Search

In a perpendicular magnetic anisotropy (PMA) system, spin–orbit torque (SOT)-induced magnetization switching shows promise in terms of high speed and stability, but additional in-plane directional symmetry breaking is necessary to achieve deterministic switching. Here, we observed all-electric magnetization switching by SOT in a conventional heavy metal/ferromagnetic structure deposited on a 3.25° miscut sapphire substrate. To better understand the origin of field-free switching, we conducted azimuthal angle-dependent PMA analysis and found that the magnetic anisotropy is slightly tilted in the direction of the miscut step. Despite a few degrees of tilting angle (<3°), we also confirmed that a slant PMA is the origin of the field-free switching by micromagnetic simulations. [ABSTRACT FROM AUTHOR]

The energy density of redox flow batteries (RFBs) is generally affected by the standard electrode potential and the solubility of the redox active species. These crucial factors are closely related to the solvent in which the active materials are dissolved. Aqueous RFBs have been widely studied due to their excellent reaction kinetics and high solubility of the redox couple in aqueous media. However, the low voltage of conventional aqueous RFBs has hindered them from being candidates for practical applications. Recently, high‐voltage aqueous RFBs are implemented based on the low negative potential of the Zn/[Zn(OH)4]2− reaction in an alkaline solution. Here, we review recent progress in the design of high energy density RFBs in both aqueous and non‐aqueous electrolytes, notably focusing on the Zn/MnO2 hybrid RFBs in detail. Furthermore, strategies for inhibiting zinc dendritic growth and stabilizing manganese redox couple in the RFBs system are discussed. [ABSTRACT FROM AUTHOR]

For deterministic magnetization switching by spin–orbit torque (SOT) in a perpendicular magnetic anisotropy system, an additional in-plane direction magnetic field is essential to break the lateral symmetry. Realizing chirality in a magnetic ordering system can be one approach for achieving asymmetry in the lateral direction for field-free magnetization switching. However, systematic analysis of the influence of the chiral spin system on deterministic switching is still scarce. We investigate the field-free SOT-induced magnetization switching by using a chiral spin configuration experimentally and theoretically with micromagnetic simulations. We designed a system in which only part of the ferromagnetic layer overlaps with the heavy metal layer in the Pt/Co/MgO structure. Therefore, a spin current exerts only on a local area of the ferromagnetic layer, which results in a Néel-type chiral spin configuration. The induced chiral spin configuration can be stabilized (or destabilized) depending on the sign of the interfacial Dzyaloshinskii–Moriya interaction and the direction of the current. The stabilized spin configuration plays a crucial role in the deterministic switching in the zero field. We expect our findings to widen the perspective on chirality-based all-electrical SOT device applications. [ABSTRACT FROM AUTHOR]

Therapeutics targeting the phosphatidylinositol 3‐kinase/mammalian target of rapamycin (PI3K/mTOR) pathway initially produce potent antitumor effects, but resistance frequently occurs. Using a phosphoproteome analysis, we found that colorectal cancer (CRC) cells exhibit resistance against PI3K/mTOR inhibition through feedback activation of multiple receptor tyrosine kinases, and their downstream focal adhesion kinase, Src and extracellular signal‐regulated kinases signaling. Unexpectedly, PI3K/mTOR blockade causes senescence, mediated by the activation of the stress kinase p38. The senescent cancer cells induce the secretion of various cytokines and this senescence‐associated secretome increases migration and invasion capabilities of CRC cells. We found that cotargeting PI3K/mTOR and bromodomain and extra‐terminal domain can suppress activation of many oncogenic kinases involved in resistance to the PI3K/mTOR inhibition, induce cell death in vitro and tumor regression in vivo, and further prolong the survival of xenograft models. Our findings provide a rationale for a novel therapeutic strategy to overcome resistance to the PI3K/mTOR inhibitors in CRC. What's new? Cancer therapeutics targeting the PI3K/mTOR pathway initially produce potent anti‐tumor effects, but resistance frequently occurs. Here, the authors carried out a phosphoproteome analysis to investigate the resistance mechanism against PI3K/mTOR inhibition in colorectal cancer from a systems perspective. They found that multiple oncogenic kinases are activated to contribute to the survival of colorectal cancer cells under PI3K/mTOR blockade, and that these cells undergo pro‐tumorigenic senescence. Cotargeting PI3K/mTOR and BET exerts potent anti‐cancer activity by suppressing the activation of several resistance‐mediating kinases. The findings provide a rationale for a novel therapeutic strategy to overcome resistance to PI3K/mTOR inhibitors in colorectal cancer. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) has been most extensively studied for characterizing genetic mutations along its development. However, we still have a poor understanding of CRC initiation due to limited measures of its observation and analysis. If we can unveil CRC initiation events, we might identify novel prognostic markers and therapeutic targets for early cancer detection and prevention. To tackle this problem, we establish the early CRC development model and perform transcriptome analysis of its single cell RNA-sequencing data. Interestingly, we find two subtypes, fast growing vs. slowly growing populations of distinct growth rate and gene signatures, and identify CCDC85B as a master regulator that can transform the cellular state of fast growing subtype cells into that of slowly growing subtype cells. We further validate this by in vitro experiments and suggest CCDC85B as a novel potential therapeutic target that may prevent malignant CRC development by suppressing stemness and uncontrolled cell proliferation. [ABSTRACT FROM AUTHOR]

A gate voltage application in a Si-based spin metal-oxide-semiconductor field-effect transistor (spin MOSFET) modulates spin accumulation voltages, where both electrical conductivity and drift velocity are modified while keeping constant electric current. An unprecedented reduction in the spin accumulation voltages in a Si spin MOSFET under negative gate voltage applications is observed in a high electric bias current regime. To support our claim, the electric bias current dependence of the spin accumulation voltage under the gate voltage applications is investigated in detail and compared with a spin drift diffusion model including the conductance mismatch effect. The drastic decrease in the mobility and spin lifetime in the Si channel is ascribable to the optical phonon emission at the high electric bias current, which consequently reduced the spin accumulation voltage. [ABSTRACT FROM AUTHOR]

We investigate stability of the spin exclusive or (XOR) gate operation in silicon(Si) -based lateral spin devices whose spin transport properties have large variations. The optimum charge current, I0, for the spin XOR gate operation is calculated by using the one dimensional spin-drift-diffusion model with variable spin polarization, interface resistance of the ferromagnetic contact, channel length and channel conductivity. I0 is strongly modulated by changing the spin transport parameters particularly under the condition with small spin polarization and short channel length. In contrast, I0 shows constant value irrespective of the interface resistance of one ferromagnetic contact under spin extraction condition. Our results provide a device design guideline for the robust spin XOR gate operation. [ABSTRACT FROM AUTHOR]

Road lane reduction with the addition of roadway countermeasures (also known as a 'road diet') is a transportation planning treatment to achieve systemic traffic improvements. Although lane reductions are expected to increase traffic safety overall, the impacts may vary by different roadway characteristics among sites and by crash types. The main objective of the study reported in this paper was to identify the effectiveness of lane reductions considering various factors including roadway characteristics through estimating crash modification factors (CMFs) for different crash types. The study first evaluated the CMFs for lane-reduction cases to check the overall safety effects using the observational before and after comparison group method. Second, the variation of CMFs due to different roadway characteristic factors was identified. Ultimately, the CMFs were developed for different crash types and severities. The results of the estimated CMFs indicated that lane reductions decreased crash frequency in general. From the CMFs with different traffic volume ranges, it was found that lane reductions have higher safety impacts to reduce total and injury crashes when there are fewer vehicles on roadways. [ABSTRACT FROM AUTHOR]

Cetuximab (CTX), a monoclonal antibody against epidermal growth factor receptor, is being widely used for colorectal cancer (CRC) with wild‐type (WT) KRAS. However, its responsiveness is still very limited and WT KRAS is not enough to indicate such responsiveness. Here, by analyzing the gene expression data of CRC patients treated with CTX monotherapy, we have identified DUSP4, ETV5, GNB5, NT5E, and PHLDA1 as potential targets to overcome CTX resistance. We found that knockdown of any of these five genes can increase CTX sensitivity in KRAS WT cells. Interestingly, we further found that GNB5 knockdown can increase CTX sensitivity even for KRAS mutant cells. We unraveled that GNB5 overexpression contributes to CTX resistance by modulating the Akt signaling pathway from experiments and mathematical simulation. Overall, these results indicate that GNB5 might be a promising target for combination therapy with CTX irrespective of KRAS mutation. From gene expression data analysis and mathematical modeling combined with cell experiments, we found that DUSP4, ETV5, GNB5, NT5E, and PHLDA1 expressions are correlated with cetuximab (CTX) resistance. In particular, we discovered that inhibition of GNB5 can overcome CTX resistance irrespective of KRAS mutation. We further revealed that GNB5 can regulate CTX resistance by dominantly modulating Akt signaling. [ABSTRACT FROM AUTHOR]

Many cities have integrated their public transportation modes to provide increased accessibility and reduced commute times. However, current transport network topology studies have focused on unimodal networks. Therefore, it is of significant interest for policymakers to examine the topology of integrated public transportation networks and to assess strategies for improving them. The objective of this study was to discuss a comprehensive analysis of an integrated public transportation network using graph theory, compare its characteristics to unimodal networks, and draw insights for improving their performance. Results demonstrate pertinent information concerning the structural composition of the Seoul Metropolitan Area's (SMA) public transportation network. Despite the integration, the spatial configuration of the network was found to have low fault tolerance. However, the highly agglomerated community structure validated the robustness of integrated networks. Network centrality measures confirmed that integration improves connectivity and spatial accessibility to suburbs within the city. The study found that the SMA's current public transportation network possesses structural defects that need to be addressed to improve its resilience and performance. Based on the outcomes of this study, the strategic creation or relocation of stations, and the construction of more links, is imperative for the enhancement of mobility. [ABSTRACT FROM AUTHOR]

Highly coordinated changes in gene expression underlie T cell activation and exhaustion. However, the mechanisms by which such programs are regulated and how these may be targeted for therapeutic benefit remain poorly understood. Here, we comprehensively profile the genomic occupancy of mSWI/SNF chromatin remodeling complexes throughout acute and chronic T cell stimulation, finding that stepwise changes in localization over transcription factor binding sites direct site-specific chromatin accessibility and gene activation leading to distinct phenotypes. Notably, perturbation of mSWI/SNF complexes using genetic and clinically relevant chemical strategies enhances the persistence of T cells with attenuated exhaustion hallmarks and increased memory features in vitro and in vivo. Finally, pharmacologic mSWI/SNF inhibition improves CAR-T expansion and results in improved anti-tumor control in vivo. These findings reveal the central role of mSWI/SNF complexes in the coordination of T cell activation and exhaustion and nominate small-molecule-based strategies for the improvement of current immunotherapy protocols. [Display omitted] • mSWI/SNF targeting and activity is specific to T cell activation and exhaustion states • Genetic and chemical disruption of cBAF complexes enhances T cell persistence • cBAF complex activities facilitate T cell exhaustion and prevent memory features • mSWI/SNF pharmacologic disruption improves CAR-T expansion and anti-tumor control mSWI/SNF ATP-dependent chromatin remodeling complexes direct chromatin accessibility and gene expression during T cell activation and exhaustion. Targeting mSWI/SNF complexes with clinically relevant small-molecule inhibitors and degraders attenuates T cell exhaustion and increases T cell persistence and anti-tumor activity in cell culture systems and in vivo. [ABSTRACT FROM AUTHOR]

BH3 mimetics are used as an efficient strategy to induce cell death in several blood malignancies, including acute myeloid leukemia (AML). Venetoclax, a potent BCL-2 antagonist, is used clinically in combination with hypomethylating agents for the treatment of AML. Moreover, MCL1 or dual BCL-2/BCL-xL antagonists are under investigation. Yet, resistance to single or combinatorial BH3-mimetic therapies eventually ensues. Integration of multiple genome-wide CRISPR/Cas9 screens revealed that loss of mitophagy modulators sensitizes AML cells to various BH3 mimetics targeting different BCL-2 family members. One such regulator is MFN2, whose protein levels positively correlate with drug resistance in patients with AML. MFN2 overexpression is sufficient to drive resistance to BH3 mimetics in AML. Insensitivity to BH3 mimetics is accompanied by enhanced mitochondria-endoplasmic reticulum interactions and augmented mitophagy flux, which acts as a prosurvival mechanism to eliminate mitochondrial damage. Genetic or pharmacologic MFN2 targeting synergizes with BH3 mimetics by impairing mitochondrial clearance and enhancing apoptosis in AML., Significance: AML remains one of the most difficult-to-treat blood cancers. BH3 mimetics represent a promising therapeutic approach to eliminate AML blasts by activating the apoptotic pathway. Enhanced mitochondrial clearance drives resistance to BH3 mimetics and predicts poor prognosis. Reverting excessive mitophagy can halt BH3-mimetic resistance in AML. This article is highlighted in the In This Issue feature, p. 1501., (©2023 American Association for Cancer Research.)

The energy density of redox flow batteries (RFBs) is generally affected by the standard electrode potential and the solubility of the redox active species. These crucial factors are closely related to the solvent in which the active materials are dissolved. Aqueous RFBs have been widely studied due to their excellent reaction kinetics and high solubility of the redox couple in aqueous media. However, the low voltage of conventional aqueous RFBs has hindered them from being candidates for practical applications. Recently, high-voltage aqueous RFBs are implemented based on the low negative potential of the Zn/[Zn(OH) 4 ] 2- reaction in an alkaline solution. Here, we review recent progress in the design of high energy density RFBs in both aqueous and non-aqueous electrolytes, notably focusing on the Zn/MnO 2 hybrid RFBs in detail. Furthermore, strategies for inhibiting zinc dendritic growth and stabilizing manganese redox couple in the RFBs system are discussed., (© 2022 Wiley-VCH GmbH.)

Cancer cells exhibit properties of cells in a less differentiated state than the adjacent normal cells in the tissue. We explored whether cancer cells can be converted to a differentiated normal-like state by restoring the gene regulatory network (GRN) of normal cells. Here, we report that colorectal cancer cells exhibit a range of developmental states from embryonic and intestinal stem-like cells to differentiated normal-like cells. To identify the transcription factors (TF) that commit stem-like colorectal cancer cells into a differentiated normal-like state, we reconstructed GRNs of normal colon mucosa and identified core TFs (CDX2, ELF3, HNF4G, PPARG, and VDR) that govern the cellular state. We further found that SET Domain Bifurcated 1 (SETDB1), a histone H3 lysine 9-specific methyltransferase, hinders the function of the identified TFs. SETDB1 depletion effectively converts stem-like colorectal cancer cells into postmitotic cells and restores normal morphology in patient-derived colorectal cancer organoids. RNA-sequencing analyses revealed that SETDB1 depletion recapitulates global gene expression profiles of normal differentiated cells by restoring the transcriptional activity of core TFs on their target genes. IMPLICATIONS: Our study provides insights into the molecular regulatory mechanism underlying the developmental hierarchy of colorectal cancer and suggests that induction of a postmitotic state may be a therapeutic alternative to destruction of cancer cells., (©2020 American Association for Cancer Research.)