STAG2 mutations regulate 3D genome organization, chromatin loops, and Polycomb signaling in glioblastoma multiforme.

Inactivating mutations of genes encoding the cohesin complex are common in a wide range of human cancers. STAG2 is the most commonly mutated subunit. Here we report the impact of stable correction of endogenous, naturally occurring STAG2 mutations on gene expression, 3D genome organization, chromatin loops, and Polycomb signaling in glioblastoma multiforme (GBM). In two GBM cell lines, correction of their STAG2 mutations significantly altered the expression of ∼10% of all expressed genes. Virtually all the most highly regulated genes were negatively regulated by STAG2 (i.e., expressed higher in STAG2-mutant cells), and one of them-HEPH-was regulated by STAG2 in uncultured GBM tumors as well. While STAG2 correction had little effect on large-scale features of 3D genome organization (A/B compartments, TADs), STAG2 correction did alter thousands of individual chromatin loops, some of which controlled the expression of adjacent genes. Loops specific to STAG2-mutant cells, which were regulated by STAG1-containing cohesin complexes, were very large, supporting prior findings that STAG1-containing cohesin complexes have greater loop extrusion processivity than STAG2-containing cohesin complexes and suggesting that long loops may be a general feature of STAG2-mutant cancers. Finally, STAG2 mutation activated Polycomb activity leading to increased H3K27me3 marks, identifying Polycomb signaling as a potential target for therapeutic intervention in STAG2-mutant GBM tumors. Together, these findings illuminate the landscape of STAG2-regulated genes, A/B compartments, chromatin loops, and pathways in GBM, providing important clues into the largely still unknown mechanism of STAG2 tumor suppression.

Clinical Trial Protocol for Porcine Islet Xenotransplantation in South Korea.

Background: Islet transplantation holds promise for treating selected type 1 diabetes mellitus patients, yet the scarcity of human donor organs impedes widespread adoption. Porcine islets, deemed a viable alternative, recently demonstrated successful longterm survival without zoonotic risks in a clinically relevant pig-to-non-human primate islet transplantation model. This success prompted the development of a clinical trial protocol for porcine islet xenotransplantation in humans. Methods: A single-center, open-label clinical trial initiated by the sponsor will assess the safety and efficacy of porcine islet transplantation for diabetes patients at Gachon Hospital. The protocol received approval from the Gachon Hospital Institutional Review Board (IRB) and the Korean Ministry of Food and Drug Safety (MFDS) under the Investigational New Drug (IND) process. Two diabetic patients, experiencing inadequate glycemic control despite intensive insulin treatment and frequent hypoglycemic unawareness, will be enrolled. Participants and their family members will engage in deliberation before xenotransplantation during the screening period. Each patient will receive islets isolated from designated pathogen-free pigs. Immunosuppressants and systemic infection prophylaxis will follow the program schedule. The primary endpoint is to confirm the safety of porcine islets in patients, and the secondary endpoint is to assess whether porcine islets can reduce insulin dose and the frequency of hypoglycemic unawareness. Conclusion: A clinical trial protocol adhering to global consensus guidelines for porcine islet xenotransplantation is presented, facilitating streamlined implementation of comparable human trials worldwide.

Effect of Quasi-One-Dimensional Properties on Source/Drain Contacts in Vertical Nanowire Field-Effect Transistors (VNWFETs).

In this study, we investigated the influence of quasi-one-dimensional (Quasi-1D) characteristics on the source and drain contact resistances within vertical nanowire (NW) field-effect transistors (FETs) of diminutive diameter. The top contact of the NW is segregated into two distinct regions: the first encompassing the upper surface, designated as the axial contact, and the second encircling the side surface, known as the radial contact, which is formed during the top-contact metal deposition process. Quantum confinement effects, prominent within Quasi-1D NWs, exert significant constraints on radial transport, consequently inducing a noticeable impact on contact resistance. Notably, in the radial direction, electron tunneling occurs only through quantized, discrete energy levels. Conversely, along the axial direction, electron tunneling freely traverses continuous energy levels. In a meticulous numerical analysis, these disparities in transport mechanisms unveiled that NWs with diameters below 30 nm exhibit a markedly higher radial contact resistance compared to their axial counterparts. Furthermore, an increase in the overlap length (less than 5 nm) contributes to a modest reduction in radial resistance; however, it remains consistently higher than the axial contact resistance.

Effect of Noncircular Channel on Distribution of Threshold Voltage in 3D NAND Flash Memory.

The instability in threshold voltage (VTH) and charge distributions in noncircular cells of three-dimensional (3D) NAND flash memory are investigated. Using TCAD simulation, we aim to identify the main factors influencing the VTH of noncircular cells. The key focus is on the nonuniform trapped electron density in the charge trapping layer (CTL) caused by the change in electric field between the circular region and the spike region. There are less-trapped electron (LT) regions within the CTL of programmed noncircular cells, which significantly enhances current flow. Remarkably, more than 50% of the total current flows through these LT regions when the spike size reaches 15 nm. We also performed a comprehensive analysis of the relationship between charge distribution and VTH in two-spike cells with different heights (HSpike) and angles between spikes (θ). The results of this study demonstrate the potential to improve the reliability of next-generation 3D NAND flash memory.

Identification of STAG2-Mutant Bladder Cancers by Immunohistochemistry.

Bladder cancer is the fifth most common cancer in the United States. Most bladder cancers are early-stage lesions confined to the mucosa or submucosa and are therefore classified as non-muscle-invasive bladder cancer (NMIBC). A minority of tumors are diagnosed after they have invaded the underlying detrusor muscle and are classified as muscle-invasive bladder cancer (MIBC). Mutational inactivation of the STAG2 tumor suppressor gene is common in bladder cancer, and we and others have recently demonstrated that STAG2 mutation status can be used as an independent prognostic biomarker to predict whether NMIBC will recur and/or progress to MIBC. Here we describe an immunohistochemistry-based assay for identifying the STAG2 mutational status of bladder tumors.

Performance Degradation in Static Random Access Memory of 10 nm Node FinFET Owing to Displacement Defects.

We comprehensively investigate displacement-defect-induced current and static noise margin variations in six-transistor (6T) static random access memory (SRAM) based on a 10 nm node fin field-effect transistor (FinFET) using technology computer-aided design (TCAD). Various defect cluster conditions and fin structures are considered as variables to estimate the worst-case scenario for displacement defects. The rectangular defect clusters capture more widely distributed charges at the fin top, reducing the on- and off-current. The read static noise margin (RSNM) is the most degraded in the pull-down transistor during the read operation. The increased fin width decreases the RSNM due to the gate field. The current per cross-sectional area increases when the fin height decreases, but the energy barrier lowering by the gate field is similar. Therefore, the reduced fin width and increased fin height structure suit the 10 nm node FinFET 6T SRAMs with high radiation hardness.

On-State Current Degradation Owing to Displacement Defect by Terrestrial Cosmic Rays in Nanosheet FET.

Silicon displacement defects are caused by various effects. For instance, epitaxial crystalline silicon growth and ion implantation often result in defects induced by the fabrication process, whereas displacement damage is induced by terrestrial cosmic radiation. Clustered displacement damage reportedly reduces the on-state current (Ion) in ordinary MOSFETs. In the case of an extremely scaled device such as a nanosheet field-effect transistor (NS-FET), the impact of displacement defect size was analyzed on the basis of the NS dimensions related to the device characteristics. In this study, we investigated the effect of displacement defects on NS-FETs using technology computer-aided design; the simulation model included quantum transport effects. The geometrical conditions, temperatures, trap concentrations, and scattering models were considered as the variables for on-state current reduction.

Influence of Radiation-Induced Displacement Defect in 1.2 kV SiC Metal-Oxide-Semiconductor Field-Effect Transistors.

The effect of displacement defect on SiC metal-oxide-semiconductor field-effect transistors (MOSFETs) due to radiation is investigated using technology computer-aided design (TCAD) simulation. The position, energy level, and concentration of the displacement defect are considered as variables. The transfer characteristics, breakdown voltage, and energy loss of a double-pulse switching test circuit are analyzed. Compared with the shallow defect energy level, the deepest defect energy level with EC - 1.55 eV exhibits considerable degradation. The on-current decreases by 54% and on-resistance increases by 293% due to the displacement defect generated at the parasitic junction field-effect transistor (JFET) region next to the P-well. Due to the existence of a defect in the drift region, the breakdown voltage increased up to 21 V. In the double-pulse switching test, the impact of displacement defect on the power loss of SiC MOSFETs is negligible.

Tuning La2O3 to high ionic conductivity by Ni-doping.

Ni-doped La2O3 was developed as an ionic conducting membrane corresponding to a conductivity of 0.187 S cm-1 at 550 °C. A peak power density of 970 mW cm-2 with an open circuit voltage of 1.05 V was achieved using 10 mol% Ni-doped La2O3 (10NLO). XPS and Raman investigations reveal that the performance enhancement is due to the high concentration of oxygen vacancies. Density functional theory calculations verify that Ni doping can tune the band structure of La2O3 to enhance its electrochemical performance. A Schottky junction barrier is formed at the anode to avoid short circuit problems and facilitate the ionic transportation at the anode/electrolyte interface. This study indicates that wide-band gap semiconductors with suitable element-doping can be tuned to be promising ionic conductors for advanced fuel cell applications.

Improvement of Fermi-Level Pinning and Contact Resistivity in Ti/Ge Contact Using Carbon Implantation.

Effects of carbon implantation (C-imp) on the contact characteristics of Ti/Ge contact were investigated. The C-imp into Ti/Ge system was developed to reduce severe Fermi-level pinning (FLP) and to improve the thermal stability of Ti/Ge contact. The current density (J)-voltage (V) characteristics showed that the rectifying behavior of Ti/Ge contact into an Ohmic-like behavior with C-imp. The lowering of Schottky barrier height (SBH) indicated that the C-imp could mitigate FLP. In addition, it allows a lower specific contact resistivity (ρc) at the rapid thermal annealing (RTA) temperatures in a range of 450-600 °C. A secondary ion mass spectrometry (SIMS) showed that C-imp facilitates the dopant segregation at the interface. In addition, transmission electron microscopy (TEM) and electron energy loss spectroscopy (EELS) mapping showed that after RTA at 600 °C, C-imp enhances the diffusion of Ge atoms into Ti layer at the interface of Ti/Ge. Thus, carbon implantation into Ge substrate can effectively reduce FLP and improve contact characteristics.

Surface-Engineered Homostructure for Enhancing Proton Transport.

Ultra-wide bandgap semiconductor samarium oxide attracts great interest because of its high stability and electronic properties. However, the ionic transport properties of Sm2 O3 have rarely been studied. In this work, Ni doping is proposed to be used for electronic structure engineering of Sm2 O3 . The formation of Ni-doping defects lowers the Fermi level to induce a local electric field, which greatly enhances the proton transport at the surface. Furthermore, ascribed to surface modification, the high concentration of vacancies and lattice disorder on the surface layer promote proton transport. A high-performance of 1438 mW cm-2 and ionic conductivity of 0.34 S cm-1 at 550 °C have been achieved using 3% mol Ni doped Sm2 O3 as electrolyte for fuel cells. The well-dispersed Ni doped surface in Sm2 O3 builds up continuous surfaces as proton channels for high-speed transport. In this work, a new methodology is presented to develop high-performance, low-temperature ceramic fuel cells.

Acetyl-CoA carboxylase-1/2 blockade locks dendritic cells in the semimature state associated with FA deprivation by favoring FAO.

Immunometabolism is rising as an intriguing topic that reveals the connection between immune cell function and metabolic processes. Especially, fatty acid metabolism plays an essential role in the dendritic cells (DCs) during the differentiation and maturation period. We questioned whether regulation of acetyl-CoA carboxylases 1 and 2-(ACC1/2), the core enzymes of fatty acid synthesis (FAS), would control DC function. Here, we report that blocking ACC1/2 to prevent FAS during DC maturation switched their cellular metabolism into fatty acid oxidation to fuel oxidative phosphorylation. This action turned DCs to utilize exogenous fatty acids to sustain their basal energy demand and maintain a stable cellular respiration rate. Coincidentally, under the ACC1/2 inhibitor treatment, LPS-treated DCs exhibited a semimaturation phenotype with a maturation-resistance feature, with decreased expression of costimulatory molecules including CD86 and CD40, along with the reduction of IL-12 and IL-6. The migratory capability of DCs has been known to relate to the glycolysis pathway, and here we showed that the ACC1/2 blockade did not affect the expression of CCR7 and DC migration. Furthermore, we found that under the ACC1/2 blocking condition, DCs pulsed with OVA failed to activate OVA-specific CD4+ T cell proliferation even though their antigen uptake capacity was intact. Together, our data suggest ACC1/2 as a promising target to control DC fate.

Generation of scalable cancer models by combining AAV-intron-trap, CRISPR/Cas9, and inducible Cre-recombinase.

Scalable isogenic models of cancer-associated mutations are critical to studying dysregulated gene function. Nonsynonymous mutations of splicing factors, which typically affect one allele, are common in many cancers, but paradoxically confer growth disadvantage to cell lines, making their generation and expansion challenging. Here, we combine AAV-intron trap, CRISPR/Cas9, and inducible Cre-recombinase systems to achieve >90% efficiency to introduce the oncogenic K700E mutation in SF3B1, a splicing factor commonly mutated in multiple cancers. The intron-trap design of AAV vector limits editing to one allele. CRISPR/Cas9-induced double stranded DNA breaks direct homologous recombination to the desired genomic locus. Inducible Cre-recombinase allows for the expansion of cells prior to loxp excision and expression of the mutant allele.  Importantly, AAV or CRISPR/Cas9 alone results in much lower editing efficiency and the edited cells do not expand due to toxicity of SF3B1-K700E. Our approach can be readily adapted to generate scalable isogenic systems where mutant oncogenes confer a growth disadvantage.

Novel Program Scheme of Vertical NAND Flash Memory for Reduction of Z-Interference.

Minimizing the variation in threshold voltage (Vt) of programmed cells is required to the extreme level for realizing multi-level-cells; as many as even 5 bits per cell recently. In this work, a recent program scheme to write the cells from the top, for instance the 170th layer, to the bottom, the 1st layer, (T-B scheme) in vertical NAND (VNAND) Flash Memory, is investigated to minimize Vt variation by reducing Z-interference. With the aid of Technology Computer Aided Design (TCAD) the Z-Interference for T-B (84 mV) is found to be better than B-T (105 mV). Moreover, under scaled cell dimensions (e.g., Lg: 31→24 nm), the improvement becomes protruding (T-B: 126 mV and B-T: 162 mV), emphasizing the significance of the T-B program scheme for the next generation VNAND products with the higher bit density.

Multimaterial Self-Aligned Nanopatterning by Simultaneous Adjacent Thin Film Deposition and Etching.

Printed component sizes in electronic circuits are approaching 10 nm, but inherent variability in feature alignment during photolithography poses a fundamental barrier for continued device scaling. Deposition-based self-aligned patterning is being introduced, but nuclei defects remain an overarching problem. This work introduces low-temperature chemically self-aligned film growth via simultaneous thin film deposition and etching in adjacent regions on a nanopatterned surface. During deposition, nucleation defects are avoided in nongrowth regions because deposition reactants are locally consumed via sacrificial etching. For a range of materials and process conditions, thermodynamic modeling confirms that deposition and etching are both energetically favorable. We demonstrate nanoscale patterning of tungsten at 220 °C with simultaneous etching of TiO2. Area selective deposition (ASD) of the sacrificial TiO2 layer produces an orthogonal sequence for self-aligned patterning of two materials on one starting pattern, i.e., TiO2 ASD on SiO2 followed by W ASD on Si-H. Experiments also show capacity for self-aligned dielectric patterning via favorable deposition of AlF3 on Al2O3 at 240 °C with simultaneous atomic layer etching of sacrificial ZnO. Simultaneous deposition and etching provides opportunities for low-temperature bottom-up self-aligned patterning for electronic and other nanoscale systems.

Photocatalytic Reaction Properties of TiO2-Supported on the Long Lasting Phosphor: Sr4Al14O25:Eu2+,Dy3.

The TiO2/Sr4Al14O25:Eu2+,Dy3+ photocatalytic composite was prepared by depositing the nano-crystalline titanium dioxide layer on the long-lasting phosphor substrate of strontium aluminate, using a low-pressure chemical vapor deposition (LP-CVD). The photocatalysis characteristic was studied by examining the photodegradation of benzene (C6H6) gas under UV, visible light illumination, and in the darkness. The photocatalytic composite of TiO2-deposited Sr4Al14O25:Eu2+,Dy3+ showed an active photocatalytic reactivity under UV-light as well as visible-light illumination. The mechanism of the photocatalysis reaction for the TiO2-deposited strontium aluminate phosphor composite was interpreted in point of the energy band structure and phosphorescent emission. The coupling of nanocrystalline TiO2 with the strontium aluminate phosphor might result in an energy band bending at the interface of TiO2/Sr4Al14O25:Eu2+,Dy3+, making the titanium dioxide at the junction to be photo-reactive even in a visible wavelength region. In addition, the depth profile of Auger electron spectroscopy (AES) confirmed a possible formation of oxygen vacancies at the interface between TiO2 and Sr4Al14O25:Eu2+,Dy3+. Then, oxygen defects create extra electrons which may excited subsequently to the conduction band and participate in a photocatalytic reaction, resulting in an enhancement of the photodecomposition of benzene. The LP-CVD TiO2-strontium aluminate phosphor was also photoactive in the darkness because of light emission from the long lasting phosphor. Also, the TiO2-deposited Sr4Al14O25:Eu2+,Dy3+ long lasting phosphor was analyzed by a XRD (X-ray diffraction), TEM (transmission electron microscopy), UV/visible spectroscopy and AES.

STAG2 as a prognostic biomarker in low-grade non-muscle invasive bladder cancer.

OBJECTIVE: Improvements to bladder cancer risk stratification guidelines are needed to better tailor post-operative surveillance and adjuvant therapy to individual patients. We previously identified STAG2 as a commonly mutated tumor suppressor gene in bladder cancer and an independent predictor of progression in NMIBC. Here we test the value of combining STAG2 immunostaining with other risk stratification biomarkers in NMIBC, and as an individual biomarker in MIBC. MATERIALS AND METHODS: STAG2 immunohistochemistry was performed on a progressor-enriched cohort of tumors from 297 patients with NMIBC, and on tumors from 406 patients with MIBC from Aarhus University Hospital in Denmark. Survival analysis was performed using Kaplan-Meier survival analysis, the log rank test, and Cox proportional hazards models. RESULTS: STAG2-negative low-grade NMIBC tumors were 2.5 times less likely to progress to muscle invasion than STAG2-positive low-grade NMIBC tumors (Log-rank test, P = 0.008). In a composite group of patients with AUA intermediate and high-risk NMIBC tumors, STAG2-negative tumors were less likely to progress (Log-rank test, P = 0.02). In contrast to NMIBC, we show that STAG2 is not useful as a prognostic biomarker in MIBC. CONCLUSIONS: STAG2 immunostaining can be used to subdivide low-grade NMIBC tumors into two groups with substantially different risks of disease progression. Furthermore, STAG2 immunostaining may be useful to enhance NMIBC risk stratification guidelines, though larger cohorts are needed to solidify this conclusion in individual risk groups. STAG2 is not useful as a biomarker in MIBC. Further study of the use of STAG2 immunostaining as a biomarker for predicting the clinical behavior in NMIBC is warranted.

Junction and energy band on novel semiconductor-based fuel cells.

Fuel cells are highly efficient and green power sources. The typical membrane electrode assembly is necessary for common electrochemical devices. Recent research and development in solid oxide fuel cells have opened up many new opportunities based on the semiconductor or its heterostructure materials. Semiconductor-based fuel cells (SBFCs) realize the fuel cell functionality in a much more straightforward way. This work aims to discuss new strategies and scientific principles of SBFCs by reviewing various novel junction types/interfaces, i.e., bulk and planar p-n junction, Schottky junction, and n-i type interface contact. New designing methodologies of SBFCs from energy band/alignment and built-in electric field (BIEF), which block the internal electronic transport while assisting interfacial superionic transport and subsequently enhance device performance, are comprehensively reviewed. This work highlights the recent advances of SBFCs and provides new methodology and understanding with significant importance for both fundamental and applied R&D on new-generation fuel cell materials and technologies.

USP13 interacts with cohesin and regulates its ubiquitination in human cells.

Cohesin is a multiprotein ring complex that regulates 3D genome organization, sister chromatid cohesion, gene expression, and DNA repair. Cohesin is known to be ubiquitinated, although the mechanism, regulation, and effects of cohesin ubiquitination remain poorly defined. We previously used gene editing to introduce a dual epitope tag into the endogenous allele of each of 11 known components of cohesin in human HCT116 cells. Here we report that mass spectrometry analysis of dual-affinity purifications identified the USP13 deubiquitinase as a novel cohesin-interacting protein. Subsequent immunoprecipitation/Western blots confirmed the endogenous interaction in HCT116, 293T, HeLa, and RPE-hTERT cells; demonstrated that the interaction occurs specifically in the soluble nuclear fraction (not in the chromatin); requires the ubiquitin-binding domains (UBA1/2) of USP13; and occurs preferentially during DNA replication. Reciprocal dual-affinity purification of endogenous USP13 followed by mass spectrometry demonstrated that cohesin is its primary interactor in the nucleus. Ectopic expression and CRISPR knockout of USP13 showed that USP13 is paradoxically required for both deubiquitination and ubiquitination of cohesin subunits in human cells. USP13 was dispensable for sister chromatid cohesion in HCT116 and HeLa cells, whereas it was required for the dissociation of cohesin from chromatin as cells transit through mitosis. Together these results identify USP13 as a new cohesin-interacting protein that regulates the ubiquitination of cohesin and its cell cycle regulated interaction with chromatin.

The Effect of Baking Heat Treatment on the Fatigue Strength and Life of Shot Peened 4340M Landing Gear Steel.

In this study, the effect of baking heat treatment on fatigue strength and fatigue life was evaluated by performing baking heat treatment after shot peening treatment on 4340M steel for landing gear. An ultrasonic fatigue test was performed to obtain the S-N curve, and the fatigue strength and fatigue life were compared. The micro hardness of shot peening showed a maximum at a hardened depth of about 50 µm and was almost uniform when it arrived at the hardened depth of about 400 µm. The overall average tensile strength after the baking heat treatment was lowered by about 80-111 MPa, but the yield strength was improved by about 206-262 MPa. The five cases of specimens showed similar fatigue strength and fatigue life in high cycle fatigue (HCF) regime. However, the fatigue limit of the baking heat treated specimens showed an increasing tendency rather than that of shot peening specimens when the fatigue life was extended to the very high cycle fatigue (VHCF) regime. The effect of baking heat treatment was identified from improved fatigue limit when baking heat was used to treat the specimen treated by shot peening containing inclusions. The optimum temperature range for the better baking heat treatment effect could be constrained not to exceed maximum 246 °C.