Extrinsic Mechanisms Research Articles

Side-jump scattering enhanced spin Hall effect in SrTiO3-implanted Pt

A spin Hall effect (SHE) enables the electrical generation and detection of spin currents for promising applications in spintronics, but heavy metals with low spin Hall angle θSH limit the development of SHE devices. In this work, we have introduced dielectric oxide material SrTiO3 into Pt by magnetron sputtering and measured the θSH on the NiCo/Pt1–x(STO)x heterostructure through spin-torque ferromagnetic resonance. Our results demonstrate that the maximum spin Hall angle in Pt0.98(STO)0.02 is 0.121 ± 0.003, which is approximately twice that of pure Pt (0.064 ± 0.003). Moreover, theoretical analysis has revealed that the spin Hall angle arises from a complementary interplay between intrinsic and extrinsic mechanisms, namely, the strong spin–orbit coupling in Pt for the intrinsic mechanism and side-jump scattering caused by scalar potential and lattice expansion at dielectric impurities for the extrinsic mechanism. This interplay significantly contributes to enhancing the spin Hall angle. This work demonstrates an effective strategy for fabricating high-performance spin Hall materials with low resistivity, large spin Hall angle, and excellent compatibility with semiconductor processes in low-power spin-torque devices.

Role of extrinsic and intrinsic toughening mechanisms in graphene nanosheets reinforced magnesium matrix layered composites

Constructing a layered structure is an effective approach to achieve a balance between strength and toughness. The toughening mechanisms of layered composites are generally considered to include reinforcement bridging, pullout, and crack deflection. However, the above toughening mechanisms are more applicable to ceramic matrix composites with predominantly cleavage fracture. For metal matrix composites with a larger fracture process zone, the energy consumption in crack propagation may be dominated by the plastic deformation at the crack tip. Therefore, elucidating the dislocation emission behavior and the interaction between graphene nanosheets (GNSs) and crack is the key to revealing the toughening mechanisms. In this work, the extrinsic and intrinsic toughening mechanisms for the layered GNS/Mg composites were investigated systematically. The three-dimensional reconstruction of the fracture morphology, combined with statistical analysis and molecular dynamic (MD) simulations, elucidates that macroscopic crack deflection in layered composites does not always result in a microscopically longer crack propagation path. The mitigation and redistribution of stress concentration and the promotion of dislocation emission at the crack tip induced by the GNS layers are proposed to be critical toughening mechanisms in the GNS/Mg layered composites.

A novel bivalent anti-c-MET/PD-1 bispecific antibody exhibits potent cytotoxicity against c-MET/PD-L1-positive colorectal cancer.

Previously, we generated a novel bispecific antibody (BsAb) simultaneously targeting both c-MET and PD-1 (PDCD1), which can bridge T cells and c-MET positive tumor cells. However, the specific mechanisms and antitumor activities of the BsAb against c-MET/PD-L1 (CD274) positive colorectal cancer (CRC) is not completely understood. In this study, in addition to the tumor intrinsic mechanism investigation with molecular biology assay in vitro, a humanized mouse model was used to evaluate antitumor activity of the BsAb in vivo. The BsAb could inhibit c-MET/PD-L1+ CRC cell migration and show strong antitumor activity against HCT116 tumors in mice, potentially by inducing the degradation of c-MET protein in a dose and time-dependent manner. The BsAb could suppress the phosphorylation of c-MET downstream proteins GRB2-associated-binding protein 1 (Gab1) and focal adhesion kinase (FAK). Considering the tumor extrinsic mechanism, the BsAb may promote phagocytosis of macrophage. Furthermore, the level of plasma exosomal-c-MET/PD-L1 is able to distinguish CRC patients from healthy controls. In summary, the BsAb exhibited potent anti-tumor activities by two distinguished mechanisms: inhibition of c-MET signal transduction and promotion of macrophage-mediated phagocytosis. Our BsAb may provide a novel therapeutic agent for patients with c-MET/PD-L1+ CRC, and the status of exosomal-c-MET/PD-L1 can serve as a biomarker to predict responsiveness to treatment of our BsAb.

(Invited) Gallium Oxides Devices for Grid-Scale Power Electronics and High Power Switched Mode RF Amplifiers

Within a decade of the first demonstration of a MESFET device, monoclinic β-Ga2O3 (Ga2O3) devices have made incredible progress in breakdown voltages, power device figure of merit and high-speed performance. It has emerged as a promising ultra-widebandgap semiconductor for next generation power, GHz switching and RF applications. In this talk, we will present an overview of our studies on fundamental transport properties, kilovolt class power MOSFETs and aggressively scaled RF devices. The large bandgap of Ga2O3 leads to a high critical field strength. This high field strength in combination with demonstrated room temperature mobility and calculated electron velocity leads to a higher Baliga’s Figure of Merit (BFoM) and Johnston Figure of Merit (JFoM) than current commercially available widebandgap technologies. Additionally, the large bandgap also enables high temperature operation and radiation hardness making it attractive for space applications such as Mars and Venus missions.In the first part, we will discuss the deep insights gained from the first-principles based transport calculations in Ga2O3. We will discuss the limits to low field mobility, saturation velocities and impact ionization coefficients. The impact of the plasmon-phonon coupling on the phonon limited transport will be discussed. We will present the experimental signatures of plasmon-phonon coupling and anti-screening behavior in ionic gated accumulation layers.Next, I will describe our work on the lateral MOSFETs with improved field plate design and beyond-kV breakdown. Temperature dependent analysis and device simulation suggest an extrinsic breakdown mechanism outside the channel. A simple and yet effective SU-8 polymer passivation technology was developed that results in significant improvement in breakdown voltages. The higher field strength of the SU-8 polymer enables a significant increase in breakdown voltage to 8 kVs in lateral MOSFETs. However, these devices show a high Ron, which is due to the depletion caused by RIE of the channel. We will present the use of ultra-high vacuum annealing techniques to improve the on-resistance of the devices still maintaining the multi-kilo-volt rating of the devices.Due to its high JFoM, Ga2O3 is a potential candidate for high power density RF amplifiers. We will also present the performance advancement that can be obtained in RF power performance using Ga2O3 technology. We will present the challenges in the technology and potential solutions. We will present the experimental DC and pulsed measurements on laterally scaled MOSFETs with 100 nm gate length. Severe DC-RF dispersion was observed which is attributed to the RIE damage and surface states on the oxide. Passivation of the devices shows reduced current collapse. Using aggressive gate lengths and gate-source spacing scaling, (AlxGa1-x)2O3/Ga2O3 heterostructure FETs were fabricated that show record high RF performance. The device transconductance was limited by the regrowth interface resistance. Ex-situ silicon nitride passivation was shown to be effective to reduce DC-RF dispersion. Recently, thin channel MOSFETs with deep-sub-micron gate lengths and source/drain regrowth have demonstrated devices with simultaneously low on resistance, high frequency, high voltages.

Effect of bimodal microstructure on the tensile properties and fracture toughness of extruded Mg-9Gd-4Y-0.5Zr alloy

The effects of bimodal microstructure on the tensile properties and fracture toughness of Mg-9Gd-4Y-0.5Zr alloys were investigated. The Mg-9Gd-4Y-0.5Zr alloy was extruded at different temperatures to produce samples with bimodal and fully dynamic recrystallized (DRXed) grain structures. The results show that the bimodal grain structure exhibits a better combination of yield strength (YS of 277 MPa) and plane strain fracture toughness (KIc = 21.5 MPa m1/2), compared to the fully DRXed microstructure (YS of 207 MPa, KIc = 16.3 MPa m1/2). The fracture mechanisms for the bimodal and fully DRXed microstructures are the ductile fracture mode and quasi-cleavage fracture mode, respectively. Both hetero-deformation induced (HDI) strengthening effect and strong basal texture can contribute to high tensile strength in the bimodal grain structured sample. As compared to the sample with fully DRXed microstructure, the stronger strain hardening capacity and larger hardened region around the crack tip in the bimodal grain structured sample can bring about the improvement in the fracture toughness. The tortuous crack propagation path and the hindrance of propagating crack by the un-DRXed grains result in larger fracture resistance and more energy dissipation. The increase of geometrically necessary dislocation (GND) density and the activation of non-basal dislocations also have positive effects on the fracture toughness of the samples with bimodal grain structure. The fracture toughness is effectively improved via intrinsic and extrinsic toughening mechanisms associated with the bimodal microstructure.

Unlocking the potential of beta sitosterol: Augmenting the suppression of oral cancer cells through extrinsic and intrinsic signalling mechanisms

The global increase in the prevalence of oral neoplasms and related deaths can be attributed to social development and lifestyle factors, leading to poor prognosis and a lack of early clinical detection. Oral cancer ranks ranked sixth mostly diagnosed cancer and is a leading cause of cancer-related deaths. In light of these circumstances, our objective was to assess the potential of β-sitosterol, a naturally occurring herbal compound, as an anticancer agent against KB cells, a representative cell line for oral cancer. Our study primarily focused on evaluating the cytotoxic effect and mRNA expression of apoptotic proteins by β-sitosterol on KB cells. The results demonstrated a remarkable cytotoxic effect, leading to cell death. Further investigation using flow cytometric analysis revealed that this cell death was mediated through the initiation of the apoptotic signalling by β-sitosterol. The use of the bioinformatic tool, STITCH, supported our study by predicting drug-protein interactions and suggesting that β-sitosterol may play a significant role in targeting apoptotic pathways. Additionally, docking results were employed to validate the findings demonstrating high binding affinity of β-sitosterol with apoptotic-mediated signalling targets. To gain deeper insights into the molecular insights, we measured mRNA levels for BAX, BCL-2, MCL-1, P53, P21, MDM2, caspase3, and caspase9. Based on our comprehensive findings, our study concludes that β-sitosterol holds significant therapeutic potential against oral cancer cells. These results strongly suggest that this herbal compound should be further explored as a potential treatment option for oral cancer for clinical trial.

Higher cytotoxic activities of CD8+ T cells and natural killer cells from peripheral blood of early diagnosed lung cancer patients

IntroductionCytotoxic (CD8+) and natural killer (NK) cells play critical roles in anti-tumor immunity. Dysfunction in these cells is considered as one of the extrinsic mechanisms for tumor relapse.AimWe aimed in this study to assess cytotoxic activities of CD8 + T and NK cells in the peripheral blood from lung cancer patients before and after induction of chemotherapy.Subjects and methodsHealthy (n = 5) volunteers and lung cancer patients (n = 15:5 before, 5 during, and 5 after induction of chemotherapy) were recruited. Flow cytometry was used to analyze the numbers of CD8 + T cells, NK and CD56+T cells and their intracellular expression of granzyme B (GzB) in fresh peripheral blood mononuclear cells (PBMCs) and after 72 h of their culture in vitro and stimulation with 5 µg/ml Concanavalin A (Con A) and 50ng/ml IL-2). In addition, the plasma levels of inflammatory cytokines were measured using luminex.ResultsAfter culture, significant increases in the number of GzB expressing cells gated on CD3+, CD4+, CD8 + and NKCD8 + T cells in the PBMCs from lung cancer patients before induction of chemotherapy as compared to control individuals as well as patients during and after induction of chemotherapy. Serum levels of IL-1 and CXCL8 in patients before induction of chemotherapy showed 37- and 40-fold increases, respectively, as compared to control individuals. Both GzB expression and cytokines levels in patients during and after chemotherapy were similar.ConclusionPolyclonal stimulation of PBMCs can restore the cytolytic activities of cytotoxic CD8 and NK cells from lung cancer patients even after chemotherapy.

Mesenchymal Stromal Cells: Heterogeneity and Therapeutical Applications.

Mesenchymal stromal cells nowadays emerge as a major player in the field of regenerative medicine and translational research. They constitute, with their derived products, the most frequently used cell type in different therapies. However, their heterogeneity, including different subpopulations, the anatomic source of isolation, and high donor-to-donor variability, constitutes a major controversial issue that affects their use in clinical applications. Furthermore, the intrinsic and extrinsic molecular mechanisms underlying their self-renewal and fate specification are still not completely elucidated. This review dissects the different heterogeneity aspects of the tissue source associated with a distinct developmental origin that need to be considered when generating homogenous products before their usage for clinical applications.

Evolution of Tungsten Fiber‐Reinforced Tungsten‐Remarks on Production and Joining

Material issues pose a significant challenge for the design of future fusion reactors. These issues require new advanced materials to be developed. W‐fiber‐reinforced W‐composite material (W f/W) incorporates extrinsic toughening mechanisms increasing the resistance against failure and thus granting steps toward application in a future fusion reactor. W f/W can be produced based on chemical vapor deposition or powder metallurgical routes. In this contribution, the efforts of upscaling the production of W f/W will be reviewed based on recent results. In addition, the activities related to enabling large‐scale production for new fusion applications are being studied. Herein, two main achievements are to be highlighted. First, an upscaled production is established to produce flat tile samples for joining tests on copper and steel, and second, a new method of joining W f/W on copper is established and tested under high heat‐flux conditions.

MicroRNA miR-263b-5p Regulates Developmental Growth and Cell Association by Suppressing Laminin A in Drosophila.

Basement membranes (BMs) play important roles under various physiological conditions in animals, including ecdysozoans. During development, BMs undergo alterations through diverse intrinsic and extrinsic regulatory mechanisms; however, the full complement of pathways controlling these changes remain unclear. Here, we found that fat body-overexpression of Drosophila miR-263b, which is highly expressed during the larval-to-pupal transition, resulted in a decrease in the overall size of the larval fat body, and ultimately, in a severe growth defect accompanied by a reduction in cell proliferation and cell size. Interestingly, we further observed that a large proportion of the larval fat body cells were prematurely disassociated from each other. Moreover, we present evidence that miR-263b-5p suppresses the main component of BMs, Laminin A (LanA). Through experiments using RNA interference (RNAi) of LanA, we found that its depletion phenocopied the effects in miR-263b-overexpressing flies. Overall, our findings suggest a potential role for miR-263b in developmental growth and cell association by suppressing LanA expression in the Drosophila fat body.

Bioinspired ceramic-polymer composites with hierarchical nacre-mimetic structure via accumulative rolling technique

Constructing nacre-mimetic architecture in ceramic-polymer composites is an effective approach to improve fracture toughness. Here, ceramic-polymer composites with nacre-mimetic brick-and-mortar structure were fabricated using an accumulative rolling technique. Non-isometric and flaky Ti3AlC2 powders with ultrafine dimensions along with Al2O3 and h-BN powders with micron-sized dimensions were employed as constituents and the effect of their size on mechanical properties was investigated. The results showed that the flaky ceramic powders were preferentially aligned along the rolling direction under the shear force exerted by the rollers, and formed staggered stacking layers. Significant differences in the characteristic dimensions of flaky ceramic powders contributed to a hierarchical structure of the composites. Compared with the composites containing merely ultrafine-sized Ti3AlC2 flakes, the strength of composites decreased when Ti3AlC2 flakes were replaced by larger Al2O3 and h-BN flakes. However, such substitution inhibited the crack propagation, leading to a stable crack growth behavior featured by rising R-curves owing to the activation of various extrinsic toughening mechanisms, including crack deflection, uncracked-ligament bridging and pull-out of ceramic platelets. The accumulative rolling technique offers a simple but effective means for toughening ceramic materials and optimizing their functional properties along specific directions.

Cancer cell plasticity during tumor progression, metastasis and response to therapy.

Cell plasticity represents the ability of cells to be reprogrammed and to change their fate and identity, enabling homeostasis restoration and tissue regeneration following damage. Cell plasticity also contributes to pathological conditions, such as cancer, enabling cells to acquire new phenotypic and functional features by transiting across distinct cell states that contribute to tumor initiation, progression, metastasis and resistance to therapy. Here, we review the intrinsic and extrinsic mechanisms driving cell plasticity that promote tumor growth and proliferation as well as metastasis and drug tolerance. Finally, we discuss how cell plasticity could be exploited for anti-cancer therapy.

Underlying Mechanisms and Tunability of the Anomalous Hall Effect in NiCo2 O4 Films with Robust Perpendicular Magnetic Anisotropy.

Their high tunability of electronic and magnetic properties makes transition-metal oxides (TMOs) highly intriguing for fundamental studies and promising for a wide range of applications. TMOs with strong ferrimagnetism provide new platforms for tailoring the anomalous Hall effect (AHE) beyond conventional concepts based on ferromagnets, and particularly TMOs with perpendicular magnetic anisotropy (PMA) are of prime importance for today's spintronics. This study reports on transport phenomena and magnetic characteristics of the ferrimagnetic TMO NiCo2 O4 (NCO) exhibiting PMA. The entire electrical and magnetic properties of NCO films are strongly correlated with their conductivities governed by the cation valence states. The AHE exhibits an unusual sign reversal resulting from a competition between intrinsic and extrinsic mechanisms depending on the conductivity, which can be tuned by the synthesis conditions independent of the film thickness. Importantly, skew-scattering is identified as an AHE contribution for the first time in the low-conductivity regime. Application wise, the robust PMA without thickness limitation constitutes a major advantage compared to conventional PMA materials utilized in today's spintronics. The great potential for applications is exemplified by two proposed novel device designs consisting only of NCO films that open a new route for future spintronics, such as ferrimagnetic high-densitymemories.

HMENA isoforms regulate cancer intrinsic type I IFN signaling and extrinsic mechanisms of resistance to immune checkpoint blockade in NSCLC

BackgroundUnderstanding how cancer signaling pathways promote an immunosuppressive program which sustains acquired or primary resistance to immune checkpoint blockade (ICB) is a crucial step in improving immunotherapy efficacy. Among the...

Integrated Extrinsic and Intrinsic Self-Healing of Polysiloxane Materials by Cleavable Molecular Cages Encapsulating Fluoride Ions.

Self-healing ability is crucial to increasing the lifetime and reliability of materials. In this study, spatiotemporal control of the healing of a polysiloxane material is achieved using a cleavable cage compound encapsulating a fluoride ion (F- ), which triggeres the dynamic rearrangement of the siloxane (Si-O-Si) networks. A self-healing siloxane-based elastomer is prepared by cross-linking polydimethylsiloxane (PDMS) with a F- -encapsulating cage-type germoxane (Ge-O-Ge) compound. This material can self-heal repeatedly under humid conditions. The F- released by hydrolytic cleavage of the cage framework contributes to rejoining of the cut pieces by promoting the local rearrangement of the siloxane networks. The use of a molecular cage encapsulating a catalyst for dynamic bond rearrangement provides a new concept for designing self-healing polysiloxane materials based on integrated extrinsic and intrinsic mechanisms.

Amniotic Band Syndrome: Head-to-Toe Manifestations and Clinical Management Guidelines.

After studying this article, the participant should be able to: 1. Understand and describe the basic principles underlying the intrinsic versus extrinsic proposed mechanisms for the development of amniotic band syndrome (ABS). 2. Discuss risk factors and conditions that are associated with the development of ABS. 3. Understand the various presentations and associated clinical implications of ABS by anatomic location. 4. Describe the basic tenets underlying various repair technique options for ABS of the extremities. 5. Discuss the common manifestations of ABS in the face and trunk. 6. Understand clinical implications of fetoscopic surgery as it relates to ABS treatment as a novel method for limb salvage in utero. Amniotic band syndrome (ABS) refers to the development of constrictive bands of fibrotic tissue in utero. It can lead to a variety of clinical manifestations after delivery. There is much debate in the plastic surgery community regarding the exact pathophysiologic mechanism for the development of ABS, and the most appropriate management. This CME article aims to provide an overview of ABS manifestations throughout the body, and to expound on the most recent advances in anticipatory and definitive management of the condition.

Genome-wide CRISPR screens define determinants of epithelial-mesenchymal transition mediated immune evasion by pancreatic cancer cells.

The genetic circuits that allow cancer cells to evade immune killing via epithelial mesenchymal plasticity remain poorly understood. Here, we showed that mesenchymal-like (Mes) KPC3 pancreatic cancer cells were more resistant to cytotoxic T lymphocyte (CTL)-mediated killing than the parental epithelial-like (Epi) cells and used parallel genome-wide CRISPR screens to assess the molecular underpinnings of this difference. Core CTL-evasion genes (such as IFN-γ pathway components) were clearly evident in both types. Moreover, we identified and validated multiple Mes-specific regulators of cytotoxicity, such as Egfr and Mfge8. Both genes were significantly higher expressed in Mes cancer cells, and their depletion sensitized Mes cancer cells to CTL-mediated killing. Notably, Mes cancer cells secreted more Mfge8 to inhibit proliferation of CD8+ T cells and production of IFN-γ and TNFα. Clinically, increased Egfr and Mfge8 expression was correlated with a worse prognosis. Thus, Mes cancer cells use Egfr-mediated intrinsic and Mfge8-mediated extrinsic mechanisms to facilitate immune escape from CD8+ T cells.

Immune escape and resistance to immunotherapy in mismatch repair deficient tumors.

Up to 30% of colorectal, endometrial and gastric cancers have a deficiency in mismatch repair (MMR) protein expression due to either germline or epigenetic inactivation. Patients with Lynch Syndrome who inherit an inactive MMR allele have an up to 80% risk for developing a mismatch repair deficient (MMRd) cancer. Due to an inability to repair DNA, MMRd tumors present with genomic instability in microsatellite regions (MS). Tumors with high MS instability (MSI-H) are characterized by an increased frequency of insertion/deletions (indels) that can encode novel neoantigens if they occur in coding regions. The high tumor antigen burden for MMRd cancers is accompanied by an inflamed tumor microenvironment (TME) that contributes to the clinical effectiveness of anti-PD-1 therapy in this patient population. However, between 40 and 70% of MMRd cancer patients do not respond to treatment with PD-1 blockade, suggesting that tumor-intrinsic and -extrinsic resistance mechanisms may affect the success of checkpoint blockade. Immune evasion mechanisms that occur during early tumorigenesis and persist through cancer development may provide a window into resistance pathways that limit the effectiveness of anti-PD-1 therapy. Here, we review the mechanisms of immune escape in MMRd tumors during development and checkpoint blockade treatment, including T cell dysregulation and myeloid cell-mediated immunosuppression in the TME. Finally, we discuss the development of new therapeutic approaches to tackle resistance in MMRd tumors, including cancer vaccines, therapies targeting immunosuppressive myeloid programs, and immune checkpoint combination strategies.

B cell abnormalities and autoantibody production in patients with partial RAG deficiency.

Mutations in the recombination activating gene 1 (RAG1) and RAG2 in humans are associated with a broad spectrum of clinical phenotypes, from severe combined immunodeficiency to immune dysregulation. Partial (hypomorphic) RAG deficiency (pRD) in particular, frequently leads to hyperinflammation and autoimmunity, with several underlying intrinsic and extrinsic mechanisms causing a break in tolerance centrally and peripherally during T and B cell development. However, the relative contributions of these processes to immune dysregulation remain unclear. In this review, we specifically focus on the recently described tolerance break and B cell abnormalities, as well as consequent molecular and cellular mechanisms of autoantibody production in patients with pRD.

XIAP promotes the expansion and limits the contraction of CD8 T cell response through cell extrinsic and intrinsic mechanisms respectively.

XIAP is an endogenous inhibitor of cell death and inactivating mutations of XIAP are responsible for X-linked lymphoproliferative disease (XLP-2) and primary immunodeficiency, but the mechanism(s) behind these contradictory outcomes have been unclear. We report that during infection of macrophages and dendritic cells with various intracellular bacteria, XIAP restricts cell death and secretion of IL-1β but promotes increased activation of NFκB and JNK which results in elevated secretion of IL-6 and IL-10. Poor secretion of IL-6 by Xiap-deficient antigen presenting cells leads to poor expansion of recently activated CD8 T cells during the priming phase of the response. On the other hand, Xiap-deficient CD8 T cells displayed increased proliferation and effector function during the priming phase but underwent enhanced contraction subsequently. Xiap-deficient CD8 T cells underwent skewed differentiation towards short lived effectors which resulted in poor generation of memory. Consequently Xiap-deficient CD8 T cells failed to provide effective control of bacterial infection during re-challenge. These results reveal the temporal impact of XIAP in promoting the fitness of activated CD8 T cells through cell extrinsic and intrinsic mechanisms and provide a mechanistic explanation of the phenotype observed in XLP-2 patients.