Search

A structural protein of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), nucleocapsid (N) protein is phosphorylated by glycogen synthase kinase (GSK)-3 on the serine/arginine (SR) rich motif located in disordered regions. Although phosphorylation by GSK-3β constitutes a critical event for viral replication, the molecular mechanism underlying N phosphorylation is not well understood. In this study, we found the putative alpha-helix L/FxxxL/AxxRL motif known as the GSK-3 interacting domain (GID), found in many endogenous GSK-3β binding proteins, such as Axins, FRATs, WWOX, and GSKIP. Indeed, N interacts with GSK-3β similarly to Axin, and Leu to Glu substitution of the GID abolished the interaction, with loss of N phosphorylation. The N phosphorylation is also required for its structural loading in a virus-like particle (VLP). Compared to other coronaviruses, N of Sarbecovirus lineage including bat RaTG13 harbors a CDK1-primed phosphorylation site and Gly-rich linker for enhanced phosphorylation by GSK-3β. Furthermore, we found that the S202R mutant found in Delta and R203K/G204R mutant found in the Omicron variant allow increased abundance and hyper-phosphorylation of N. Our observations suggest that GID and mutations for increased phosphorylation in N may have contributed to the evolution of variants.

Die-embedded (DE) packaging technologies in recent years have ventured into advanced packaging structures, such as fan-out wafer level packages (FOWLPs) or package-on-packages (PoPs). They offer higher density at lower costs, despite many challenges, such as the die-shift and warpage problems often observed during the molding process, caused by the high shrinkage and high coefficients of thermal expansion (CTEs) of the molding materials. This in turn makes it difficult to accurately mount the high-density fine-pitch bumps and adversely affects the overall yield, especially in processes using large-size substrates. Glass, known for its superior dimensional and thermal stability and its low or tunable CTEs, can be advantageous in reducing die-shift and warpages as opposed to other alternative material solutions for the molding process. In this paper, we propose a packaging solution based on a glass substrate incorporating a plurality of precisely dimensioned cavities, with a chip positioned in each cavity to prevent them from shifting during processing. Corning® Adaptive Formed Glass (AFG), a laminate glass with a unique clad/core/clad structure, allows for effectively forming cavities with high dimensional precision and positional accuracies as well as surface flatness through a wet etch process. Using a 0.5mm thick laminate Corning® AFG glass, we successfully designed and fabricated three types of DE packages with lab scale tools at Korea Electronics Technology Institute (KETI): single- and double-sided DE packages, and package-on-packages (POPs). High etching selectivity over 20:1, which was achieved by carefully designing the core and clad glass compositions, enabled a wet-etch cavity forming process with accurate cavity depths and flat bottom surfaces (< ± 2.5μm) with relative ease. A double-sided DE package with a total thickness of 600μm was fabricated with two 125μm-thick IC chips, one embedded on each side of the substrate, and connected by metallized through glass vias (TGVs). A POP measured at 5.1×5.1×1.27 mm3 was also successfully demonstrated by using two built-in double-sided DE packages joined by flip-chip bonding, equivalent to stacking four layers of conventional single-sided DE packages. The double-sided DE packages and POPs presented in this paper are believed to be the world’s first demonstration on glass. The work also manifests the immense potential of Corning® AFG glass in enabling higher density IC packaging and large-size panel-level (or wafer-level) packaging.

PDF file - 59K, PKCK2 activity dependent stabilization of exogenous Snail. A, MCF-7 cells that have low PKCK2 activity were co-transfected with Flag tagged Snail expression vector along either with empty vector or with Myc tagged PKCK2� expression vector. B, HCE4 cells were transfected with Flag-Snail and then were treated or un-treated with TBB, a pharmacologic inhibitor of PKCK2. C, PKCK2 activity was measured for each condition. S92 represents a vector expressing wild type snail, S92A (serine 92 replaced with alanine) mutant represents a vector expressing non-phosphorylatable form of snail, and S92E (serine 92 replaced with glutamic acid) represents a vector expressing mutant snail to mimic constitutive phosphorylation

PDF file - 71K, Western blot analysis for type of cadherin expressed in TE2, TE3, HCE4, and HCE7 (A) and for epithelial or mesenchymal markers and PKB/Akt activation in TE3 and HCE7 cells (B)

PDF file - 79K, Expression level of molecules involved in E-cadherin down-regulation. Western blot analysis was performed using total cell lysates (A) or lysates from cytoplasmic or nuclear fraction (B). The indicated Abs were used. RT-PCR was performed to examine mRNA expression level of Axin2 in TE2 and HCE4 cells and GAPDH was used as an internal control

In a joint transmission (JT) system using orthogonal frequency-division modulation (OFDM), performance degradation due to asynchronous interference resulting from the time difference of arrival is unavoidable. We propose an affinity propagation clustering (APC) algorithm for radio remote heads clustering for downlink JT in an asynchronous OFDM system. In particular, by closely connecting the principles of APC and JT with synchronization mismatch, we newly design pairwise similarities and preferences of the APC algorithm. The proposed algorithm provides 1.5 times higher 5-percentile user spectral efficiency than the APC algorithm with a conventional similarity matrix, and it has the same time complexity in term of big O notation.

Distributed congestion control (DCC) improves system performance by lowering channel congestion in vehicular environments with high vehicle density. The 3rd Generation Partnership Project standard defines the related metrics of channel busy ratio (CBR) and introduces possible rate and power control mechanisms to mitigate channel congestion in cellular vehicle-to-everything (C-V2X) sidelink. However, the DCC of C-V2X is not sufficiently specified to implement these controls. In this letter, we propose a novel DCC algorithm based on deep reinforcement learning (DRL) to improve congestion control performance in C-V2X sidelink. The proposed algorithm allows the DRL agent to observe a CBR state and select the packet transmission rate that can maximize the reward of packet delivery rate (PDR) while maintaining higher channel utilization. Simulation results show that the proposed algorithm provides performance gain in terms of PDR and sidelink throughput compared with the existing DCC method.

Introduction The importance of fatty acid oxidation (FAO) in the bioenergetics of glioblastoma (GBM) is being realized. Etomoxir (ETO), a carnitine palmitoyltransferase 1 (CPT1) inhibitor exerts cytotoxic effects in GBM, which involve interrupting the FAO pathway. We hypothesized that FAO inhibition could affect the outcomes of current standard temozolomide (TMZ) chemotherapy against GBM. Methods The FAO-related gene expression was compared between GBM and the tumor-free cortex. Using four different GBM tumorspheres (TSs), the effects of ETO and/or TMZ was analyzed on cell viability, tricarboxylate (TCA) cycle intermediates and adenosine triphosphate (ATP) production to assess metabolic changes. Alterations in tumor stemness, invasiveness, and associated transcriptional changes were also measured. Mouse orthotopic xenograft model was used to elucidate the combinatory effect of TMZ and ETO. Results GBM tissues exhibited overexpression of FAO-related genes, especially CPT1A, compared to the tumor-free cortex. The combined use of ETO and TMZ further inhibited TCA cycle and ATP production than single uses. This combination treatment showed superior suppression effects compared to treatment with individual agents on the viability, stemness, and invasiveness of GBM TSs, as well as better downregulation of FAO-related gene expression. The results of in vivo study showed prolonged survival outcomes in the combination treatment group. Conclusion ETO, an FAO inhibitor, causes a lethal energy reduction in the GBM TSs. When used in combination with TMZ, ETO effectively reduces GBM cell stemness and invasiveness and further improves survival. These results suggest a potential novel treatment option for GBM.

Ischemia-reperfusion injury is a major cause of acute kidney injury. Recent studies on the pathophysiology of ischemia-reperfusion-induced acute kidney injury showed that immunologic responses significantly affect kidney ischemia-reperfusion injury and repair. Nuclear factor (NF)-ĸB signaling, which controls cytokine production and cell survival, is significantly involved in ischemia-reperfusion-induced acute kidney injury, and its inhibition can ameliorate ischemic acute kidney injury. Using EXPLOR, a novel, optogenetically engineered exosome technology, we successfully delivered the exosomal super-repressor inhibitor of NF-ĸB (Exo-srIĸB) into B6 wild type mice before/after kidney ischemia-reperfusion surgery, and compared outcomes with those of a control exosome (Exo-Naïve)-injected group. Exo-srIĸB treatment resulted in lower levels of serum blood urea nitrogen, creatinine, and neutrophil gelatinase-associated lipocalin in post-ischemic mice than in the Exo-Naïve treatment group. Systemic delivery of Exo-srIĸB decreased NF-ĸB activity in post-ischemic kidneys and reduced apoptosis. Post-ischemic kidneys showed decreased gene expression of pro-inflammatory cytokines and adhesion molecules with Exo-srIĸB treatment as compared with the control. Intravital imaging confirmed the uptake of exosomes in neutrophils and macrophages. Exo-srIĸB treatment also significantly affected post-ischemic kidney immune cell populations, lowering neutrophil, monocyte/macrophage, and T cell frequencies than those in the control. Thus, modulation of NF-ĸB signaling through exosomal delivery can be used as a novel therapeutic method for ischemia-reperfusion-induced acute kidney injury.

Limited treatment options are currently available for glioblastoma (GBM), an extremely lethal type of brain cancer. For a variety of tumor types, bioenergetic deprivation through inhibition of cancer-specific metabolic pathways has proven to be an effective therapeutic strategy. Here, we evaluated the therapeutic effects and underlying mechanisms of dual inhibition of carnitine palmitoyltransferase 1A (CPT1A) and glucose-6-phosphate dehydrogenase (G6PD) critical for fatty acid oxidation (FAO) and the pentose phosphate pathway (PPP), respectively, against GBM tumorspheres (TSs).Therapeutic efficacy against GBM TSs was determined by assessing cell viability, neurosphere formation, and 3D invasion. Liquid chromatography-mass spectrometry (LC-MS) and RNA sequencing were employed for metabolite and gene expression profiling, respectively. Anticancer efficacy in vivo was examined using an orthotopic xenograft model.CPT1A and G6PD were highly expressed in GBM tumor tissues. Notably, siRNA-mediated knockdown of both genes led to reduced viability, ATP levels, and expression of genes associated with stemness and invasiveness. Similar results were obtained upon combined treatment with etomoxir and dehydroepiandrosterone (DHEA). Transcriptome analyses further confirmed these results. Data from LC-MS analysis showed that this treatment regimen induced a considerable reduction in the levels of metabolites associated with the TCA cycle and PPP. Additionally, the combination of etomoxir and DHEA inhibited tumor growth and extended survival in orthotopic xenograft model mice.Our collective findings support the utility of dual suppression of CPT1A and G6PD with selective inhibitors, etomoxir and DHEA, as an efficacious therapeutic approach for GBM.

Histone acetylation involves the transfer of a two-carbon unit to nucleus as embedded in low-concentration metabolites. We find that lactate, a high-concentration metabolic by-product, can be a major carbon source for histone acetylation, through oxidation-dependent metabolism. Both in cells and in purified nucleus, 13C3-lactate carbons are incorporated into histone H4 (maximum incorporation: ~60%). In purified nucleus, this process depends on nucleus-localized lactate dehydrogenase (LDHA), the knockout of which abrogates the incorporation. Heterologous expression of nucleus-localized LDHA rescues the KO effect. Lactate itself increases histone acetylation, whereas inhibition of LDHA reduces the acetylation. In vitro and in vivo settings exhibit different lactate incorporation patterns, suggesting an influence of the microenvironment. Higher nuclear LDHA localization is observed in pancreatic cancer than in normal tissues, showing the disease relevance. Overall, lactate and nuclear LDHA can be major structural and regulatory players in the metabolism-epigenetics axis controlled by cell’s own or environmental status.

This study investigates the effect of driving frequency on the ability of a dielectric barrier discharge (DBD) plasma to reduce the radar cross section (RCS) in the Ku -band. Analysis based on the Drude model suggests that the electron density of the plasma will increase with the driving frequency, implying that the plasma will be more effective in terms of RCS reduction. Experimental results based on a multifingered DBD generator reveal that an RCS reduction of up to 4.1 dB is achieved at 18 GHz, which is a 1.3 dB increase due to increasing the driving frequency from 1 to 2 kHz. Finally, the electron density, which is extracted by fitting the simulated RCS results, increased by as much as approximately 330% due to the increase in the driving frequency from 1 to 2 kHz. As the driving frequency increases, the frequency of collision between plasma particles increases. Therefore, the ionization of gas molecules is enhanced, resulting in a higher electron density. The experimental results also suggest that enhancement in the RCS reduction is larger when the electric field intensity between the two electrodes of the DBD generator is greater. As a result, the plasma becomes electromagnetically more lossy and is more effective for reducing the RCS. Experimental results are provided and analyzed based on the electromagnetic parameters used for modeling the plasma.

This study presents the micro-Doppler signature (MDS) of small drones based on resonance phenomena. The MDS analysis of a drone is conducted for various detection conditions. The Doppler frequencie...

This letter presents a novel technique for radar cross section (RCS) feature extraction using discrete scattering center modeling and a basis pursuit denoising (BPDN) algorithm for compressive sensing. From the Stratton–Chu formula, a high-frequency assumption has been applied to define the target object as a combination of independent point scatterers. Using the BPDN solver, complex-valued scattering sources are determined from a matrix equation for the scattering problem. Using a numerical example, it has been verified that the proposed method can extract the RCS feature accurately, and the measurement efficiency is much higher compared to that of conventional methods.

We investigated a role of bone morphogenic protein 7 (BMP7), a member of the TGF-β superfamily on pathogenic mechanism of Graves' orbitopathy (GO). The therapeutic effects of BMP7 on inflammation and fibrosis were evaluated in cultured Graves' orbital fibroblasts.Expression of BMP7 was compared in cultured orbital tissue explants from GO (n = 12) and normal control (n = 12) subjects using real-time PCR. Orbital fibroblasts were cultured from orbital connective tissues obtained from GO (n = 3) and normal control patients (n = 3). Cells were pretreated with recombinant human BMP7 (rhBMP7) before stimulation with TGF-β, IL-1β, and TNF-α. Fibrosis-related proteins and inflammatory cytokines were analyzed by Western blotting. The activation of signaling molecules in inflammation and fibrosis was also analyzed.The expressions of BMP7 mRNA were lower in GO orbital tissues than control. Fibrosis-related proteins, fibronectin, collagen 1α, and α-SMA induced by TGF-β were suppressed by treating rhBMP7, and rhBMP7 upregulated TGF-β induced SMAD1/5/8 protein expression, whereas downregulated SMAD2/3. Increased pro-inflammatory molecules, IL-6, IL-8, and intercellular adhesion molecule-1 (ICAM-1) by IL-1β or TNF-α were blocked by rhBMP7 treatment, and the expression of phosphorylated NFκB and Akt was suppressed by rhBMP7 treatment.BMP7 transcript levels were downregulated in Graves' orbital tissues. Exogenous BMP7 treatment showed inhibitory effects on the production of profibrotic proteins and proinflammatory cytokines in orbital fibroblasts. Our results provide a molecular basis of BMP7 as a new potential therapeutic agent through the opposing mechanism of profibrotic TGF-β/SMAD signaling and proinflammatory cytokine production.

This paper presents an electromagnetic-mechanical repair patch (EMRP) to restore the mechanical and electromagnetic (EM) wave absorption performance of a radar-absorbing structure (RAS) damaged by lightning strike. Several researchers have primarily focused on ensuring high repair efficiency, particularly in terms of the primary load-bearing properties of repaired fiber-reinforced plastics. However, no study has proposed a practical repair approach that considers the multi-functionality of the radar-absorbing structure. The EMRP method can be used to repair lightning strike damage in a radar-absorbing structure with electroless nickel-plated glass fabric, considering the need to maintain structural integrity and electrical continuity to achieve a high repair efficiency. Damage due to an artificial lightning strike was assessed in terms of area and depth of the damage using image processing, ultrasonic C-scan, and micro X-ray inspection. The EM characteristics of one-dimensional return loss scanning and the echo radar-cross-section level were measured to verify the stealth performance of the repaired radar absorber in the X-band. In addition, the tensile test results demonstrated that the repaired radar absorber had a high recovery rate of 93% compared to the pristine radar absorber. The experimental results obtained in this study validate the use of the proposed EMRP method in repairing radar-absorbing structures.

Passive component-based soft resonators have been spotlighted in the field of wearable and implantable devices due to their remote operation capability and tunable properties. As the output signal ...

In this paper, a microwave fluidic glucose sensor based on dual complementary split ring resonators (CSRRs) with a switching circuit is proposed for non-invasive and continuous glucose concentration detection. A CSRR has been designed to detect subtle changes in the dielectric constant of glucose solutions, and the electric field distribution is utilized to determine the effective sensing region. In a well-controlled environment, the glucose concentration can be detected by tracking the transmission coefficient of the designed CSRR. However, because the variations in dielectric constant with the glucose concentration are very small, the environmental factors (i.e., ambient temperature and relative humidity) can be dominant compared to the glucose concentration. To qualify the effect of the environmental factors, the variation in the transmission coefficient of the CSRR has been measured when the ambient temperature condition is varied from 293 K to 313 K and the relative humidity is varied from 30% to 90% inside temperature- and humidity-controlled chamber. Moreover, the environmental effects are calibrated out using two identical CSRRs with the switching circuit: one detects changes in the glucose concentration, while the other operates as a reference for environmental factors. After the elimination of the environmental effects, glucose concentrations in the range of 0 mg/dL to 400 mg/dL have been measured, and the sensitivity is 0.008dB/(100mg/dL). In addition, the reproducibility of the proposed sensor is verified by repeated measurements. It is demonstrated that the proposed sensor can detect glucose concentrations under practical environmental conditions.

Purpose Glioblastoma (GBM) is the most aggressive type of brain tumor and has poor survival outcomes, even after a combination of surgery, radiotherapy, and chemotherapy. Temozolomide is the only agent that has been shown to be effective against GBM, suggesting that combination of temozolomide with other agents may be more effective. Niclosamide, an FDA approved anthelmintic agent, has shown anti-cancer effects against human colon, breast, prostate cancers as well as GBM. However, the efficacy of the combination of niclosamide with temozolomide against GBM tumorspheres (TSs) has not been determined. We hypothesized that the combined treatment could effectively suppress GBM TSs. Methods GBM TSs (TS15-88, GSC11) were treated with niclosamide and/or temozolomide. Combined effects of two drugs were evaluated by measuring viability, neurosphere formation, and 3D-invasion in collagen matrix. Transcriptional profiles of GBM TS were analyzed using RNA sequencing. In vivo anticancer efficacy of combined drugs was tested in a mouse orthotopic xenograft model. Results Combination treatment of niclosamide and temozolomide significantly inhibited the cell viability, stemness, and invasive properties of GBM TSs. This combined treatment significantly down-regulated the expression of epithelial mesenchymal transition-related markers, Zeb1, N-cadherin, and β-catenin. The combined treatment also significantly decreased tumor growth in orthotopic xenograft models. Conclusion The combination of niclosamide and temozolomide effectively decreased the stemness and invasive properties of GBM TSs, suggesting that this regimen may be therapeutically effective in treating patients with GBM.

This study proposes an innovative patch antenna design for multi-band operation and high radiation efficiency. The design target is the structural shape of a patch and a ground plane. The operating...

This study proposes a novel signal processing method for detecting the vital signs of multiple adjacent subjects using a 24 GHz frequency modulated continuous wave Doppler radar. Radar-based vital signs sensors have attracted significant attention because of their contactless and unobtrusive mode of measurement. However, limited-bandwidth, fixed-beam systems have been restricted to single subjects because a high resolution is required to detect the vital signs of multiple adjacent subjects. As the range resolution is determined by the frequency bandwidth, a novel method is proposed that doubles the effective frequency bandwidth by using a modified waveform. The proposed method can distinguish between two subjects sitting 40 cm apart, overcoming the 60 cm Rayleigh resolution for a frequency bandwidth of 250 MHz. The computational complexity of the proposed method is considerably low when compared with high-resolution algorithms such as the multiple signal classification algorithm. Furthermore, the method easily suppresses stationary clutter by using phase deviation. To validate the performance of the proposed method, experiments were conducted with two subjects lying side by side on a bed. The results indicate the excellent performance, with enhanced range and high detection accuracy. This method has many potential applications, including monitoring infants and sleep apnea patients.

This paper presents the electromagnetic interference characteristics of the high-definition multimedia interface (HDMI), a well-known display interface, and quantitatively offers the possibility of information from the leakage in the perspective of radio communication. After analyzing the leakage characteristics, a pseudo-signal model is generated based on the characteristics and behavioral features of the software-defined radio. Subsequently, the model is utilized to investigate the performance of frame-averaging to improve the low signal-to-noise ratio of sensitive information contained in the leakage. In addition, the frame-averaging scheme is quantitatively analyzed under various environmental assumptions. Based on these contributions, the paper offers several indexes that quantitatively present meaningful information in EM leakage. Finally, the actual measurement results are compared with those of the pseudo-model to verify our work.

Considering the high metastatic potential of colorectal cancer (CRC), the inhibition of metastasis is important for anti-CRC therapy.

A structural protein of SARS-CoV-2, nucleocapsid (N) protein is abundantly expressed during viral replication. The N protein is phosphorylated by glycogen synthase kinase (GSK)-3 on the serine/arginine (SR) rich motif located in disordered regions. Although phosphorylation by GSK-3β constitutes a critical event for viral replication, the molecular mechanism underlying N phosphorylation is not well understood. In this study, we found the putative alpha-helix L/FxxxL/AxxRL motif known as the GSK-3 interacting domain (GID), commonly found in many endogenous GSK-3β binding proteins, such as Axins, FRATs, WWOX and GSKIP. Indeed, N interacts with GSK-3β similarly to Axin, and Leu to Glu substitution of the GID abolished the interaction, with loss of N phosphorylation. Unlike with endogenous GID proteins, the N interaction neither disturbs endogenous GSK-3 activity nor regulates subsequent canonical Wnt activity and the Snail-EMT program. Notably, N abundance in SARS-CoV-2 is incomparably high compared to other coronaviruses, such as 229E, OC43 and HKU1. Compared to other coronaviruses, N harbors a CDK1 primed phosphorylation site and Gly-rich linker for enhanced phosphorylation by GSK-3β. Furthermore, we found that the S202R mutant found in Delta and R203K/G204R mutant found in the Omicron variant allows increased abundance and hyper-phosphorylation of N. Our observations suggest that the emergence of GID and mutations for increased phosphorylation in N may have contributed to the emergence of SARS-CoV-2 and evolution of variants, respectively. Further study, especially in a BSL3-equipped facility, is required to elucidate the functional importance of GID and N phosphorylation in SARS-CoV-2 and variants.