Translocation of cytosolic human Cdc73 to stress granules plays a role in arsenic stress-induced stabilization of p53 mRNA.

Cells trigger the assembly of stress granules (SGs) under various stress conditions. Among the many proteins recruited to SGs are RNA-binding proteins and transcription regulators. Here, we report the translocation of human (h)Cdc73, a component of the PAF1 transcription complex, to cytosolic SGs in response to arsenic stress. The hCdc73 protein possesses a long intrinsically disordered region (IDR) from amino acids 256-416, the presence of which is required for the translocation of hCdc73 to cytosolic SGs. The purified hCdc73 IDR formed droplets in vitro, and the light-activated assembly of hCdc73-IDR-mCherry-CRY2 was verified. For translocation of hCdc73 to SGs, physical interactions with SG carrier proteins, such as FMR1, are also needed. Previously, we reported that the cytosolic hCdc73-eEF1Bγ complex controls the stability of p53 mRNA. Under arsenic stress, selective sequestration of cytosolic hCdc73, but not eEF1Bγ (EEF1G) or p53 (TP53) mRNA, was detected. As a result, a transient increase in p53 mRNA at the post-transcriptional level was observed. In conclusion, we propose that the availability of mRNAs for stress-responsive genes can be controlled by restraining their negative regulators within SGs.

Homotypic SCOTIN assemblies form ER-endosome membrane contacts and regulate endosome dynamics.

The ER regulates the spatiotemporal organization of endolysosomal systems by membrane contact. In addition to tethering via heterotypic interactions on both organelles, we present a novel ER-endosome tethering mechanism mediated by homotypic interactions. The single-pass transmembrane protein SCOTIN is detected in the membrane of the ER and endosomes. In SCOTIN-knockout (KO) cells, the ER-late endosome contacts are reduced, and the perinuclear positioning of endosomes is disturbed. The cytosolic proline-rich domain (PRD) of SCOTIN forms homotypic assemblies in vitro and is necessary for ER-endosome membrane tethering in cells. A region of 28 amino acids spanning 150-177 within the SCOTIN PRD is essential to elicit membrane tethering and endosomal dynamics, as verified by reconstitution in SCOTIN-KO cells. The assembly of SCOTIN (PRD) is sufficient to mediate membrane tethering, as purified SCOTIN (PRD), but not SCOTIN (PRDΔ150-177), brings two different liposomes closer in vitro. Using organelle-specific targeting of a chimeric PRD domain shows that only the presence on both organellar membranes enables the ER-endosome membrane contact, indicating that the assembly of SCOTIN on heterologous membranes mediates organelle tethering.

Isolation and whole genome sequencing of North American lineage class I avian orthoavulavirus 1 isolated from wild Eurasian teal in South Korea.

We report the first North American origin class I avian orthoavulavirus 1 (AOAV-1) isolated from a faecal dropping of wild Eurasian teal (Anas crecca) in South Korea. Whole genome sequencing and comparative phylogenetic analysis revealed that the AOAV-1/Eurasian teal/South Korea/KU1405-3/2017 virus belongs to the sub-genotype 1.2 of class I AOAV-1. Phylogenetic analysis suggested multiple introductions of the North American sub-genotype 1.2 viruses into Asia and its establishment in the wild bird population in East Asia since May 2011. These results provide information on the epidemiology of AOAV-1, particularly the role of migratory wild birds in exchanging viruses between the Eurasian and North American continents. Enhanced genomic surveillance is required to improve our understanding on the evolution and transmission dynamics of AOAV-1 in wild birds.

Novel Highly Pathogenic Avian Influenza A(H5N1) Clade 2.3.4.4b Virus in Wild Birds, South Korea.

We isolated 5 highly pathogenic avian influenza A(H5N1) clade 2.3.4.4.b viruses from wild waterfowl feces in South Korea during November 2022. Whole-genome sequencing and phylogenetic analysis revealed novel genotypes produced by reassortment with Eurasian low pathogenicity avian influenza viruses. Enhanced surveillance will be required to improve prevention and control strategies.

Impact of COVID-19 infection and vaccination in pancreatobiliary IgG4-related disease patients: An international multicenter study.

BACKGROUND AND AIM: Dedicated studies evaluating the impact of COVID-19 on outcomes of pancreatobiliary IgG4 related disease (IgG4-RD) patients are scarce. Whether COVID-19 infection or vaccination would trigger IgG4-RD exacerbation remains unknown. METHODS: Pancreatobiliary IgG4-RD patients ≥ 18 years old with active follow-up since January 2020 from nine referral centers in Asia, Europe, and North America were included in this multicenter retrospective study. Outcome measures include incidence and severity of COVID-19 infection, IgG4-RD disease activity and treatment status, interruption of indicated IgG4-RD treatment. Prospective data on COVID-19 vaccination status and new COVID-19 infection during the Omicron outbreak were also retrieved in the Hong Kong cohort. RESULTS: Of the 124 pancreatobiliary IgG4-RD patients, 25.0% had active IgG4-RD, 71.0% were on immunosuppressive therapies and 80.6% had ≥ 1 risk factor for severe COVID. In 2020 (pre-vaccination period), two patients (1.6%) had COVID-19 infection (one requiring ICU admission), and 7.2% of patients had interruptions in indicated immunosuppressive treatment for IgG4-RD. Despite a high vaccination rate (85.0%), COVID-19 infection rate has increased to 20.0% during Omicron outbreak in the Hong Kong cohort. A trend towards higher COVID-19 infection rate was noted in the non-fully vaccinated/unvaccinated group (17.6% vs 33.3%, P = 0.376). No IgG4-RD exacerbation following COVID-19 vaccination or infection was observed. CONCLUSION: While a low COVID-19 infection rate with no mortality was observed in pancreatobiliary IgG4-RD patients in the pre-vaccination period of COVID-19, infection rate has increased during the Omicron outbreak despite a high vaccination rate. No IgG4-RD exacerbation after COVID-19 infection or vaccination was observed.

Intrinsic variation effect in memristive neural network with weight quantization.

To analyze the effect of the intrinsic variations of the memristor device on the neuromorphic system, we fabricated 32 × 32 Al2O3/TiOx-based memristor crossbar array and implemented 3 bit multilevel conductance as weight quantization by utilizing the switching characteristics to minimize the performance degradation of the neural network. The tuning operation for 8 weight levels was confirmed with a tolerance of ±4µA (±40µS). The endurance and retention characteristics were also verified, and the random telegraph noise (RTN) characteristics were measured according to the weight range to evaluate the internal stochastic variation effect. Subsequently, a memristive neural network was constructed by off-chip training with differential memristor pairs for the Modified National Institute of Standards and Technology (MNIST) handwritten dataset. The pre-trained weights were quantized, and the classification accuracy was evaluated by applying the intrinsic variations to each quantized weight. The intrinsic variations were applied using the measured weight inaccuracy given by the tuning tolerance, RTN characteristics, and the fault device yield. We believe these results should be considered when the pre-trained weights are transferred to a memristive neural network by off-chip training.

Navigation Path Based Universal Mobile Manipulator Integrated Controller (NUMMIC).

As the demand for service robots increases, a mobile manipulator robot which can perform various tasks in a dynamic environment attracts great attention. There are some controllers that control mobile platform and manipulator arm simultaneously for efficient performance, but most of them are difficult to apply universally since they are based on only one mobile manipulator model. This lack of versatility can be a big problem because most mobile manipulator robots are made by connecting a mobile platform and manipulator from different companies. To overcome this problem, this paper proposes a simultaneous controller which can be applied not only to one model but also to various types of mobile manipulator robots. The proposed controller has three main characteristics, which are as follows: (1) establishing a pose that motion planning can be carried out in any position, avoiding obstacles and stopping in a stable manner at the target coordinates, (2) preventing the robot from collision with surrounding obstacles while driving, (3) defining a safety area where the manipulator does not hit the obstacles while driving and executing the manipulation accordingly. Our controller is fully compatible with Robot Operating System (ROS) and has been used successfully with three different types of mobile manipulator robots. In addition, we conduct motion planning experiments on five targets, each in two simulation worlds, and two motion planning scenarios using real robots in real-world environments. The result shows a significant improvement in time compared to existing control methods in various types of mobile manipulator and demonstrates that the controller works successfully in the real environment. The proposed controller is available on GitHub.

Nicotinamide phosphoribosyltransferase regulates the cell differentiation and mineralization in cultured odontoblasts.

The aim of the present study was to investigate the physiological role of nicotinamide phosphoribosyltransferase (NAMPT) associated with odontogenic differentiation during tooth development in mice. Mouse dental papilla cell-23 (MDPC- 23) cells cultured in differentiation media were stimulated with the specific NAMPT inhibitor, FK866, and Visfatin (NAMPT) for up to 10 days. The cells were evaluated after 0, 4, 7, and 10 days. Cell viability was measured using the 3-(4,5-dimethylthiazol- 2-yl)-2,5-diphenyltetrazolium bromide assay. The mineralization assay was performed by staining MDPC-23 cells with Alizarin Red S solution. After cultivation, MDPC-23 cells were harvested for quantitative PCR or Western blotting. Analysis of variance was performed using StatView 5.0 software (SAS Institute Inc., Cary, NC, USA). Statistical significance was set at p < 0.05. The expression of NAMPT increased during the differentiation of murine odontoblast-like MDPC-23 cells. Furthermore, the up-regulation of NAMPT promoted odontogenic differentiation and accelerated mineralization through an increase in representative odontoblastic biomarkers, such as dentin sialophosphoprotein, dentin matrix protein-1, and alkaline phosphatase in MDPC-23 cells. However, treatment of the cells with the NAMPT inhibitor, FK866, attenuated odontogenic differentiation, as evidenced by the suppression of odontoblastic biomarkers. These data indicate that NAMPT regulated odontoblastic differentiation through the regulation of odontoblastic biomarkers. The increase in NAMPT expression in odontoblasts was closely related to the formation of the extracellular matrix and dentin via the Runx signaling pathway. Therefore, these data suggest that NAMPT is a critical regulator of odontoblast differentiation during tooth development.

3-bit multilevel operation with accurate programming scheme in TiOx/Al2O3memristor crossbar array for quantized neuromorphic system.

As interest in artificial intelligence (AI) and relevant hardware technologies has been developed rapidly, algorithms and network structures have become significantly complicated, causing serious power consumption issues because an enormous amount of computation is required. Neuromorphic computing, a hardware AI technology with memory devices, has emerged to solve this problem. For this application, multilevel operations of synaptic devices are important to imitate floating point weight values in software AI technologies. Furthermore, weight transfer methods to desired weight targets must be arranged for off-chip training. From this point of view, we fabricate 32 × 32 memristor crossbar array and verify the 3-bit multilevel operations. The programming accuracy is verified for 3-bit quantized levels by applying a reset-voltage-control programming scheme to the fabricated TiOx/Al2O3-based memristor array. After that, a synapse composed of two differential memristors and a fully-connected neural network for modified national institute of standards and technology (MNIST) pattern recognition are constructed. The trained weights are post-training quantized in consideration of the 3-bit characteristics of the memristor. Finally, the effect of programming error on classification accuracy is verified based on the measured data, and we obtained 98.12% classification accuracy for MNIST data with the programming accuracy of 1.79% root-mean-square-error. These results imply that the proposed reset-voltage-control programming scheme can be utilized for a precise tuning, and expected to contribute for the development of a neuromorphic system capable of highly precise weight transfer.

A novel physical unclonable function (PUF) using 16 × 16 pure-HfOxferroelectric tunnel junction array for security applications.

As the computing paradigm has shifted toward edge computing, improving the security of edge devices is attracting significant attention. However, because edge devices have limited resources in terms of power and area, it is difficult to apply a conventional cryptography system to protect them. On the other hand, as a simple security application, a physical unclonable function (PUF) can be implemented without power and area problems because it provides a security key by utilizing process variations without additional external circuits. Ferroelectric tunnel junctions (FTJs) are 2-terminal devices that store information by changing the resistance of a ferroelectric material, where the resistance is determined by the polarization states of the ferroelectric domains. Because polycrystalline ferroelectric materials have a multi-domain nature, domain variation can also be used as a randomness source to induce cell-to-cell variations along with process variations. In this paper, we demonstrate PUF operations of a low-power, small area 16 × 16 hafnium oxide (pure-HfOx)-based FTJ array using certain metrics. It is clear that the proposed array consisting of scaled FTJs has adequate randomness for security applications such that the array-level PUF operations are robust against model-based machine learning attacks.

Analytically and empirically consistent characterization of the resistive switching mechanism in a Ag conducting-bridge random-access memory device through a pseudo-liquid interpretation approach.

A new physical analysis of the filament formation in a Ag conducting-bridge random-access memory (CBRAM) device in consideration of the existence of inter-atomic attractions caused by metal bonding is suggested. The movement of Ag atoms inside the switching layer is characterized hydrodynamically using the Young-Laplace equation during set and reset operations. Both meridional and azimuthal curvatures of the Ag filament protruding from the Ag electrode are accurately calculated to track down the exact shape of the Ag filament with change in the applied voltage. The second-order partial differential equation for the Ag filament geometry is derived from the equation of equilibrium between the electrostatic pressure and the Laplace one. The solution to the equation is numerically obtained, and furthermore, the abrupt set operation in the forming process, bipolar resistive-switching, and the threshold switching operation in the reset operations are successfully simulated in accordance with the numerical solutions. Also, it is demonstrated that the currents extracted from the suggested model show good agreement with the I-V characteristics measured from the fabricated Ag CBRAM device.

Compensation of a Second Harmonic Wave Included in an Incident Ultrasonic Wave for the Precise Measurement of the Acoustic Nonlinearity Parameter.

The incident second harmonic wave is a problematic issue for the precise measurement of the acoustic nonlinearity parameter. This paper proposes a compensation method to remove the effect of the incident second harmonic component in the measurement of the absolute acoustic nonlinearity parameter using the calibration method. For this, the second harmonic component detected by the receiving transducer is considered as the sum of the component due to material nonlinearity and the component included in the incident signal and a numerical calculation model is developed as a function of the propagation distance. In the model, the factors related to the material nonlinear parameter and the magnitude of the incident second harmonic component are unknown and these are determined by finding a value that best matches the experimental data according to the change in the propagation distance; compensation for the incident second harmonic component is then achieved. The case where the phase of the second harmonic wave due to material nonlinearity is opposite to that of the fundamental wave is also considered. To verify the validity of the proposed method, fused silica and aluminum alloy Al6061-T6 specimens with different thicknesses corresponding to the propagation distance are tested. The experimental results show that the nonlinear parameters changed significantly according to the propagation distance before compensation but were very stable after compensation. Additionally, the average values of the nonlinear parameter are 11.04 in the fused silica, which is within the literature value range (10.1 to 12.4), and that for the Al6061-T6 is 6.59, which is close to the literature value range (4.5 to 6.12).

Oxysterol 25-hydroxycholesterol as a metabolic pathophysiological factors of osteoarthritis induces apoptosis in primary rat chondrocytes.

The aim of the present study was to investigate the pathophysiological etiology of osteoarthritis that is mediated by the apoptosis of chondrocytes exposed to 25-hydroxycholesterol (25-HC), an oxysterol synthesized by the expression of cholesterol-25-hydroxylase (CH25H) under inflammatory conditions. Interleukin-1ß induced the apoptosis of chondrocytes in a dose- dependent manner. Furthermore, the production of 25-HC increased in the chondrocytes treated with interleukin-1ß through the expression of CH25H. 25-HC decreased the viability of chondrocytes. Chondrocytes with condensed nucleus and apoptotic populations increased by 25-HC. Moreover, the activity and expression of caspase-3 were increased by the death ligand-mediated extrinsic and mitochondria-dependent intrinsic apoptotic pathways in the chondrocytes treated with 25-HC. Finally, 25-HC induced not only caspase-dependent apoptosis, but also induced proteoglycan loss in articular cartilage ex vivo cultured rat knee joints. These data indicate that 25-HC may act as a metabolic pathophysiological factor in osteoarthritis that is mediated by progressive chondrocyte death in the articular cartilage with inflammatory condition.

In Silico Identification of Potential Inhibitor Against a Fungal Histone Deacetylase, RPD3 from Magnaporthe Oryzae.

Histone acetylation and deacetylation play an essential role in the epigenetic regulation of gene expression. Histone deacetylases (HDAC) are a group of zinc-binding metalloenzymes that catalyze the removal of acetyl moieties from lysine residues from histone tails. These enzymes are well known for their wide spread biological effects in eukaryotes. In rice blast fungus, Magnaporthe oryzae, MoRPD3 (an ortholog of Saccharomyces cerevisiae Rpd3) was shown to be required for growth and development. Thus in this study, the class I HDAC, MoRpd3 is considered as a potential drug target, and its 3D structure was modelled and validated. Based on the model, a total of 1880 compounds were virtually screened (molecular docking) against MoRpd3 and the activities of the compounds were assessed by docking scores. The in silico screening suggested that [2-[[4-(2-methoxyethyl) phenoxy] methyl] phenyl] boronic acid (-8.7 kcal/mol) and [4-[[4-(2-methoxyethyl) phenoxy] methyl] phenyl] boronic acid (-8.5 kcal/mol) are effective in comparison to trichostatin A (-7.9 kcal/mol), a well-known general HDAC inhibitor. The in vitro studies for inhibition of appressorium formation by [2-[[4-(2-methoxyethyl) phenoxy] methyl] phenyl] boronic acid has resulted in the maximum inhibition at lower concentrations (1 µM), while the trichostatin A exhibited similar levels of inhibition at 1.5 µM. These findings thus suggest that 3D quantitative structure activity relationship studies on [2-[[4-(2-methoxyethyl) phenoxy] methyl] phenyl] boronic acid compound can further guide the design of more potential and specific HDAC inhibitors.

Role of Hydrogen Bonding on Transport of Coadsorbed Gases in Metal-Organic Frameworks Materials.

Coadsorption of multicomponents in metal-organic framework (MOF) materials can lead to a number of cooperative effects, such as modification of adsorption sites or during transport. In this work, we explore the incorporation of NH3 and H2O into MOFs preloaded with small molecules such as CO, CO2, and SO2. We find that NH3 (or H2O) first displaces a certain amount of preadsorbed molecules in the outer portion of MOF crystallites, and then substantially hinders diffusion. Combining in situ spectroscopy with first-principles calculations, we show that hydrogen bonding between NH3 (or H2O) is responsible for an increase of a factor of 7 and 8 in diffusion barrier of CO and CO2 through the MOF channels. Understanding such cooperative effects is important for designing new strategies to enhance adsorption in nanoporous materials.

Nano-cone resistive memory for ultralow power operation.

SiN x -based nano-structure resistive memory is fabricated by fully silicon CMOS compatible process integration including particularly designed anisotropic etching for the construction of a nano-cone silicon bottom electrode (BE). Bipolar resistive switching characteristics have significantly reduced switching current and voltage and are demonstrated in a nano-cone BE structure, as compared with those in a flat BE one. We have verified by systematic device simulations that the main cause of reduction in the performance parameters is the high electric field being more effectively concentrated at the tip of the cone-shaped BE. The greatly improved nonlinearity of the nano-cone resistive memory cell will be beneficial in the ultra-high-density crossbar array.

Ultralow power switching in a silicon-rich SiNy/SiNx double-layer resistive memory device.

Here we demonstrate low-power resistive switching in a Ni/SiNy/SiNx/p++-Si device by proposing a double-layered structure (SiNy/SiNx), where the two SiN layers have different trap densities. The LRS was measured to be as low as 1 nA at a voltage of 1 V, because the SiNx layer maintains insulating properties for the LRS. The single-layered device suffers from uncontrollability of the conducting path, accompanied by the inherent randomness of switching parameters, weak immunity to breakdown during the reset process, and a high operating current. On the other hand, for a double-layered device, the effective conducting path in each layer, which can determine the operating current, can be well controlled by the ICC during the initial forming and set processes. A one-step forming and progressive reset process is observed for a low-power mode, which differs from the high-power switching mode that shows a two-step forming and reset process. Moreover, nonlinear behavior in the LRS, whose origin can be attributed to the P-F conduction and F-N tunneling driven by abundant traps in the silicon-rich SiNx layer, would be beneficial for next-generation nonvolatile memory applications by using a conventional passive SiNx layer as an active dielectric.

Effects of ß-hydroxy-ß-methyl butyrate on working memory and cognitive flexibility in an animal model of aging.

OBJECTIVES: Normal aging results in cognitive decline and nutritional interventions have been suggested as potential approaches for mitigating these deficits. Here, we used rats to investigate the effects of short- and long-term dietary supplementation with the leucine metabolite ß-hydroxy-ß-methyl butyrate (HMB) on working memory and cognitive flexibility. METHODS: Beginning ∼12 months of age, male and female Long-Evans rats were given twice daily access to sipper tubes containing calcium HMB (450 mg/kg) or vehicle (285 mg/kg calcium lactate) in a sucrose solution (20% w/v). Supplementation continued for 1 or 7 months (middle- and old-age (OA) groups, respectively) before testing began. Working memory was assessed by requiring rats to respond on a previously sampled lever following various delays. Cognitive flexibility was assessed by training rats to earn food according to a visual strategy and then, once acquired, shifting to an egocentric response strategy. RESULTS: Treatment with HMB improved working memory performance in middle-age (MA) males and OA rats of both sexes. In the cognitive flexibility task, there was a significant age-dependent deficit in acquisition of the visual strategy that was not apparent in OA males treated with HMB. Furthermore, HMB ameliorated an apparent deficit in visual strategy acquisition in MA females. DISCUSSION: Together, these findings suggest that daily nutritional supplementation with HMB facilitates learning and improves working memory performance. As such, HMB supplementation may mitigate age-related cognitive deficits and may therefore be an effective tool to combat this undesirable feature of the aging process.

Innervation of the medial prefrontal cortex by tyrosine hydroxylase immunoreactive fibers during adolescence in male and female rats.

Adolescence is associated with continued maturation of the cerebral cortex, particularly the medial prefrontal cortex (mPFC). We have previously documented pruning in the number of neurons, dendrites, and synapses in the rat mPFC from preadolescence to adulthood, with the period of pubertal onset being particularly important. We hypothesized that dopaminergic innervation of this region, critical for executive functions, would also be influenced by pubertal onset. Here, we measured changes in the volume of tyrosine hydroxylase (TH) immunoreactive axons in all layers of the male and female mPFC from preadolescence to adulthood (postnatal Day (P) 25, 35, 45, 60, and 90) as a marker of dopaminergic innervation. Assessing both total fiber volume and length, TH fibers were quantified by multiplying the mPFC volume by fiber density. While there were subtle layer-specific changes, TH fiber volume and length increased between P25 and P90 in both males and females. Contrary to our hypothesis, a role for pubertal onset in TH innervation of this region was not discernable. In summary, axons immunoreactive for TH increase with similar trajectories in the mPFC of male and female rats from pre-puberty to young adulthood.

Reversible Fermi Level Tuning of a Sb2Te3 Topological Insulator by Structural Deformation.

For three-dimensional (3D) topological insulators that have a layered structure, strain was used to control critical physical properties. Here, we show that tensile strain decreases bulk carrier density while accentuating transport of topological surface state using temperature-dependent resistance and magneto-resistance measurements, terahertz-time domain spectroscopy and density functional theory calculations. The induced strain was confirmed by transmittance X-ray scattering measurements. The results show the possibility of reversible topological surface state device control using structural deformation.