reveal that GRK2 phosphorylation enables active SMO to bind PKA-C directly. Lastly, the SMO-GRK2-PKA pathway underlies Hh signal transduction in a range of cellular and in vivo models. Thus, GRK2 phosphorylation of ciliary SMO and the ensuing PKA-C binding and inactivation are critical initiating events for the intracellular steps in Hh signaling. More broadly, our study suggests an expanded role for GRKs in enabling direct GPCR interactions with diverse intracellular effectors.

Abstract Background In emergency settings, difficult intubations often occur unexpectedly despite pre-intubation assessments. Traditional glottic view scoring systems for direct laryngoscope may not apply to video laryngoscopy. With video laryngoscopy, the vertical location of the glottis on the monitor can be clearly defined. If the glottis location is associated with intubation difficulty, it could serve as a simple indicator for anticipating intubation challenges. This study aimed to investigate the relationship between the glottis screen location during video laryngoscopy-guided intubation and the success and timing of the first-attempt intubation. Methods We retrospectively analyzed laryngoscopy recordings from adult intubations in the emergency department of a tertiary teaching hospital in Chiayi, Taiwan, using the C-MAC video laryngoscope between March 2020 and April 2023. The vertical screen location of the vocal cords, determined by the arytenoid cartilage position after laryngeal blade engagement, was categorized into upper and lower locations for analysis. The primary outcome was first-attempt intubation success within 90 s, analyzed using Kaplan-Meier survival curves and multivariable Cox proportional hazard analysis. Results Among 209 laryngoscopy records, 113 had the arytenoid in the lower field of view and 96 in the upper field. Kaplan-Meier analysis showed a significantly lower cumulative success rate for intubations with a higher arytenoid location (log-rank test, P

Abstract In urban areas, emergency vehicles (EVs) need efficient traffic signal preemption to ensure timely responses during peak hours. While emergency vehicle traffic signal preemption (EVTSP) has garnered significant attention in the literature, the issues of queue spillbacks and negative impacts on non‐priority traffic have been relatively underreported. These issues are particularly critical during peak hours, notably in densely populated urban areas. This study presents an EVTSP system that considers queue spillbacks on approaches along the routes of EVs and the negative impacts of signal preemption on non‐priority traffic. The proposed control system has four key components: (1) a queue length management algorithm to ensure that an EV will not be impeded by excessive queues, particularly on its initial approaches along its route; (2) a signal preemption algorithm to guarantee uninterrupted passage of an EV even for approaches experiencing queue spillbacks; (3) a traffic status recovery algorithm to alleviate the extra waiting time for non‐priority vehicles after an EV crosses each intersection; and (4) a signal plan recovery algorithm to smoothly transit traffic signals to normal operation. The experimental results confirm that the proposed system considerably improves the travel time of an EV and mitigates the negative impacts on non‐priority traffic.

Background: Few studies have studied the efficacy of using immersive virtual reality (iVR) to teach surgical skills, especially by using real-world iVR recordings rather than simulations. This study aimed to investigate whether viewing 360° iVR instructional recordings produces greater improvements in basic suturing skills of students without prior medical training, beyond traditional methods like reading written manuals or watching 2D instructional videos. Materials and methods: This was a partially blinded randomized cohort study. 44 pre-university students (aged 17) were randomized equally to either the written instruction manual, 2D instructional video, or iVR recordings. All students first watched a silent 2D demonstration video of the suturing task, before attempting to place three simple interrupted sutures on a piece of meat as a baseline. The time taken for the first attempt was recorded. Students were then given an hour to train using their allocated modality. They attempted the suturing task again, and timings were re-recorded. Four blinded surgically-trained judges independently assessed the quality of the stitches placed both pre and post-intervention. One-way analysis of variance tests (ANOVAs) and independent two-sample t-tests were used to determine the effect of training modality on improvements in suturing scores and time taken to complete suturing from pre to post-training. Results: For suturing scores, the iVR group showed significantly larger score improvements than the Written Manual group (p = 0.031, Cohen's D = 0.92), while this iVR advantage was less pronounced when compared with the 2D Video group (p = 0.16, Cohen's D = 0.65). Similarly for time taken to complete suturing, the iVR group had significantly larger time improvements than the Written Manual group (p = 0.045), although this difference was less robust compared to the 2D Instructional Video group (p = 0.34). Conclusion: This study demonstrates that iVR training using real-world 360° instructional recordings produced significantly greater training gains in suturing scores and efficiency compared to reading written text. iVR training also led to larger training gains in both outcome measures than viewing 2D instructional videos, although the differences between them did not reach statistical significance.

Abstract This work presents a series of novel quinoidal organic semiconductors based on diselenophene‐dithioalkylthiophene (DSpDST) conjugated cores with various side‐chain lengths (‐thiohexyl, ‐thiodecyl, and ‐thiotetradecyl, designated DSpDSTQ‐6, DSpDSTQ‐10, and DSpDSTQ‐14, respectively). The purpose of this research is to develop solution‐processable organic semiconductors using dicyanomethylene end‐capped organic small molecules for organic field effect transistors (OFETs) application. The physical, electrochemical, and electrical properties of these new DSpDSTQs are systematically studied, along with their performance in OFETs and thin film morphologies. Additionally, the molecular structures of DSpDSTQ are determined through density functional theory (DFT) calculations and single‐crystal X‐ray diffraction analysis. The results reveal the presence of intramolecular S (alkyl)···Se (selenophene) interactions, which result in a planar SR‐containing DSpDSTQ core, thereby promoting extended π‐orbital interactions and efficient charge transport in the OFETs. Moreover, the influence of thioalkyl side chain length on surface morphologies and microstructures is investigated. Remarkably, the compound with the shortest thioalkyl chain, DSpDSTQ‐6, demonstrates ambipolar carrier transport with the highest electron and hole mobilities of 0.334 and 0.463 cm2 V−1 s−1, respectively. These findings highlight the excellence of ambipolar characteristics of solution‐processable OFETs based on DSpDSTQs even under ambient conditions.

Abstract Four conjugated polymers are integrated with a bacteriorhodopsin D94N‐HmBRI in organic field‐effect transistors (OFETs) with the device architecture of doped Si bottom gate/SiO2 bottom electric/semiconducting polymer/Au electrodes/D94N‐HmBRI top dielectric. Photosensitivity of D94N‐HmBRI in the devices is validated. It is proposed that light activates the conformational change of all‐trans retinal to 13‐cis retinal in D94N‐HmBRI. The D94N‐HmBRI layer then applies momentary dipoles to the semiconductors, affecting threshold voltage, resulting in photosensitivity. Film‐thickness variation, capacitance determination, and grazing‐incidence X‐ray scattering are performed to support the proposed working principle. Quasi dual‐gate OFETs with a highly doped silicon wafer as the bottom gate and light as the top gate are thus realized by combining conjugated polymers with D94N‐HmBRI.

The Fe–Mn–Al–C lightweight steel has been widely studied due to its higher strength-to-weight ratio and potential applications for automotive vehicles, energy, transportation and mining industries. In general, the strength and ductility of the Fe–Mn–Al–C lightweight steel can be improved by the formation of nano-sized (Fe,Mn)3AlCx κ-carbide precipitates by a proper heat treatment below 800 °C. In this work, a unique micrometer scale κ-carbide phase transformation phenomenon induced by the pack aluminization in the Fe–29Mn–9Al–0.9C lightweight steel was firstly reported.Extremely large columnar-like (Fe,Mn)3AlCx κ-carbide grains with average length of 18.1 μm embedded in the Fe3Al matrix were discovered in the interdiffusion zone of aluminization layer, which were totally different from these nanoscale κ-carbides precipitated in the austenitic steel matrix. The increased Al content in the pack aluminide coating/substrate interface reduced the chemical potential of carbon and became the driving force for carbon diffusion toward the coating/substrate interface. Therefore, due to the extremely low solubility of carbon in the Fe3Al phase and the inward diffusion of carbon atoms, very long columnar-like (Fe,Mn)3AlCx κ-carbide phases were thus produced in the interdiffusion zone. The average chemical concentration of the κ-carbide was 43.9Fe–27.3Mn–20.3Al–8.5 C (in at.%). The average hardness, elastic modulus and the lattice parameter of κ-carbide were 8.8 ± 0.3 GPa, 285 ± 10 GPa and 0.3764 nm, respectively. This study provided detailed chemical compositions, hardness and elastic modulus of (Fe,Mn)3AlCx κ-carbide phase for better understanding the carbide precipitation and strengthening mechanism of Fe–Mn–Al–C lightweight steel.

ObjectivesComputed tomography (CT) has been increasingly used in the diagnosis of acute aortic syndrome, and a number of high-risk CT imaging features have been reported. We aimed to identify CT imaging findings suggesting high-risk for acute aortic syndrome by examining clinical outcomes of patients with acute type A aortic intramural hematoma (TAIMH).MethodsThis retrospective study analyzed the relationship of clinical patient characteristics and imaging features with mortality and aortic events in 63 patients receiving initial medical treatment for TAIMH. Multivariate regression analysis was used to determine the predictors of aortic events, and the Kaplan–Meier method was used to analyze survival and aortic events.ResultsDuring a median follow-up of 4.2 years, 25 patients experienced aortic events and 40% of these occurred within 7 days of admission. In total, 12 patients experienced aortic death and 12 patients underwent open aortic surgery or endovascular stenting for aortic disease. In multivariate regression analysis, penetrating atherosclerotic ulcers (PAUs) or ulcer-like projections (ULPs) (P = 0.04) and pericardial effusion (P = 0.03) were independent predictors of aortic events. In the Cox regression model, PAUs/ULPs (P = 0.04) and pericardial effusion (P = 0.04) were independently associated with lower aortic event-free survival.ConclusionIdentification of high-risk CT features is important for clinical decision-making during TAIMH treatment. Early and frequent CT imaging follow-up is required in patients receiving medical treatment. PAUs/ULP and pericardial effusion were the strongest predictors of adverse aortic events.

Diabetic wounds exhibit chronic inflammation and delayed tissue proliferation or remodeling, mainly owing to prolonged proinflammatory (M1) macrophage activity and defects in transition to prohealing/proremodeling (M2a/M2c; CD206+ and/or CD163+) macrophages. We found that topical treatment with ON101, a plant-based potential therapeutic for diabetic foot ulcers, increased M2c-like (CD163+ and CD206+) cells and suppressed M1-like cells, altering the inflammatory gene profile in a diabetic mouse model compared with that in the controls. An in vitro macrophage-polarizing model revealed that ON101 directly suppressed CD80+ and CD86+ M1-macrophage polarization and M1-associated proinflammatory cytokines at both protein and transcriptional levels. Notably, conditioned medium collected from ON101-treated M1 macrophages reversed the M1-conditioned medium‒mediated suppression of CD206+ macrophages. Furthermore, conditioned medium from ON101-treated adipocyte progenitor cells significantly promoted CD206+ and CD163+ macrophages but strongly inhibited M1-like cells. ON101 treatment also stimulated the expression of GCSF and CXCL3 genes in human adipocyte progenitor cells. Interestingly, treatment with recombinant GCSF protein enhanced both CD206+ and CD163+ M2 markers, whereas CXCL3 treatment only stimulated CD163+ M2 macrophages. Depletion of cutaneous M2 macrophages inhibited ON101-induced diabetic wound healing. Thus, ON101 directly suppressed M1 macrophages and facilitated the GCSF- and CXCL3-mediated transition from M1 to M2 macrophages, lowering inflammation and leading to faster diabetic wound healing.

ObjectivesVeno-arterial extracorporeal membrane oxygenation (ECMO) is increasingly used to treat high-risk pulmonary embolism (PE). However, its efficacy and safety remain uncertain. This retrospective cohort study aimed to determine whether ECMO could improve the clinical outcomes of patients with high-risk PE.MethodsForty patients with high-risk PE, who were admitted to Kaohsiung Chang Gung Memorial Hospital between January 2012 and December 2019, were included in this study. Demographic data and clinical outcomes were compared between patients treated without ECMO (non-ECMO group) and those treated with ECMO (ECMO group). Appropriate statistical tools were used to compare variables between groups and the survival was analyzed using the Kaplan–Meier method.ResultsThe overall in-hospital mortality rate was 55%, in which 65% (26/40) of patients presented with cardiac arrest with a mortality rate of 77%, which was higher than that of patients without cardiac arrest (14%). There was no significant difference in major complications and in-hospital mortality between the non-ECMO and ECMO groups. However, in subgroup analysis, compared with patients treated without ECMO, earlier ECMO treatment was associated with a reduced risk of cardiac arrest (P = 0.023) and lower in-hospital mortality (P = 0.036). A log-rank test showed a significantly higher cumulative overall survival in the earlier ECMO treatment group (P = 0.033).ConclusionsIn this retrospective cohort study, earlier ECMO treatment was associated with lower in-hospital mortality among unstable patients without cardiac arrest. Our findings suggest that ECMO can be considered as an initial treatment option for patients with high-risk PE in higher-volume hospitals.

With advancements in cardiopulmonary rehabilitation over the past few decades, the survival rate of patients with congenital heart disease (CHD) has increased. However, the Cardiopulmonary fitness (CPF) of these patients is poor. Here, we aimed to investigate CPF in preschoolers with CHD (aged 4 to 6 years) using cardiopulmonary exercise testing. We retrospectively compared 102 healthy preschoolers with 80 preschoolers with CHD. The latter had lower peak oxygen consumption, oxygen consumption at anaerobic threshold and metabolic equivalent at anaerobic threshold. The same result was observed in boys with CHD, but not in girls, when sex was sub-analyzed. Considering the body composition, children with CHD had a lower fat-free mass index (FFMI) than their healthy peers. Healthy preschoolers with a normal body mass index (BMI) had higher anaerobic threshold and peak metabolic equivalent values than overweight or underweight children. This was categorized under the BMI reference of the Ministry of Health and Welfare in Taiwan. In conclusion, the CPF difference between the CHD and healthy groups was identified as early as in preschool age, and better CPF in healthy preschoolers within the normal BMI range suggests the importance of weight control in young children.

Hybrid natural products produced via mixed biosynthetic pathways are unique and often surprise one with unexpected medicinal properties in addition to their fascinating structural complexity/diversity. In view of chemical structures, hybridization is a way of diversifying natural products usually through dimerization of two similar or dissimilar subcomponents through a C–C or N–C covalent linkage. Here, we report four structurally attractive diterpene–alkaloid conjugates polyalongarins A–D (1–4), clerodane-containing aporphine and proaporphine alkaloids, the first of its kind from the barks of Taiwanese Polyalthia longifolia (Sonn.) Thwaites var. pendula. In addition to conventional spectroscopic analysis, single crystal X-ray crystallography was employed to determine the chemical structures and stereo-configurations of 1. Compounds 1–4 were subsequently subjected to in vitro antiviral examination against DENV2 by evaluating the expression level of the NS2B protein in DENV2-infected Huh-7 cells. These compounds display encouraging anti-DENV2 activity with superb EC50 (2.8–6.4 μM) and CC50 values (50.4–200 μM). The inhibitory mechanism of 1–4 on NS2B was further explored drawing on in-silico molecular docking analysis. Based on calculated binding affinities and predicted interactions between the functional groups of 1–4 and the allosteric-site residues of the DENV2 NS2B-NS3 protease, our analysis concludes that the clerodane–aporphine/proaporphine-type hybrids are novel and effective DENV NS2B-NS3 protease inhibitors.

Surgery-related isolated proximal median neuropathy is a rare complication. Brachial plexus injury is a possible complication after major cardiac surgery; however, isolated mononeuropathy is less frequently documented. We present an unusual case of isolated proximal median neuropathy after aortic dissection repair surgery in a 39-year-old man. Electrodiagnostic study and ultrasound examinations helped in localizing the lesion to the axillary region. Serial follow-ups showed improvement in electrodiagnostic parameters, which were compatible with clinical symptoms. Partial recovery was achieved at the seventh month follow-up. This case report aimed to increase awareness of nerve stretching during open heart surgery and demonstrate the diagnosis and clinical follow-up by concomitant use of electrodiagnostic and nerve ultrasound studies.

Construction of a phenanthrodithiophene diimide core has been accomplished through photo-induced 6π electrocyclization. It is generated with the formation of anthradithiophene diimide. The product distribution is illuminated by the help of DFT calculations. The discrepancy in the optical and electrochemical properties between both compounds is identified. Time-dependent DFT calculations are carried out, yielding theoretical UV-vis spectra, which agree well with the experimental patterns. Electronic transitions for the two compounds can be clarified. Overall, this study provides a new synthetic approach to accessing phenanthrodithiophene diimide and elucidates the reaction mechanism and optical and electrochemical properties. [ABSTRACT FROM AUTHOR]