FBXW7-mediated stability regulation of signal transducer and activator of transcription 2 in melanoma formation.

In this study, we provide critical evidence that STAT2 stability regulation plays an essential role in melanoma cell proliferation and colony growth. We found that the interaction of FBXW7 and STAT2 induced STAT2 destabilization via a ubiquitination-mediated proteasomal degradation pathway. Notably, GSK3ß-mediated STAT2 phosphorylation facilitated STAT2-FBXW7 interactions via the DNA binding domain of STAT2 and domains 1, 2, 6, and 7 of FBXW7 WD40. Importantly, the inverse correlation between protein levels of STAT2 and FBXW7 were observed not only in human melanoma cells but also in a human skin cancer tissue array. The relationship between protein levels of STAT2 and FBXW7, cell proliferation, and colony growth were similarly observed in the melanoma cell lines SK-MEL-2, -5, and -28. Moreover, STAT2 knockdown in melanoma cells suppressed melanoma cell proliferation and colony formation. These data demonstrated that FBXW7-mediated STAT2 stability regulation plays an essential role in melanoma cell proliferation and cancer growth.

Fargesin Inhibits EGF-Induced Cell Transformation and Colon Cancer Cell Growth by Suppression of CDK2/Cyclin E Signaling Pathway.

Although the lignan compound fargesin is a major ingredient in Shin-Yi, the roles of fargesin in carcinogenesis and cancer cell growth have not been elucidated. In this study, we observed that fargesin inhibited cell proliferation and transformation by suppression of epidermal growth factor (EGF)-stimulated G1/S-phase cell cycle transition in premalignant JB6 Cl41 and HaCaT cells. Unexpectedly, we found that signaling pathway analyses showed different regulation patterns in which fargesin inhibited phosphatidylinositol 3-kinase/AKT signaling without an alteration of or increase in mitogen activated protein kinase (MAPK) in JB6 Cl41 and HaCaT cells, while both signaling pathways were abrogated by fargesin treatment in colon cancer cells. We further found that fargesin-induced colony growth inhibition of colon cancer cells was mediated by suppression of the cyclin dependent kinase 2 (CDK2)/cyclin E signaling axis by upregulation of p21WAF1/Cip1, resulting in G1-phase cell cycle accumulation in a dose-dependent manner. Simultaneously, the suppression of CDK2/cyclin E and induction of p21WAF1/Cip1 were correlated with Rb phosphorylation and c-Myc suppression. Taken together, we conclude that fargesin-mediated c-Myc suppression inhibits EGF-induced cell transformation and colon cancer cell colony growth by the suppression of retinoblastoma (Rb)-E2F and CDK/cyclin signaling pathways, which are mainly regulated by MAPK and PKB signaling pathways.

Sulforaphane mitigates mast cell-mediated allergic inflammatory reactions in in silico simulation and in vitro models.

Objectives: Sulforaphane, a major ingredient isolated from Brassica oleracea var. italica (broccoli), is known to exhibit anti-inflammatory, anti-cancer, and anti-diabetic effects. In this study, we employed an in vitro model of phorbol 12-myristate 13-acetate and a23187 (PMACI)-stimulated human mast cells (HMC-1 cells) to investigate the anti-allergic inflammatory effects and mechanisms of sulforaphane and Brassica oleracea var. italica extracts.Methods: Cytokine levels were measured by ELISA and quantitative real-time-PCR methods. Caspase-1 activity was determined by caspase-1 assay. Binding mode of sulforaphane within caspase-1 was determined by molecular docking simulation. Protein expression was determined by Western blotting.Results: Water extract of Brassica oleracea var. italica (WE) significantly reduced thymic stromal lymphopoietin (TSLP) secretion and caspase-1 activity on activated HMC-1 cells. In the molecular docking simulation and in vitro caspase-1 assays, sulforaphane regulated caspase-1 activity by docking with the identical binding site of caspase-1. Sulforaphane significantly inhibited the levels of inflammatory mediators including TSLP, tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, and IL-8 in a dose-dependent manner. Immunoblotting experiments revealed that sulforaphane and WE reduced translocation of NF-κBp65 into the nucleus and phosphorylation of IκBα in the cytosol. Furthermore, phosphorylation of mitogen-activated protein kinases (MAPK) was down-regulated by treatment with sulforaphane or WE.Conclusion: Our findings suggest that sulforaphane and WE have anti-allergic inflammatory effects by intercepting caspase-1/NF-κB/MAPKs signaling pathways.

Role of paroxysmal depolarization in focal seizure activity.

We analyze the role of inhibition in sustaining focal epileptic seizure activity. We review ongoing seizure activity at the mesoscopic scale that can be observed with microelectrode arrays as well as at the macroscale of standard clinical EEG. We provide clinical, experimental, and modeling data to support the hypothesis that paroxysmal depolarization (PD) is a critical component of the ictal machinery. We present dual-patch recordings in cortical cultures showing reduced synaptic transmission associated with presynaptic occurrence of PD, and we find that the PD threshold is cell size related. We further find evidence that optically evoked PD activity in parvalbumin neurons can promote propagation of neuronal excitation in neocortical networks in vitro. Spike sorting results from microelectrode array measurements around ictal wave propagation in human focal seizures demonstrate a strong increase in putative inhibitory firing with an approaching excitatory wave, followed by a sudden reduction of firing at passage. At the macroscopic level, we summarize evidence that this excitatory ictal wave activity is strongly correlated with oscillatory activity across a centimeter-sized cortical network. We summarize Wilson-Cowan-type modeling showing how inhibitory function is crucial for this behavior. Our findings motivated us to develop a network motif of neurons in silico, governed by a reduced version of the Hodgkin-Huxley formalism, to show how feedforward, feedback, PD, and local failure of inhibition contribute to observed dynamics across network scales. The presented multidisciplinary evidence suggests that the PD not only is a cellular marker or epiphenomenon but actively contributes to seizure activity.NEW & NOTEWORTHY We present mechanisms of ongoing focal seizures across meso- and macroscales of microelectrode array and standard clinical recordings, respectively. We find modeling, experimental, and clinical evidence for a dual role of inhibition across these scales: local failure of inhibition allows propagation of a mesoscopic ictal wave, whereas inhibition elsewhere remains intact and sustains macroscopic oscillatory activity. We present evidence for paroxysmal depolarization as a mechanism behind this dual role of inhibition in shaping ictal activity.

RSK2-Mediated ELK3 Activation Enhances Cell Transformation and Breast Cancer Cell Growth by Regulation of c-fos Promoter Activity.

Ribosomal S6 kinase 2 (RSK2), regulated by Ras/Raf/MEKs/ERKs, transmits upstream activation signals to downstream substrates including kinases and transcription and epigenetic factors. We observed that ELK members, including ELK1, 3, and 4, highly interacted with RSK2. We further observed that the RSK2-ELK3 interaction was mediated by N-terminal kinase and linker domains of RSK2, and the D and C domains of ELK3, resulting in the phosphorylation of ELK3. Importantly, RSK2-mediated ELK3 enhanced c-fos promoter activity. Notably, chemical inhibition of RSK2 signaling using kaempferol (a RSK2 inhibitor) or U0126 (a selective MEK inhibitor) suppressed EGF-induced c-fos promoter activity. Moreover, functional deletion of RSK2 by knockdown or knockout showed that RSK2 deficiency suppressed EGF-induced c-fos promoter activity, resulting in inhibition of AP-1 transactivation activity and Ras-mediated foci formation in NIH3T3 cells. Immunocytofluorescence assay demonstrated that RSK2 deficiency reduced ELK3 localization in the nucleus. In MDA-MB-231 breast cancer cells, knockdown of RSK2 or ELK3 suppressed cell proliferation with accumulation at the G1 cell cycle phase, resulting in inhibition of foci formation and anchorage-independent cancer colony growth in soft agar. Taken together, these results indicate that a novel RSK2/ELK3 signaling axis, by enhancing c-Fos-mediated AP-1 transactivation activity, has an essential role in cancer cell proliferation and colony growth.

Rough-Surface-Enabled Capacitive Pressure Sensors with 3D Touch Capability.

Fabrication strategies that pursue "simplicity" for the production process and "functionality" for a device, in general, are mutually exclusive. Therefore, strategies that are less expensive, less equipment-intensive, and consequently, more accessible to researchers for the realization of omnipresent electronics are required. Here, this study presents a conceptually different approach that utilizes the inartificial design of the surface roughness of paper to realize a capacitive pressure sensor with high performance compared with sensors produced using costly microfabrication processes. This study utilizes a writing activity with a pencil and paper, which enables the construction of a fundamental capacitor that can be used as a flexible capacitive pressure sensor with high pressure sensitivity and short response time and that it can be inexpensively fabricated over large areas. Furthermore, the paper-based pressure sensors are integrated into a fully functional 3D touch-pad device, which is a step toward the realization of omnipresent electronics.

In vitro and in vivo evaluation of the effect of puerarin on hepatic cytochrome p450-mediated drug metabolism.

Puerarin (8-ß-D-glucopyranosyl-7-hydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) is a major pharmacological component of Puerariae Radix, the root of Pueraria lobata. We investigated the effect of puerarin on hepatic cytochrome P450-mediated drug metabolism in rats and humans. The in vitro cytochrome P450 inhibitory effect of puerarin in human and rat liver microsomes was evaluated using the following model cytochrome P450 substrates: phenacetin for CYP1A, diclofenac for CYP2C, dextromethorphan for CYP2D, and testosterone for CYP3A. The in vivo pharmacokinetics of intravenous and oral buspirone, a probe substrate for CYP3A, was studied with single simultaneous intravenous coadministration of puerarin in rats. In the in vitro cytochrome P450 inhibition study, the rate of disappearance of testosterone was significantly reduced in the presence of 10 µM PU, while that of other cytochrome P450 substrates was not significantly affected in both human and rat liver microsomes, suggesting that puerarin inhibits the in vitro hepatic CYP3A-mediated metabolism in the human and rat systems (IC50 = 15.5 ± 3.9 µM). After intravenous administration of buspirone with single simultaneous coadministration of intravenous puerarin at a dose of 10 mg/kg in rats, the total area under the plasma concentration-time curve from time zero to time infinity was increased while time-averaged total body clearance decreased. When buspirone was orally administered in rats with the 10 mg/kg intravenous puerarin coadministration, both total area under the plasma concentration-time curve from time zero to time infinity and the extent of absolute oral bioavailability were significantly increased. Therefore, results of the in vitro microsomal and in vivo pharmacokinetic studies suggest the possible inhibition of hepatic CYP3A-mediated drug metabolism by puerarin administration, potentially leading to metabolism-mediated herb-drug interactions with clinical significance.

ELK3 destabilization by speckle-type POZ protein suppresses prostate cancer progression and docetaxel resistance.

Accumulating evidence demonstrates that the activity regulation of ELK3, a member of the E26 transformation-specific oncogene family, is critical to regulating cell proliferation, migration, and survival in human cancers. However, the molecular mechanisms of how ELK3 induces chemoresistance in prostate cancer (PCa) have not been elucidated. In this study, we found that SPOP and ELK3 are an interacting partner. The interaction between SPOP and ELK3 resulted in increased ELK3 ubiquitination and destruction, assisted by checkpoint kinase-mediated ELK3 phosphorylation. Notably, the modulation of SPOP-mediated ELK3 protein stability affected the c-Fos-induced cell proliferation and invasion of PCa cells. The clinical involvement of the SPOP-ELK3 axis in PCa development was confirmed by an immunohistochemical assay on 123 PCa tissues, with an inverse correlation between increased ELK3 and decreased SPOP being present in ~80% of the specimens. This observation was supported by immunohistochemistry analysis using a SPOP-mutant PCa specimen. Finally, docetaxel treatment induced cell death by activating checkpoint kinase- and SPOP-mediated ELK3 degradation, while SPOP-depleted or SPOP-mutated PCa cells showed cell death resistance. Notably, this observation was correlated with the protein levels of ELK3. Taken together, our study reveals the precise mechanism of SPOP-mediated degradation of ELK3 and provides evidence that SPOP mutations contribute to docetaxel resistance in PCa.

Dysregulated CREB3 cleavage at the nuclear membrane induces karyoptosis-mediated cell death.

Cancer cells often exhibit resistance to apoptotic cell death, but they may be vulnerable to other types of cell death. Elucidating additional mechanisms that govern cancer cell death is crucial for developing new therapies. Our research identified cyclic AMP-responsive element-binding protein 3 (CREB3) as a crucial regulator and initiator of a unique cell death mechanism known as karyoptosis. This process is characterized by nuclear shrinkage, deformation, and the loss of nuclear components following nuclear membrane rupture. We found that the N-terminal domain (aa 1-230) of full-length CREB3 (CREB3-FL), which is anchored to the nuclear inner membrane (INM), interacts with lamins and chromatin DNA. This interaction maintains a balance between the outward force exerted by tightly packed DNA and the inward constraining force, thereby preserving INM integrity. Under endoplasmic reticulum (ER) stress, aberrant cleavage of CREB3-FL at the INM leads to abnormal accumulation of the cleaved form of CREB3 (CREB3-CF). This accumulation disrupts the attachment of CREB3-FL to the INM, resulting in sudden rupture of the nuclear membrane and the onset of karyoptosis. Proteomic studies revealed that CREB3-CF overexpression induces a DNA damage response akin to that caused by UVB irradiation, which is associated with cellular senescence in cancer cells. These findings demonstrated that the dysregulation of CREB3-FL cleavage is a key factor in karyoptotic cell death. Consequently, these findings suggest new therapeutic strategies in cancer treatment that exploit the process of karyoptosis.

A guide towards optimal detection of transient oscillatory bursts with unknown parameters.

Objectives. Recent event-based analyses of transient neural activities have characterized the oscillatory bursts as a neural signature that bridges dynamic neural states to cognition and behaviors. Following this insight, our study aimed to (1) compare the efficacy of common burst detection algorithms under varying signal-to-noise ratios and event durations using synthetic signals and (2) establish a strategic guideline for selecting the optimal algorithm for real datasets with undefined properties.Approach.We tested the robustness of burst detection algorithms using a simulation dataset comprising bursts of multiple frequencies. To systematically assess their performance, we used a metric called 'detection confidence', quantifying classification accuracy and temporal precision in a balanced manner. Given that burst properties in empirical data are often unknown in advance, we then proposed a selection rule to identify an optimal algorithm for a given dataset and validated its application on local field potentials of basolateral amygdala recorded from male mice (n=8) exposed to a natural threat.Main Results.Our simulation-based evaluation demonstrated that burst detection is contingent upon event duration, whereas accurately pinpointing burst onsets is more susceptible to noise level. For real data, the algorithm chosen based on the selection rule exhibited superior detection and temporal accuracy, although its statistical significance differed across frequency bands. Notably, the algorithm chosen by human visual screening differed from the one recommended by the rule, implying a potential misalignment between human priors and mathematical assumptions of the algorithms.Significance.Therefore, our findings underscore that the precise detection of transient bursts is fundamentally influenced by the chosen algorithm. The proposed algorithm-selection rule suggests a potentially viable solution, while also emphasizing the inherent limitations originating from algorithmic design and volatile performances across datasets. Consequently, this study cautions against relying solely on heuristic-based approaches, advocating for a careful algorithm selection in burst detection studies.

Using spectral characterization to identify healthcare-associated infection (HAI) patients for clinical contact precaution.

Healthcare-associated infections (HAIs) are a major problem in hospital infection control. Although HAIs can be suppressed using contact precautions, such precautions are expensive, and we can only apply them to a small fraction of patients (i.e., a limited budget). In this work, we focus on two clinical problems arising from the limited budget: (a) choosing the best patients to be placed under precaution given a limited budget to minimize the spread (the isolation problem), and (b) choosing the best patients to release when limited budget requires some of the patients to be cleared from precaution (the clearance problem). A critical challenge in addressing them is that HAIs have multiple transmission pathways such that locations can also accumulate 'load' and spread the disease. One of the most common practices when placing patients under contact precautions is the regular clearance of pathogen loads. However, standard propagation models like independent cascade (IC)/susceptible-infectious-susceptible (SIS) cannot capture such mechanisms directly. Hence to account for this challenge, using non-linear system theory, we develop a novel spectral characterization of a recently proposed pathogen load based model, 2-MODE-SIS model, on people/location networks to capture spread dynamics of HAIs. We formulate the two clinical problems using this spectral characterization and develop effective and efficient algorithms for them. Our experiments show that our methods outperform several natural structural and clinical approaches on real-world hospital testbeds and pick meaningful solutions.

Unlocking the Potential of Colloidal Quantum Dot/Organic Hybrid Solar Cells: Band Tunable Interfacial Layer Approach.

Hybrid colloidal quantum dot (CQD)/organic architectures are promising candidates for emerging optoelectronic devices having high performance and inexpensive fabrication. For unlocking the potential of CQD/organic hybrid devices, enhancing charge extraction properties at electron transport layer (ETL)/CQD interfaces is crucial. Hence, we carefully adjust the interface properties between the ETL and CQD layer by incorporating an interfacial layer for the ETL (EIL) using several types of cinnamic acid ligands. The EIL having a cascading band offset (ΔEC) between the ETL and CQD layer suppresses the potential barrier and the local charge accumulation at ETL/CQD interfaces, thereby reducing the bimolecular recombination. An optimal EIL effectively expands the depletion region that facilitates charge extraction between the ETL and CQD layer while preventing the formation of shallow traps. Representative devices with an EIL exhibit a maximum power conversion efficiency of 14.01% and retain over 80% of initial performances after 300 h under continuous maximum power point operation.

Omni-directional wind-driven triboelectric nanogenerator with cross-shaped dielectric film.

Triboelectric nanogenerators (TENGs) are actively being researched and developed to become a new external power unit for various electronics and applications. Wind is proposed as a mechanical energy source to flutter the dielectric film in wind-driven TENGs as it is clean, abundant, ubiquitous, and sustainable. Herein, we propose a TENG structure with dielectric films bent in four directions to collect the wind energy supply from all directions, unlike the conventional wind-driven TENGs which can only harvest the wind energy from one direction. Aluminum (Al) layer was intercalated within the dielectric film to improve electrostatic induction, resulting in improved triboelectric performances. Maximum open-circuit voltage (Voc) of 233 V, short-circuit current (Isc) of 348 µA, and output power density of 46.1 W m- 2 at an external load of 1 MΩ under a wind speed of 9 m s- 1 were revealed, and it faithfully lit "LED" characters composed of 25 LEDs.

Empathy With Patients and Post-Traumatic Stress Response in Verbally Abused Healthcare Workers.

OBJECTIVE: The current study examined the differential empathic capacity, post-traumatic symptoms, and coping strategies in healthcare workers (HCWs) according to the exposure of verbal or physical workplace violence (WPV). METHODS: Using online survey, a total of 422 HCWs employed at a training general hospital of South Korea participated and completed self-reporting questionnaires including the WPV questionnaire with coping strategy, the Jefferson Scale of Physician Empathy. RESULTS: Those who experienced either only verbal violence or both physical and verbal violence had lower Jefferson Scale of Physician Empathy scores (p<0.05). Posttraumatic stress symptom severity was higher among people who experienced verbal violence than physical violence. HCWs' exposure to verbal violence was associated with severe posttraumatic symptoms and a low level of empathy with patients (p<0.05). More than half of the victims of verbal violence responded that they did not take any action, receive organizational protection, or peer support, while most physically-abused HCWs received institutional intervention or help from others. CONCLUSION: Our findings highlight the critical importance of reducing verbal violence, which may represent a larger psychological burden compared to physical violence, by actively implementing effective strategies and policies at the institutional level.

Molecular Sieve Based on a PMMA/ZIF-8 Bilayer for a CO-Tolerable H2 Sensor with Superior Sensing Performance.

Semiconductor sensors equipped with Pd catalysts are promising candidates as low-powered and miniaturized surveillance devices that are used to detect flammable hydrogen (H2) gas. However, the following issues remain unresolved: (i) a sluggish sensing speed at room temperature and (ii) deterioration of sensing performance caused by interfering gases, particularly, carbon monoxide (CO). Herein, a bilayer comprising poly(methyl methacrylate) (PMMA) and zeolitic imidazolate framework-8 (ZIF-8) is utilized as a molecular sieve for diode-type H2 sensors based on a Pd-decorated indium-gallium-zinc oxide film on a p-type silicon substrate. While the PMMA effectively blocks the penetration of CO gas molecules into the sensing entity, the ZIF-8 improves sensing performances by modifying the catalytic activity of Pd, which is preferable for splitting H2 and O2 molecules. Consequently, the bilayer-covered sensor achieves outstanding CO tolerance with superior sensing figures of merit (response/recovery times of <10 s and sensing response of >5000% at 1% H2).

Burnout as a Mediator in the Relationship between Work-Life Balance and Empathy in Healthcare Professionals.

OBJECTIVE: This cross-sectional study aimed to 1) explore the relationships among work-life balance (WLB), burnout, and empathy and 2) investigate the roles of the subtypes of burnout relating to WLB and empathy. METHODS: A total of 105 health care professionals from a general hospital in Seoul were assessed using the Maslach Burnout Inventory, Jefferson Scale of Physician Empathy, and a one-sentence-question on subjective WLB. Multiple questions on psychiatric problems, including sleep problems, anxiety, depressive symptom, and alcohol problems, were also included. RESULTS: In the mediation analyses, personal achievement was considered as a potential mediating variable between WLB and empathy. The direct effect (ß=3.93, 95% CI: 1.21-6.64) and the indirect effect (ß=1.95, 95% CI: 0.52-3.76) of WLB on empathy were also significant. CONCLUSION: Interventions encouraging personal achievement may help mitigate burnout of health professionals.

High-Performance Photovoltaic Hydrogen Sensing Platform with a Light-Intensity Calibration Module.

Although battery-free gas sensors (e.g., photovoltaic or triboelectric sensors) have recently appeared to resolve the power consumption issue of conventional chemiresistors, severe technical barriers still remain. Especially, their signals varying under ambient conditions such as light intensity restrict the utilization of these sensors. Insufficient sensing performances (low response and slow sensing rate) of previous battery-free sensors are also an obstacle for practical use. Herein, a photovoltaic hydrogen (H2)-sensing platform having constant sensing responses regardless of light conditions is demonstrated. The platform consists of two photovoltaic units: (1) a palladium (Pd)-decorated n-IGZO/p-Si photodiode covered with a microporous zeolitic imidazolate framework-8 (ZIF-8) film and (2) a device with the same configuration, but without the Pd catalyst as a reference to calibrate the base current of sensor (1). The platform after calibration yields accurate response values in real time regardless of unknown irradiance. Besides, the sensing performances (e.g., sensing response of 1.57 × 104% at 1% H2 with a response time <15 s) of our platform are comparable with those of the conventional resistive H2 sensors, which yield unprecedented results in photovoltaic H2 sensors.

Publisher Correction: Ultrafast quantum beats of anisotropic excitons in atomically thin ReS2.

In the originally published HTML and PDF versions of this article, Figs. 3g and 4d contained typesetting errors affecting the way the data points were displayed. This has now been corrected in the HTML and PDF versions.

Ultrafast quantum beats of anisotropic excitons in atomically thin ReS2.

Quantum beats, periodic oscillations arising from coherent superposition states, have enabled exploration of novel coherent phenomena. Originating from strong Coulomb interactions and reduced dielectric screening, two-dimensional transition metal dichalcogenides exhibit strongly bound excitons either in a single structure or hetero-counterpart; however, quantum coherence between excitons is barely known to date. Here we observe exciton quantum beats in atomically thin ReS2 and further modulate the intensity of the quantum beats signal. Surprisingly, linearly polarized excitons behave like a coherently coupled three-level system exhibiting quantum beats, even though they exhibit anisotropic exciton orientations and optical selection rules. Theoretical studies are also provided to clarify that the observed quantum beats originate from pure quantum coherence, not from classical interference. Furthermore, we modulate on/off quantum beats only by laser polarization. This work provides an ideal laboratory toward polarization-controlled exciton quantum beats in two-dimensional materials.

Spatially Pressure-Mapped Thermochromic Interactive Sensor.

A thermochromic-based interactive sensor that can generate local color switching and pressure mapping is developed using a 2D array of resistive pressure sensor switch. This thermochromic-based interactive sensor will enable the visualization of localized information in arbitrary shapes with dynamic responses in the context of serial/parallel pressure mapping and quantifying capability without optoelectronic arrays.