Upregulated Expression of Activation-Induced Cytidine Deaminase in Ocular Adnexal Marginal Zone Lymphoma with IgG4-Positive Cells

Immunoglobulin G4-related disease (IgG4-RD) is a systemic disorder characterized by tissue fibrosis and intense lymphoplasmacytic infiltration, causing progressive organ dysfunction. Activation-induced cytidine deaminase (AID), a deaminase normally expressed in activated B-cells in germinal centers, edits ribonucleotides to induce somatic hypermutation and class switching of immunoglobulin. While AID expression is strictly controlled under physiological conditions, chronic inflammation has been noted to induce its upregulation to propel oncogenesis. We examined AID expression in IgG4-related ophthalmic disease (IgG4-ROD; n = 16), marginal zone lymphoma with IgG4-positive cells (IgG4+ MZL; n = 11), and marginal zone lymphoma without IgG4-positive cells (IgG4- MZL; n = 12) of ocular adnexa using immunohistochemical staining. Immunohistochemistry revealed significantly higher AID-intensity index in IgG4-ROD and IgG4+ MZL than IgG4- MZL (p < 0.001 and = 0.001, respectively). The present results suggest that IgG4-RD has several specific causes of AID up-regulation in addition to inflammation, and AID may be a driver of oncogenesis in IgG4-ROD to IgG4+ MZL.     

AP2M1 Supports TGF-β Signals to Promote Collagen Expression by Inhibiting Caveolin Expression

The extracellular matrix (ECM) is important for normal development and disease states, including inflammation and fibrosis. To understand the complex regulation of ECM, we performed a suppressor screening using Caenorhabditis elegans expressing the mutant ROL-6 collagen protein. One cuticle mutant has a mutation in dpy-23 that encodes the μ2 adaptin (AP2M1) of clathrin-associated protein complex II (AP-2). The subsequent suppressor screening for dpy-23 revealed the lon-2 mutation. LON-2 functions to regulate body size through negative regulation of the tumor growth factor-beta (TGF-β) signaling pathway responsible for ECM production. RNA-seq analysis showed a dominant change in the expression of collagen genes and cuticle components. We noted an increase in the cav-1 gene encoding caveolin-1, which functions in clathrin-independent endocytosis. By knockdown of cav-1, the reduced TGF-β signal was significantly restored in the dpy-23 mutant. In conclusion, the dpy-23 mutation upregulated cav-1 expression in the hypodermis, and increased CAV-1 resulted in a decrease of TβRI. Finally, the reduction of collagen expression including rol-6 by the reduced TGF-β signal influenced the cuticle formation of the dpy-23 mutant. These findings could help us to understand the complex process of ECM regulation in organism development and disease conditions.     

Synthesis of Hollow Three-Dimensional Channels LiNi_(0.5)Mn_(1.5)O_4 Microsphere by PEO Soft Template Assisted with Solvothermal Method

A appropriate size with three-dimension(3 D) channels for lithium diffusion plays an important role in constructing highperforming LiNi_(0.5)Mn_(1.5)O_4(LNMO) cathode materials, as it can not only reduce the transport path of lithium ions and electrons, but also reduce the side effects and withstand the structural strain in the process of repetitive Li~+ intercalation/deintercalation. In this work, an e fficient method for designing the hollow LNMO microsphere with 3 D channels structure by using polyethylene oxide(PEO) as soft template agent assisted solvothermal method is proposed. Experimental results indicate that PEO can make the reagents mingle evenly and nucleate slowly in the solvothermal process, thus obtaining a homogeneous distribution of carbonate precursors. In the final LNMO products, the hollow 3 D channels structure obtained by the decomposition of PEO and carbonate precursor in the calcination can provide abundant electroactive zones and electron/ion transport paths during the charge/discharge process, which benefits to improve the cycling performance and rate capability. The LNMO prepared by adding 1 g PEO possesses the most outstanding electrochemical performance, which presented an excellent discharge capacity of 143.1 mAh g~(-1) at 0.1 C and with a capacity retention of 92.2% after 100 cycles at 1 C. The superior performance attributed to the 3 D channels structure of hollow microspheres, which provide uninterrupted conductive systems and therefore achieve the stable transfer for electron/ion.     

Korean automatic spacing using pretrained transformer encoder and analysis

Automatic spacing in Korean is used to correct spacing units in a given input sentence. The demand for automatic spacing has been increasing owing to frequent incorrect spacing in recent media, such as the Internet and mobile networks. Therefore, herein, we propose a transformer encoder that reads a sentence bidirectionally and can be pretrained using an out-of-task corpus. Notably, our model exhibited the highest character accuracy (98.42%) among the existing automatic spacing models for Korean. We experimentally validated the effectiveness of bidirectional encoding and pretraining for automatic spacing in Korean. Moreover, we conclude that pretraining is more important than fine-tuning and data size.     

Investigation of the microwave dielectric properties of the Li4x/3Zn2−2xTi1+2x/3O4 system by P–V–L theory and vibration spectroscopy

Li_4x/3Zn_2–2xTi_1+2x/3O₄ microwave dielectric ceramics with a spinel phase were prepared via a high-temperature solid-phase method. P–V–L theory, vibration spectra, and XPS were utilized to establish the links between the intrinsic and extrinsic factors and the microwave dielectric properties. According to the characterization, the change in permittivity (ε_r) was ascribed to the increase in the average bond ionicity of Ti–O(Af_iTi-O) and the polar mode of the lattice vibration; the change in quality factor(Q × f) resulted from the change in the Ti–O lattice energy (AU_Ti-O) and existence of oxygen vacancy; the increase in temperature coefficient of the resonance frequency (τ_f) was triggered by the increase in the Ti–O bond energy. The Li_0.6Zn_1.1Ti_1.3O₄ ceramics (x = 0.45) sintered at 1125 °C finally obtained optimal microwave dielectric constants of ε_r = 17.3, Q × f = 76,318 GHz and τ_f = -58 ppm/°C.     

High-Performance All-Solid-State Supercapacitor Electrode Materials Using Freestanding Electrospun Carbon Nanofiber Mats of Polyacrylonitrile and Novolac Blends

Herein, this paper reports a facile method to prepare electrospun carbon nanofiber mats (ECNFMs) with high specific surface area and interconnected structure using polyacrylonitrile (PAN) as a precursor and novolac resin (NOC) as a polymer sacrificial pore-making agent. Without additional treatment, the prepared ECNFMs have a highly porous structure because NOC decomposes in a wider temperature range than most polymer activators. The NOC content in the PAN nanofibers shows important effects on porosity. The BET specific surface area of ECNFMs reaches a maximum of 1468 m² g⁻¹ when the precursor nanofibers contained 30 wt% NOC (ECNFM-3) after carbonization at 1000 °C. The supercapacitor device from ECNFM-3 electrode and all-solid-state electrolyte shows excellent cycling durability and high specific capacitance: ≈99.72% capacitance retention after 10 000 charge/discharge cycles and ≈320 mF cm⁻² at 0.25 mA cm⁻². Furthermore, it shows a large energy density of ≈11.1 $\mu$Wh cm⁻² under the power density of 500 mW m⁻². Activation of carbon nanofibers simply by the addition of NOC into precursor nanofibers can offer a handy way to prepare ECNFMs for high-performance all-solid-state supercapacitors and other potential applications.     

Development of Phosphodiesterase–Protein-Kinase Complexes as Novel Targets for Discovery of Inhibitors with Enhanced Specificity

Phosphodiesterases (PDEs) hydrolyze cyclic nucleotides to modulate multiple signaling events in cells. PDEs are recognized to actively associate with cyclic nucleotide receptors (protein kinases, PKs) in larger macromolecular assemblies referred to as signalosomes. Complexation of PDEs with PKs generates an expanded active site that enhances PDE activity. This facilitates signalosome-associated PDEs to preferentially catalyze active hydrolysis of cyclic nucleotides bound to PKs and aid in signal termination. PDEs are important drug targets, and current strategies for inhibitor discovery are based entirely on targeting conserved PDE catalytic domains. This often results in inhibitors with cross-reactivity amongst closely related PDEs and attendant unwanted side effects. Here, our approach targeted PDE–PK complexes as they would occur in signalosomes, thereby offering greater specificity. Our developed fluorescence polarization assay was adapted to identify inhibitors that block cyclic nucleotide pockets in PDE–PK complexes in one mode and disrupt protein-protein interactions between PDEs and PKs in a second mode. We tested this approach with three different systems—cAMP-specific PDE8–PKAR, cGMP-specific PDE5–PKG, and dual-specificity RegA–R_D complexes—and ranked inhibitors according to their inhibition potency. Targeting PDE–PK complexes offers biochemical tools for describing the exquisite specificity of cyclic nucleotide signaling networks in cells.     

Idiosyncratic Drug-Induced Liver Injury: Mechanistic and Clinical Challenges

Idiosyncratic drug-induced liver injury (IDILI) remains a significant problem for patients and drug development. The idiosyncratic nature of IDILI makes mechanistic studies difficult, and little is known of its pathogenesis for certain. Circumstantial evidence suggests that most, but not all, IDILI is caused by reactive metabolites of drugs that are bioactivated by cytochromes P450 and other enzymes in the liver. Additionally, there is overwhelming evidence that most IDILI is mediated by the adaptive immune system; one example being the association of IDILI caused by specific drugs with specific human leukocyte antigen (HLA) haplotypes, and this may in part explain the idiosyncratic nature of these reactions. The T cell receptor repertoire likely also contributes to the idiosyncratic nature. Although most of the liver injury is likely mediated by the adaptive immune system, specifically cytotoxic CD8+ T cells, adaptive immune activation first requires an innate immune response to activate antigen presenting cells and produce cytokines required for T cell proliferation. This innate response is likely caused by either a reactive metabolite or some form of cell stress that is clinically silent but not idiosyncratic. If this is true it would make it possible to study the early steps in the immune response that in some patients can lead to IDILI. Other hypotheses have been proposed, such as mitochondrial injury, inhibition of the bile salt export pump, unfolded protein response, and oxidative stress although, in most cases, it is likely that they are also involved in the initiation of an immune response rather than representing a completely separate mechanism. Using the clinical manifestations of liver injury from a number of examples of IDILI-associated drugs, this review aims to summarize and illustrate these mechanistic hypotheses.     

Alterations of Gut Microbiota by Overnutrition Impact Gluconeogenic Gene Expression and Insulin Signaling

A high-fat, Western-style diet is an important predisposing factor for the onset of type 2 diabetes and obesity. It causes changes in gut microbial profile, reduction of microbial diversity, and the impairment of the intestinal barrier, leading to increased serum lipopolysaccharide (endotoxin) levels. Elevated lipopolysaccharide (LPS) induces acetyltransferase P300 both in the nucleus and cytoplasm of liver hepatocytes through the activation of the IRE1-XBP1 pathway in the endoplasmic reticulum stress. In the nucleus, induced P300 acetylates CRTC2 to increase CRTC2 abundance and drives Foxo1 gene expression, resulting in increased expression of the rate-limiting gluconeogenic gene G6pc and Pck1 and abnormal liver glucose production. Furthermore, abnormal cytoplasm-appearing P300 acetylates IRS1 and IRS2 to disrupt insulin signaling, leading to the prevention of nuclear exclusion and degradation of FOXO1 proteins to further exacerbate the expression of G6pc and Pck1 genes and liver glucose production. Inhibition of P300 acetyltransferase activity by chemical inhibitors improved insulin signaling and alleviated hyperglycemia in obese mice. Thus, P300 acetyltransferase activity appears to be a therapeutic target for the treatment of type 2 diabetes and obesity.