Thermal Dehydrogenation Impact on Positive Bias Stability of Amorphous InSnZnO Thin-Film Transistors.

Recently, the growing demand for amorphous oxide semiconductor thin-film transistors (AOS TFTs) with high mobility and good stability to implement ultrahigh-resolution displays has made tracking the role of hydrogen in oxide semiconductor films increasingly important. Hydrogen is an essential element that contributes significantly to the field effect mobility and bias stability characteristics of AOS TFTs. However, because hydrogen is the lightest atom and has high reactivity to metal and oxide materials, elucidating its impact on AOS thin films has been challenging. Therefore, in this study, we propose controlling the hydrogen quantities in amorphous InSnZnO (a-ITZO) thin films through thermal dehydrogenation to precisely reveal the hydrogen influences on the electrical characteristics of a-ITZO TFTs. The as-deposited device containing 15.69 × 1015 atoms/cm2 of hydrogen exhibited a relatively low saturation mobility of 18.1 cm2/V·s and poor positive bias stress stability. However, depending on the extent of thermal dehydrogenation, not only did the hydrogen quantity and interface defect density (DIT) decrease but also the conductivity and surface energy increased due to the rise in oxygen vacancies and hydroxyl groups in a-ITZO thin films. As a result, the a-ITZO TFT with a hydrogen amount of 4.828 × 1015 atoms/cm2 showed that the saturation mobility improved up to 36.8 cm2/V·s, and positive bias stress stability was remarkably enhanced. Hence, we report the ability to manage the hydrogen quantity with thermal dehydrogenation and demonstrate that high-performance a-ITZO TFTs can be realized when an appropriate hydrogen concentration is achieved.

APOE3-R136S mutation confers resilience against tau pathology via cGAS-STING-IFN inhibition.

The Christchurch mutation (R136S) on the APOE3 (E3S/S) gene is associated with low tau pathology and slowdown of cognitive decline despite the causal PSEN1 mutation and high levels of amyloid beta pathology in the carrier1. However, the molecular effects enabling E3S/S mutation to confer protection remain unclear. Here, we replaced mouse Apoe with wild-type human E3 or E3S/S on a tauopathy background. The R136S mutation markedly mitigated tau load and protected against tau-induced synaptic loss, myelin loss, and spatial learning. Additionally, the R136S mutation reduced microglial interferon response to tau pathology both in vivo and in vitro, suppressing cGAS-STING activation. Treating tauopathy mice carrying wild-type E3 with cGAS inhibitor protected against tau-induced synaptic loss and induced similar transcriptomic alterations to those induced by the R136S mutation across brain cell types. Thus, cGAS-STING-IFN inhibition recapitulates the protective effects of R136S against tauopathy.

HDAC6 preserves BNIP3 expression and mitochondrial integrity by deacetylating p53 at lysine 320.

HDAC6 has been reported as a deacetylase of p53 at multiple lysine residues, associated with the canonical functions of p53, such as apoptosis and tumor suppression. We have previously reported that p53 acetylation at the lysine 320 site accumulates due to the genetic ablation of HDAC6 in mice liver. However, the biological processes affected by K320 acetylation of p53 are yet to be elucidated. In this study, we demonstrate that K320 acetylation of p53 is regulated by HDAC6 deacetylase activity. HDAC6 knockout mouse brains exhibit a significant accumulation of K320 acetylated p53 compared to other tissues. The level of K320 acetylation of p53 inversely correlates with the level of BNIP3, a direct target of p53 and essential for mitophagy. Notably, overexpressing the deacetylation mimic K320R mutant p53 restored BNIP3 expression in HDAC6 knockout MEFs. Furthermore, we observed that neurons are particularly susceptible to the genetic ablation of HDAC6, impacting BNIP3 expression, which inversely correlates with the accumulation of abnormal mitochondria characterized by swollen cristae. Our findings suggest that HDAC6 plays a crucial role in maintaining BNIP3 expression by deacetylating p53 at the K320 site, which is linked to the structural integrity of mitochondria.

Instant Assembly of Collagen for Scaffolding, Tissue Engineering, and Bioprinting.

Controllable assembly of cells and tissues offers potential for advancing disease and development modeling and regenerative medicine. The body's natural scaffolding material is the extracellular matrix, composed largely of collagen I. However, challenges in precisely controlling collagen assembly limit collagen's applicability as a primary bioink or glue for biofabrication. Here, we introduce a set of biopatterning methods, termed Tunable Rapid Assembly of Collagenous Elements (TRACE), that enables instant gelation and rapid patterning of collagen I solutions with wide range of concentrations. Our methods are based on accelerating the gelation of collagen solutions to instantaneous speeds via macromolecular crowding, allowing versatile patterning of both cell-free and cell-laden collagen-based bioinks. We demonstrate notable applications, including macroscopic organoid engineering, rapid free-form 3D bioprinting, contractile cardiac ventricle model, and patterning of high-resolution (below 5 (m) collagen filament. Our findings enable more controllable and versatile applications for multi-scale collagen-based biofabrication.

ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes.

Recent developments in genome sequencing have expanded the knowledge of genetic factors associated with late-onset Alzheimer's disease (AD). Among them, genetic variant ε4 of the APOE gene (APOE4) confers the greatest disease risk. Dysregulated glucose metabolism is an early pathological feature of AD. Using isogenic ApoE3 and ApoE4 astrocytes derived from human induced pluripotent stem cells, we find that ApoE4 increases glycolytic activity but impairs mitochondrial respiration in astrocytes. Ultrastructural and autophagy flux analyses show that ApoE4-induced cholesterol accumulation impairs lysosome-dependent removal of damaged mitochondria. Acute treatment with cholesterol-depleting agents restores autophagic activity, mitochondrial dynamics, and associated proteomes, and extended treatment rescues mitochondrial respiration in ApoE4 astrocytes. Taken together, our study provides a direct link between ApoE4-induced lysosomal cholesterol accumulation and abnormal oxidative phosphorylation.

Silicone engineered anisotropic lithography for ultrahigh-density OLEDs.

Ultrahigh-resolution patterning with high-throughput and high-fidelity is highly in demand for expanding the potential of organic light-emitting diodes (OLEDs) from mobile and TV displays into near-to-eye microdisplays. However, current patterning techniques so far suffer from low resolution, consecutive pattern for RGB pixelation, low pattern fidelity, and throughput issue. Here, we present a silicone engineered anisotropic lithography of the organic light-emitting semiconductor (OLES) that in-situ forms a non-volatile etch-blocking layer during reactive ion etching. This unique feature not only slows the etch rate but also enhances the anisotropy of etch direction, leading to gain delicate control in forming ultrahigh-density multicolor OLES patterns (up to 4500 pixels per inch) through photolithography. This patterning strategy inspired by silicon etching chemistry is expected to provide new insights into ultrahigh-density OLED microdisplays.

SIRT1 suppresses in vitro decidualization of human endometrial stromal cells through the downregulation of forkhead box O1 expression.

SIRT1 regulates survival, DNA repair, and metabolism in human cells and has pleiotropic effects on age-related diseases through either deacetylating target proteins or inhibiting gene transcription. Forkhead box O1 (FOXO1) is one of the most important transcription factors during decidualization. Prolactin (PRL) and insulin-like growth factor-binding protein 1 (IGFBP1) are well-known FOXO1-dependent genes in decidualizing cells. To determine whether SIRT1 plays a role in decidualization, we investigated morphological changes in cells following artificially stimulated decidualization and expression levels of PRL, IGFBP1, and FOXO1 in the immortalized non-neoplastic human endometrial stromal cell line T HESCs. SIRT1 expression decreased in the decidualization condition and SIRT1 inhibited morphological changes caused by decidualization of T HESCs. SIRT1 suppressed PRL, IGFBP1, and FOXO1 expression; inhibited FOXO1, PRL, and IGFBP1 promoter activity; and decreased histone protein acetylation of the FOXO1 promoter. We found that FOXO1 expression increased in the secretory phase compared with the proliferative phase, whereas SIRT1 expression decreased in the secretory phase in the human endometrium. We also revealed that SIRT1 may inhibit embryo implantation according to the blastocyst-like spheroid implantation assay. Collectively, these results indicate that SIRT1 suppresses decidualization of human endometrial stromal cells by inhibiting FOXO1 expression.

Vacuum-free solution-based metallization (VSM) of a-IGZO using trimethylaluminium solution.

This research demonstrates a method to reduce the resistance of amorphous indium-gallium-zinc-oxide (a-IGZO) using a "vacuum-free solution-based metallization" (VSM) process, which revolutionizes the metallization process thanks to its simplicity, by simply dipping the a-IGZO into trimethyl aluminium (TMA, (CH3)3Al) solution. From the XPS results, it was found that oxygen vacancies were generated after the VSM process, resulting in the enhanced conductivity. Various metallization time and solution temperature conditions were investigated, and the measured conductivity of the a-IGZO could be enhanced up to 20.32 S cm-1, which is over 105 times larger compared to that of the untreated a-IGZO. By utilizing the VSM process, self-aligned top-gate (SATG) a-IGZO thin-film-transistors (TFTs) were successfully fabricated, and to provide an explanation for the mechanism, X-ray photoelectron spectroscopy (XPS) was employed.

APOE4-carrying human astrocytes oversupply cholesterol to promote neuronal lipid raft expansion and Aß generation.

The ε4 allele of APOE-encoding apolipoprotein (ApoE) is one of the strongest genetic risk factors for Alzheimer's disease (AD). One of the overarching questions is whether and how this astrocyte-enriched risk factor initiates AD-associated pathology in neurons such as amyloid-ß (Aß) accumulation. Here, we generate neurons and astrocytes from isogenic human induced pluripotent stem cells (hiPSCs) carrying either APOE ε3 or APOE ε4 allele and investigate the effect of astrocytic ApoE4 on neuronal Aß production. Secretory factors in conditioned media from ApoE4 astrocytes significantly increased amyloid precursor protein (APP) levels and Aß secretion in neurons. We further found that increased cholesterol secretion from ApoE4 astrocytes was necessary and sufficient to induce the formation of lipid rafts that potentially provide a physical platform for APP localization and facilitate its processing. Our study reveals the contribution of ApoE4 astrocytes to amyloidosis in neurons by expanding lipid rafts and facilitating Aß production through an oversupply of cholesterol.

A Synthetic CPP33-Conjugated HOXA9 Active Domain Peptide Inhibits Invasion Ability of Non-Small Lung Cancer Cells.

Homeobox A9 (HOXA9) expression is associated with the aggressive growth of cancer cells and poor prognosis in lung cancer. Previously, we showed that HOXA9 can serve as a potential therapeutic target for the treatment of metastatic non-small cell lung cancer (NSCLC). In the present study, we have carried out additional studies toward the development of a peptide-based therapeutic agent. Vectors expressing partial DNA fragments of HOXA9 were used to identify a unique domain involved in the inhibition of NSCLC cell invasion. Next, we performed in vitro invasion assays and examined the expression of EMT-related genes in transfected NSCLC cells. The C-terminal fragment (HOXA9-C) of HOXA9 inhibited cell invasion and led to upregulation of CDH1 and downregulation of SNAI2 in A549 and NCI-H1299 cells. Reduced SNAI2 expression was consistent with the decreased binding of transcription factor NF-kB to the SNAI2 promoter region in HOXA9-C overexpressing cells. Based on the above results, we synthesized a cell-permeable peptide, CPP33-HADP (HOXA9 active domain peptide), for lung-specific delivery and tested its therapeutic efficiency. CPP33-HADP effectively reduced the invasion ability of NSCLC cells in both in vitro and in vivo mouse models. Our results suggest that CPP33-HADP has significant potential for therapeutic applications in metastatic NSCLC.

Decursinol from Angelica gigas Nakai enhances endometrial receptivity during implantation.

BACKGROUND: Embryo implantation is essential for a successful pregnancy, and an elaborate synchronization between the receptive endometrium and trophoblast is required to achieve this implantation. To increase 'endometrial receptivity', the endometrium undergoes transformation processes including responses of adhesion molecules and cellular and molecular cell to cell communication. Many natural substances from traditional herbs have been studied to aid in the achievement of successful implantation. In this study, we investigated positive effects on embryonic implantation with decursinol that is a major compound extracted from Angelica gigas Nakai known to be associated with promotion of healthy pregnancy in the traditional Korean herbal medicine. METHODS: Expression of cell adhesion molecules after treatment of endometrial epithelial cells by decursinol (40 or 80 µM) was determined using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blot analysis. The alteration of endometrial receptivity by decursinol (40 or 80 µM) was identified with the in vitro implantation model between Ishikawa cells and JAr cell spheroids (diameter, 143 ± 16 µm). Exosomes secreted from Ishikawa cells after treatment of 80 µM decursinol or dimethyl sulfoxide (DMSO) as the vehicle were investigated with invasion of JAr cells and attachment of JAr spheroids to Ishikawa cells. RESULTS: Decursinol significantly (P < 0.05) increased the expression of important endometrial adhesion molecules such as integrin ß1, ß3, ß5 and L-selectin mRNAs and integrin ß5 and L-selectin in protein. The adhesion rate of JAr spheroids to decursinol-treated Ishikawa cells also increased significantly which was 2.4-fold higher than that of the control (P < 0.05). Furthermore, decursinol induced an increase in the release of exosomes from Ishikawa cells and decursinol-induced exosomes showed autocrine (to Ishikawa cells) and paracrine (to JAr cells) positive effects on our implantation model. CONCLUSION: These results propose that decursinol could serve as a new and alternative solution for patients who are infertile.

Postmortem proteomics to discover biomarkers for forensic PMI estimation.

The assessment of postmortem degradation of skeletal muscle proteins has emerged as a novel approach to estimate the time since death in the early to mid-postmortem phase (approximately 24 h postmortem (hpm) to 120 hpm). Current protein-based methods are limited to a small number of skeletal muscle proteins, shown to undergo proteolysis after death. In this study, we investigated the usability of a target-based and unbiased system-wide protein analysis to gain further insights into systemic postmortem protein alterations and to identify additional markers for postmortem interval (PMI) delimitation. We performed proteomic profiling to globally analyze postmortem alterations of the rat and mouse skeletal muscle proteome at defined time points (0, 24, 48, 72, and 96 hpm), harnessing a mass spectrometry-based quantitative proteomics approach. Hierarchical clustering analysis for a total of 579 (rat) and 896 (mouse) quantified proteins revealed differentially expressed proteins during the investigated postmortem period. We further focused on two selected proteins (eEF1A2 and GAPDH), which were shown to consistently degrade postmortem in both rat and mouse, suggesting conserved intra- and interspecies degradation behavior, and thus preserved association with the PMI and possible transferability to humans. In turn, we validated the usefulness of these new markers by classical Western blot experiments in a rat model and in human autopsy cases. Our results demonstrate the feasibility of mass spectrometry-based analysis to discover novel protein markers for PMI estimation and show that the proteins eEF1A2 and GAPDH appear to be valuable markers for PMI estimation in humans.

Whole grain cereal attenuates obesity-induced muscle atrophy by activating the PI3K/Akt pathway in obese C57BL/6N mice.

Whole grain comprises starchy endosperm, germ, and bran tissues, which contain fibers, minerals, vitamins, and several phytochemicals. Whole grain cereal (WGC)-based food products supply beneficial nutrients (essential for health care) and macronutrients (essential for body maintenance and support). The present study investigated the inhibitory effect of WGC on obesity-induced muscle atrophy in obese C57BL/6N mice. WGC attenuated the body weight gain, fat pad mass, adipocyte size, food efficiency ratio, serum lipid profile, and non-alcoholic fatty liver. Furthermore, WGC increased muscle mass and muscle strength by activating the phosphatidylinositol 3-kinase/protein kinase B pathway. Accordingly, WGC up-regulated the expression of factors that regulate muscle hypertrophy and myogenesis, whereas it down-regulated the atrophy-related factors. Overall, these results demonstrate that WGC effectively attenuates obesity-induced muscle atrophy as well as overall obesity, suggesting that WGC can be used as a functional food.

HDAC6 regulates thermogenesis of brown adipocytes through activating PKA to induce UCP1 expression.

Mitochondrial uncoupling protein 1 (UCP1) is responsible for nonshivering thermogenesis in brown adipose tissue (BAT). UCP1 increases the conductance of the inner mitochondrial membrane (IMM) for protons to make BAT mitochondria generate heat rather than ATP. HDAC6 is a cytosolic deacetylase for non-histone substrates to regulate various cellular processes, including mitochondrial quality control and dynamics. Here, we showed that the body temperature of HDAC6 knockout mice is slightly decreased in normal hosing condition. Interestingly, UCP1 was downregulated in BAT of HDAC6 knockout mice, which extensively linked mitochondrial thermogenesis. Mechanistically, we showed that cAMP-PKA signaling plays a key role in HDAC6-dependent UCP1 expression. Notably, the size of brown adipocytes and lipid droplets in HDAC6 knockout BAT is increased. Taken together, our findings suggested that HDAC6 contributes to mitochondrial thermogenesis in BAT by increasing UCP1 expression through cAMP-PKA signaling pathway.

HDAC6 deficiency induces apoptosis in mesenchymal stem cells through p53 K120 acetylation.

The acetylation of p53 is critical in modulating its pro-apoptotic roles. However, its regulatory mechanism and physiological significance are unclear. Here, we show HDAC6 negatively regulates pro-apoptotic acetylation of p53 at lysine residue 120 (K120) in mesenchymal stem cells (MSCs). The loss of HDAC6 expression in MSCs increases K120 acetylation of p53, which is successfully reversed by the wild-type but not by catalytically dead HDAC6. Deletion of HDAC6 induces caspase-dependent apoptosis by promoting transactivation of Bax and suppression of Bcl-2. Moreover, HDAC6 deficiency leads to mitochondrial dysfunction characterized by aberrant reactive oxygen species production and defective oxidative phosphorylation, which is reversed by ectopic expression of wild-type or acetylation mimetic p53. This study demonstrates that HDAC6 is a critical regulator of a pro-apoptotic p53 K120 acetylation and mitochondrial function in MSCs, suggesting that the modulation of HDAC6 activity could be a novel approach to improve MSC- based therapies.

RAP80 binds p32 to preserve the functional integrity of mitochondria.

RAP80, a member of the BRCA1-A complex, is a well-known crucial regulator of cell cycle checkpoint and DNA damage repair in the nucleus. However, it is still unclear whether Rap80 localizes to another region outside the nucleus and plays different roles with its partners. Here, we found mitochondrial p32 as a novel binding partner of RAP80 by using yeast two-hybrid screening. RAP80 directly binds the internal region of p32 through its arginine rich C-terminal domain. Based on the interaction, we showed that a subset of RAP80 localizes to mitochondria where p32 exists. Loss of function study revealed that RAP80 deficiency reduces the protein level of p32 and p32 dependent mitochondrial translating proteins such as Rieske and COX1. As a result, mitochondrial membrane potential and oxygen consumption are reduced in RAP80 knockdown cells, indicating mitochondrial dysfunction. Our study identifies a novel interaction between RAP80 and p32, which is important for preserving intact mitochondrial function.

Oral Supplementation with Cocoa Extract Reduces UVB-Induced Wrinkles in Hairless Mouse Skin.

Cacao beans contain various bioactive phytochemicals that could modify the pathogeneses of certain diseases. Here, we report that oral administration of cacao powder (CP) attenuates UVB-induced skin wrinkling by the regulation of genes involved in dermal matrix production and maintenance. Transcriptome analysis revealed that 788 genes are down- or upregulated in the CP supplemented group, compared with the UVB-irradiated mouse skin controls. Among the differentially expressed genes, cathepsin G and serpin B6c play important roles in UVB-induced skin wrinkle formation. Gene regulatory network analysis also identified several candidate regulators responsible for the protective effects of CP supplementation against UVB-induced skin damage. CP also elicited antiwrinkle effects via inhibition of UVB-induced matrix metalloproteinases-1 expression in both the human skin equivalent model and human dermal fibroblasts. Inhibition of UVB-induced activator protein-1 via CP supplementation is likely to affect the expression of matrix metalloproteinases-1. CP supplementation also downregulates the expression of cathepsin G in human dermal fibroblasts. 5-(3',4'-Dihydroxyphenyl)-γ-valerolactone, a major in vivo metabolite of CP, showed effects similar to CP supplementation. These results suggest that cacao extract may offer a protective effect against photoaging by inhibiting the breakdown of dermal matrix, which leads to an overall reduction in wrinkle formation.

Rapid fluorescence detection of hypoxic microenvironments by nitro-benzyl conjugated chitosan nanoparticles encapsulating hydrophobic fluorophores.

In this study, hypoxia-responsive chitosan nanoparticles (HRCNs) were synthesized by the conjugation of nitro-benzyl derivatives into chitosan polymers and the subsequent self-assembly of them with hydrophobic fluorophores. The nitro-benzyl substrate of HRCNs could be selectively reduced by NTR/NADH that was overexpressed under hypoxic conditions, while it was not responsive to reductive agents (GSH or DTT) commonly existing in biological systems. The HRCN encapsulated with Rhodamine 6G (HRCN-R6G) was successfully applied for the rapid determination of the hypoxic status of lung carcinoma cells (A549) within 30 min, while several hours were required in a conventional assay. In the hypoxic microenvironment, the fluorescence intensity of HRCN-R6G was 2.6-fold higher than that in normoxic conditions. Taken together, the HRCN-R6G is expected to be used for the rapid diagnosis and treatment of hypoxia-related acute diseases, after the incorporation of therapeutic drugs into them.

A fermented barley and soybean formula enhances skin hydration.

Skin hydration is one of the primary aims of beauty and anti-aging treatments. Barley (Hordeum vulgare) and soybean (Glycine max) are major food crops, but can also be used as ingredients for the maintenance of skin health. We developed a natural product-based skin treatment using a barley and soybean formula (BS) incorporating yeast fermentation, and evaluated its skin hydration effects as a dietary supplement in a clinical study. Participants ingested a placebo- (n = 33) or BS- (3 g/day) containing drink (n = 32) for 8 weeks. A significant increase in hydration in the BS group as compared to the placebo group was observed on the faces of subjects after 4 and 8 weeks, and on the forearm after 4 weeks. Decreases in stratum corneum (SC) thickness were also observed on the face and forearm. BS enhanced hyaluronan (HA) and skin barrier function in vitro and reduced Hyal2 expression in human dermal fibroblasts (HDF). BS also recovered ultraviolet (UV) B-induced downregulation of HA in HaCaT cells. These results suggest that BS has promising potential for development as a health functional food to enhance skin health.