MGMT function determines the differential response of ATR inhibitors with DNA-damaging agents in glioma stem cells for GBM therapy.

Background: The most prevalent cancer treatments cause cell death through DNA damage. However, DNA damage response (DDR) repair pathways, initiated by tumor cells, can withstand the effects of anticancer drugs, providing justification for combining DDR inhibitors with DNA-damaging anticancer treatments. Methods: Cell viability assays were performed with CellTiter-Glo assay. DNA damage was evaluated using Western blotting analysis. RNA-seq and single-cell level expression were used to identify the DDR signatures. In vivo, studies were conducted in mice to determine the effect of ATris on TMZ sensitization. Results: We found a subpopulation of glioma sphere-forming cells (GSCs) with substantial synergism with temozolomide (TMZ) using a panel of 3 clinical-grade ataxia-telangiectasia- and Rad3-related kinase inhibitors (ATRis), (elimusertib, berzosertib, and ceralasertib). Interestingly, most synergistic cell lines had O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, indicating that ATRi mainly benefits tumors with no MGMT repair. Further, TMZ activated the ATR-checkpoint kinase 1 (Chk1) axis in an MGMT-dependent way. TMZ caused ATR-dependent Chk1 phosphorylation and DNA double-strand breaks as shown by increased γH2AX. Increased DNA damage and decreased Chk1 phosphorylation were observed upon the addition of ATRis to TMZ in MGMT-methylated (MGMT-) GSCs. TMZ also improved sensitivity to ATRis in vivo, as shown by increased mouse survival with the TMZ and ATRi combination treatment. Conclusions: This research provides a rationale for selectively targeting MGMT-methylated cells using ATRis and TMZ combination. Overall, we believe that MGMT methylation status in GBM could serve as a robust biomarker for patient selection for ATRi combined with TMZ.

Neuronal differentiation drives the antitumor activity of mitogen-activated protein kinase kinase (MEK) inhibition in glioblastoma.

Background: Epidermal growth factor receptor (EGFR) amplification is found in nearly 40%-50% of glioblastoma cases. Several EGFR inhibitors have been tested in glioblastoma but have failed to demonstrate long-term therapeutic benefit, presumably because of acquired resistance. Targeting EGFR downstream signaling with mitogen-activated protein kinase kinase 1 and 2 (MEK1/2) inhibitors would be a more effective approach to glioblastoma treatment. We tested the therapeutic potential of MEK1/2 inhibitors in glioblastoma using 3D cultures of glioma stem-like cells (GSCs) and mouse models of glioblastoma. Methods: Several MEK inhibitors were screened in an unbiased high-throughput platform using GSCs. Cell death was evaluated using flow cytometry and Western blotting (WB) analysis. RNA-seq, real-time quantitative polymerase chain reaction, immunofluorescence, and WB analysis were used to identify and validate neuronal differentiation. Results: Unbiased screening of multiple MEK inhibitors in GSCs showed antiproliferative and apoptotic cell death in sensitive cell lines. An RNA-seq analysis of cells treated with trametinib, a potent MEK inhibitor, revealed upregulation of neurogenesis and neuronal differentiation genes, such as achaete-scute homolog 1 (ASCL1), delta-like 3 (DLL3), and neurogenic differentiation 4 (NeuroD4). We validated the neuronal differentiation phenotypes in vitro and in vivo using selected differentiation markers (ß-III-tubulin, ASCL1, DLL3, and NeuroD4). Oral treatment with trametinib in an orthotopic GSC xenograft model significantly improved animal survival, with 25%-30% of mice being long-term survivors. Conclusions: Our findings demonstrated that MEK1/2 inhibition promotes neuronal differentiation in glioblastoma, a potential additional mechanism of action of MEK1/2 inhibitors. Thus, MEK inhibitors could be efficacious in glioblastoma patients with activated EGFR/MAPK signaling.

Epitaxially Driven Phase Selectivity of Sn in Hybrid Quantum Nanowires.

Hybrid semiconductor-superconductor nanowires constitute a pervasive platform for studying gate-tunable superconductivity and the emergence of topological behavior. Their low dimensionality and crystal structure flexibility facilitate unique heterostructure growth and efficient material optimization, crucial prerequisites for accurately constructing complex multicomponent quantum materials. Here, we present an extensive study of Sn growth on InSb, InAsSb, and InAs nanowires and demonstrate how the crystal structure of the nanowires drives the formation of either semimetallic α-Sn or superconducting ß-Sn. For InAs nanowires, we observe phase-pure superconducting ß-Sn shells. However, for InSb and InAsSb nanowires, an initial epitaxial α-Sn phase evolves into a polycrystalline shell of coexisting α and ß phases, where the ß/α volume ratio increases with Sn shell thickness. Whether these nanowires exhibit superconductivity or not critically relies on the ß-Sn content. Therefore, this work provides key insights into Sn phases on a variety of semiconductors with consequences for the yield of superconducting hybrids suitable for generating topological systems.

Mechanisms of NLRP3 inflammasome-mediated hepatic stellate cell activation: Therapeutic potential for liver fibrosis.

The liver injury leads to an inflammatory response, which causes the activation of hepatic stellate cells (HSCs) that further secrete ECM proteins and play an important role in liver fibrosis. Moreover, the inflammatory response is a driving force for fibrogenesis, which is triggered by many types of injuries. Exaggerated inflammatory immune responses are mediated by cytoplasmic protein complexes known as inflammasomes, which are involved in many chronic liver diseases. Inflammasomes are pattern recognition receptors (PRRs) that can sense any microbial motifs known as pathogen-associated molecular patterns (PAMPs), and host- or environmental-derived stress signals known as damage-associated molecular patterns (DAMPs). The inflammasomes cause caspase-mediated proteolytic cleavage of pro-IL-1ß and pro-IL-18 into active IL-1ß and IL-18. In this review, we provide a comprehensive summary of the important roles of NLRP3 inflammasome in the pathogenesis of liver fibrosis with an emphasis on several direct and indirect pathways responsible for the NLRP3 inflammasome-mediated HSCs activation and fibrogenesis. In addition, we discuss the general pharmacological and genetics strategies for the inhibition of NLRP3 inflammasome activation and its downstream signaling with examples of emerging pharmacotherapeutics, targeting the NLRP3 inflammasome signaling as well as a possible way to develop effective and safer NLRP3 inflammasome inhibitors.

Developmental and reproductive toxic effects of exposure to microplastics: A review of associated signaling pathways.

Microplastics (MPs), small pieces of plastic (∼5 mm), are released into the environment not only as a result of the decomposition of large-sized plastics but also from day-to-day use of plastic products. Chronic exposure to MPs has been attributed to harmful effects on aquatic organisms and rodents. Effects include gastrointestinal toxicity, hepatotoxicity, neurotoxicity, and reproductive and developmental toxicities. Exposure to MPs may also potentially affect human health. Herein, we reviewed the impact of MPs on male and female reproductive systems and the associated mechanisms involved in the reproductive and developmental toxicities of MPs. We performed a literature search in Google Scholar and PubMed using the following keywords: MPs and reproductive toxicity; MPs and developmental studies; MPs and infertility; MPs and aquatics; and MPs and rodents. Evidence of MPs accumulation has been reported in many organs of humans and experimental models. The harmful effects of MPs have been manifested in male and female reproductive systems of mammalian and aquatic animals, including developmental effects on gametes, embryos, and their offspring. This review describes various signaling pathways involved in MPs-associated male and female reproductive and developmental toxicities.

Photon-Assisted Tunneling of High-Order Multiple Andreev Reflections in Epitaxial Nanowire Josephson Junctions.

Semiconductor/superconductor hybrids exhibit a range of phenomena that can be exploited for the study of novel physics and the development of new technologies. Understanding the origin of the energy spectrum of such hybrids is therefore a crucial goal. Here, we study Josephson junctions defined by shadow epitaxy on InAsSb/Al nanowires. The devices exhibit gate-tunable supercurrents at low temperatures and multiple Andreev reflections (MARs) at finite voltage bias. Under microwave irradiation, photon-assisted tunneling (PAT) of MARs produces characteristic oscillating sidebands at quantized energies, which depend on MAR order, n, in agreement with a recently suggested modification of the classical Tien-Gordon equation. The scaling of the quantized energy spacings with microwave frequency provides independent confirmation of the effective charge, ne, transferred by the nth-order tunneling process. The measurements suggest PAT as a powerful method for assigning the origin of low-energy spectral features in hybrid Josephson devices.

EGFR suppresses p53 function by promoting p53 binding to DNA-PKcs: a noncanonical regulatory axis between EGFR and wild-type p53 in glioblastoma.

BACKGROUND: Epidermal growth factor receptor (EGFR) amplification and TP53 mutation are the two most common genetic alterations in glioblastoma multiforme (GBM). A comprehensive analysis of the TCGA GBM database revealed a subgroup with near mutual exclusivity of EGFR amplification and TP53 mutations indicative of a role of EGFR in regulating wild-type-p53 (wt-p53) function. The relationship between EGFR amplification and wt-p53 function remains undefined and this study describes the biological significance of this interaction in GBM. METHODS: Mass spectrometry was used to identify EGFR-dependent p53-interacting proteins. The p53 and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) interaction was detected by co-immunoprecipitation. We used CRISPR-Cas9 gene editing to knockout EGFR and DNA-PKcs and the Edit-R CRIPSR-Cas9 system for conditional knockout of EGFR. ROS activity was measured with a CM-H2DCFDA probe, and real-time PCR was used to quantify expression of p53 target genes. RESULTS: Using glioma sphere-forming cells (GSCs), we identified, DNA-PKcs as a p53 interacting protein that functionally inhibits p53 activity. We demonstrate that EGFR knockdown increased wt-p53 transcriptional activity, which was associated with decreased binding between p53 and DNA-PKcs. We further show that inhibition of DNA-PKcs either by siRNA or an inhibitor (nedisertib) increased wt-p53 transcriptional activity, which was not enhanced further by EGFR knockdown, indicating that EGFR suppressed wt-p53 activity through DNA-PKcs binding with p53. Finally, using conditional EGFR-knockout GSCs, we show that depleting EGFR increased animal survival in mice transplanted with wt-p53 GSCs. CONCLUSION: This study demonstrates that EGFR signaling inhibits wt-p53 function in GBM by promoting an interaction between p53 and DNA-PKcs.

Signatures of Andreev Blockade in a Double Quantum Dot Coupled to a Superconductor.

We investigate an electron transport blockade regime in which a spin triplet localized in the path of current is forbidden from entering a spin-singlet superconductor. To stabilize the triplet, a double quantum dot is created electrostatically near a superconducting Al lead in an InAs nanowire. The quantum dot closest to the normal lead exhibits Coulomb diamonds, and the dot closest to the superconducting lead exhibits Andreev bound states and an induced gap. The experimental observations compare favorably to a theoretical model of Andreev blockade, named so because the triplet double dot configuration suppresses Andreev reflections. Observed leakage currents can be accounted for by finite temperature. We observe the predicted quadruple level degeneracy points of high current and a periodic conductance pattern controlled by the occupation of the normal dot. Even-odd transport asymmetry is lifted with increased temperature and magnetic field. This blockade phenomenon can be used to study spin structure of superconductors. It may also find utility in quantum computing devices that use Andreev or Majorana states.

Andreev Interference in the Surface Accumulation Layer of Half-Shell InAsSb/Al Hybrid Nanowires.

Understanding the spatial distribution of charge carriers in III-V nanowires proximity coupled to superconductors is important for the design and interpretation of experiments based on hybrid quantum devices. In this letter, the gate-dependent surface accumulation layer of half-shell InAsSb/Al nanowires is studied by means of Andreev interference in a parallel magnetic field. Both uniform hybrid nanowires and devices featuring a short Josephson junction fabricated by shadow lithography, exhibit periodic modulation of the switching current. The period corresponds to a flux quantum through the nanowire diameter and is consistent with Andreev bound states occupying a cylindrical surface accumulation layer. The spatial distribution is tunable by a gate potential as expected from electrostatic models.

Intrinsic Interferon Signaling Regulates the Cell Death and Mesenchymal Phenotype of Glioblastoma Stem Cells.

Interferon (IFN) signaling contributes to stemness, cell proliferation, cell death, and cytokine signaling in cancer and immune cells; however, the role of IFN signaling in glioblastoma (GBM) and GBM stem-like cells (GSCs) is unclear. Here, we investigated the role of cancer-cell-intrinsic IFN signaling in tumorigenesis in GBM. We report here that GSCs and GBM tumors exhibited differential cell-intrinsic type I and type II IFN signaling, and high IFN/STAT1 signaling was associated with mesenchymal phenotype and poor survival outcomes. In addition, chronic inhibition of IFN/STAT1 signaling decreased cell proliferation and mesenchymal signatures in GSCs with intrinsically high IFN/STAT1 signaling. IFN-ß exposure induced apoptosis in GSCs with intrinsically high IFN/STAT1 signaling, and this effect was abolished by the pharmacological inhibitor ruxolitinib and STAT1 knockdown. We provide evidence for targeting IFN signaling in a specific sub-group of GBM patients. IFN-ß may be a promising candidate for adjuvant GBM therapy.

Multiterminal Quantized Conductance in InSb Nanocrosses.

By studying the time-dependent axial and radial growth of InSb nanowires (NWs), the conditions for the synthesis of single-crystalline InSb nanocrosses (NCs) by molecular beam epitaxy are mapped. Low-temperature electrical measurements of InSb NC devices with local gate control on individual terminals exhibit quantized conductance and are used to probe the spatial distribution of the conducting channels. Tuning to a situation where the NC junction is connected by few-channel quantum point contacts in the connecting NW terminals, it is shown that transport through the junction is ballistic except close to pinch-off. Combined with a new concept for shadow-epitaxy of patterned superconductors on NCs, the structures reported here show promise for the realization of non-trivial topological states in multi-terminal Josephson junctions.

Prevalence of mental health symptoms and its effect on insomnia among healthcare workers who attended hospitals during COVID-19 pandemic: A survey in Dhaka city.

BACKGROUND: During the COVID-19 pandemic, the high workload, risk of infection, and safety issues for family members may pose a threat to the mental health of healthcare workers (HCWs) working in hospital settings. The study aimed to find out the prevalence of anxiety, depression, and insomnia symptoms were among HCWs, as well as the factors related to these mental health issues. METHODS: We conducted an online survey of HCWs employed in Dhaka city from June 6 to July 6, 2020. Symptoms of anxiety, depression, and insomnia were measured using the Generalized Anxiety Disorder, the depression module of the Patient Health Questionnaire, and the Insomnia Severity Index, respectively. The related factors of anxiety, depression, and insomnia symptoms were identified using three regression models. RESULTS: This research included responses from 294 HCWs (mean ± standard deviation age: 28.86 ± 5.5 years; 43.5% were female). Anxiety, depression, and insomnia symptoms were found in 20.7%, 26.5%, and 44.2% of HCWs, respectively. The variable financial difficulties was commonly found as an associated factor for anxiety, depression, and insomnia symptoms. Female HCWs were more prone to mental health symptoms and insomnia compared to male HCWs (Adjusted odds ratio- AOR = 2.20, 95% CI = 1.27-3.79). The depression symptoms among HCWs were found to be a factor for insomnia (AOR = 6.321, 95% CI = 3.158-12.650). CONCLUSION: In the current pandemic, the high prevalence of mental health symptoms among HCWs indicates that this occupational group being associated with increased mental distress. Increasing financial support for HCWs and providing support to female workers in care facilities could help to alleviate the burden of mental illness. Supportive, training, and educational strategies, particularly through knowledge and communication platforms, could be recommended to the care facilities, which can reduce the burden of mental health symptoms among HCWs.

Flame Retardants-Mediated Interferon Signaling in the Pathogenesis of Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is a growing concern worldwide, affecting 25% of the global population. NAFLD is a multifactorial disease with a broad spectrum of pathology includes steatosis, which gradually progresses to a more severe condition such as nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and eventually leads to hepatic cancer. Several risk factors, including exposure to environmental toxicants, are involved in the development and progression of NAFLD. Environmental factors may promote the development and progression of NAFLD by various biological alterations, including mitochondrial dysfunction, reactive oxygen species production, nuclear receptors dysregulation, and interference in inflammatory and immune-mediated signaling. Moreover, environmental contaminants can influence immune responses by impairing the immune system's components and, ultimately, disease susceptibility. Flame retardants (FRs) are anthropogenic chemicals or mixtures that are being used to inhibit or delay the spread of fire. FRs have been employed in several household and outdoor products; therefore, human exposure is unavoidable. In this review, we summarized the potential mechanisms of FRs-associated immune and inflammatory signaling and their possible contribution to the development and progression of NAFLD, with an emphasis on FRs-mediated interferon signaling. Knowledge gaps are identified, and emerging pharmacotherapeutic molecules targeting the immune and inflammatory signaling for NAFLD are also discussed.

The promise of DNA damage response inhibitors for the treatment of glioblastoma.

Glioblastoma (GBM), the most aggressive primary brain tumor, has a dismal prognosis. Despite our growing knowledge of genomic and epigenomic alterations in GBM, standard therapies and outcomes have not changed significantly in the past two decades. There is therefore an urgent unmet need to develop novel therapies for GBM. The inter- and intratumoral heterogeneity of GBM, inadequate drug concentrations in the tumor owing to the blood-brain barrier, redundant signaling pathways contributing to resistance to conventional therapies, and an immunosuppressive tumor microenvironment, have all hindered the development of novel therapies for GBM. Given the high frequency of DNA damage pathway alterations in GBM, researchers have focused their efforts on pharmacologically targeting key enzymes, including poly(ADP-ribose) polymerase (PARP), DNA-dependent protein kinase, ataxia telangiectasia-mutated, and ataxia telangiectasia and Rad3-related. The mainstays of GBM treatment, ionizing radiation and alkylating chemotherapy, generate DNA damage that is repaired through the upregulation and activation of DNA damage response (DDR) enzymes. Therefore, the use of PARP and other DDR inhibitors to render GBM cells more vulnerable to conventional treatments is an area of intense investigation. In this review, we highlight the growing body of data behind DDR inhibitors in GBM, with a focus on putative predictive biomarkers of response. We also discuss the challenges involved in the successful development of DDR inhibitors for GBM, including the intracranial location and predicted overlapping toxicities of DDR agents with current standards of care, and propose promising strategies to overcome these hurdles.

Depletion of CLK2 sensitizes glioma stem-like cells to PI3K/mTOR and FGFR inhibitors.

The Cdc2-like kinases (CLKs) regulate RNA splicing and have been shown to suppress cell growth. Knockdown of CLK2 was found to block glioma stem-like cell (GSC) growth in vivo through the AKT/FOXO3a/p27 pathway without activating mTOR and MAPK signaling, suggesting that these pathways mediate resistance to CLK2 inhibition. We identified CLK2 binding partners using immunoprecipitation assays and confirmed their interactions in vitro in GSCs. We then tested the cellular viability of several signaling inhibitors in parental and CLK2 knockdown GSCs. Our results demonstrate that CLK2 binds to 14-3-3τ isoform and prevents its ubiquitination in GSCs. Stable CLK2 knockdown increased PP2A activity and activated PI3K signaling. Treatment with a PI3K/mTOR inhibitor in CLK2 knockdown cells led to a modest reduction in cell viability compared to drug treatment alone at a lower dose. However, FGFR inhibitor in CLK2 knockdown cells led to a decrease in cell viability and increased apoptosis. Reduced expression of CLK2 in glioblastoma, in combination with FGFR inhibitors, led to synergistic apoptosis induction and cell cycle arrest compared to blockade or either kinase alone.

Nicotinamide attenuates cyclophosphamide-induced hepatotoxicity in SD rats by reducing oxidative stress and apoptosis.

Cyclophosphamide (CP) is a widely used anticancer and immunosuppressant drug. Nevertheless, clinical utilization of CP is limited due to considerable adverse effects and toxicities. Nicotinamide (NMD) is a micronutrient and the effect of NMD against CP-induced hepatotoxicity is yet unexplored. The present study was designed to evaluate the chemoprotective effect of NMD against CP-induced hepatic injury in Sprague-Dawley rats. Hepatotoxicity was induced by the administration of CP (30 mg/kg/day) for 10 consecutive days by intraperitoneal injection. The chemoprotective effect of NMD treatment (200 mg/kg) against CP-induced hepatotoxicity was evaluated by the oxidative stress, liver function, histopathological changes, and DNA damage. NMD cotreatment significantly reduced CP-induced oxidative stress, histological changes, and apoptosis in the liver. The present study demonstrated that NMD treatment ameliorated CP-induced hepatic damage by improving the antioxidant system and reducing DNA damage. The present findings revealed that NMD supplementation might be useful to reduce CP-associated hepatotoxicity, and thereby can increase the therapeutic utility of CP.

Highly Transparent Gatable Superconducting Shadow Junctions.

Gate-tunable junctions are key elements in quantum devices based on hybrid semiconductor-superconductor materials. They serve multiple purposes ranging from tunnel spectroscopy probes to voltage-controlled qubit operations in gatemon and topological qubits. Common to all is that junction transparency plays a critical role. In this study, we grow single-crystalline InAs, InSb, and InAs1-xSbx semiconductor nanowires with epitaxial Al, Sn, and Pb superconductors and in situ shadowed junctions in a single-step molecular beam epitaxy process. We investigate correlations between fabrication parameters, junction morphologies, and electronic transport properties of the junctions and show that the examined in situ shadowed junctions are of significantly higher quality than the etched junctions. By varying the edge sharpness of the shadow junctions, we show that the sharpest edges yield the highest junction transparency for all three examined semiconductors. Further, critical supercurrent measurements reveal an extraordinarily high ICRN, close to the KO-2 limit. This study demonstrates a promising engineering path toward reliable gate-tunable superconducting qubits.

Role of Neutrophils and Myeloid-Derived Suppressor Cells in Glioma Progression and Treatment Resistance.

Recent efforts in brain tumor research have been directed towards the modulation of the immune system for therapeutic interventions. Several human cancers, including gliomas, are infiltrated with immune cell types-including neutrophils and myeloid-derived suppressor cells-that contribute to tumor progression, invasiveness, and treatment resistance. The role of tumor-associated neutrophils and myeloid-derived suppressor cells in cancer biology remains elusive, as these cells can exert a multitude of pro-tumor and antitumor effects. In this review, we provide the current understanding and novel insights on the role of neutrophils and myeloid-derived suppressor cells in glioma progression and treatment resistance, as well as the mechanisms of pleiotropic behaviors in these cells during disease progression, with an emphasis on possible strategies to reprogram these cells towards their antitumor actions.

Semiconductor-Ferromagnetic Insulator-Superconductor Nanowires: Stray Field and Exchange Field.

Nanowires can serve as flexible substrates for hybrid epitaxial growth on selected facets, allowing for the design of heterostructures with complex material combinations and geometries. In this work we report on hybrid epitaxy of freestanding vapor-liquid-solid grown and in-plane selective area grown semiconductor-ferromagnetic insulator-superconductor (InAs/EuS/Al) nanowire heterostructures. We study the crystal growth and complex epitaxial matching of wurtzite and zinc-blende InAs/rock-salt EuS interfaces as well as rock-salt EuS/face-centered cubic Al interfaces. Because of the magnetic anisotropy originating from the nanowire shape, the magnetic structure of the EuS phase is easily tuned into single magnetic domains. This effect efficiently ejects the stray field lines along the nanowires. With tunnel spectroscopy measurements of the density of states, we show that the material has a hard induced superconducting gap, and magnetic hysteretic evolution which indicates that the magnetic exchange fields are not negligible. These hybrid nanowires fulfill key material requirements for serving as a platform for spin-based quantum applications, such as scalable topological quantum computing.

Coherent Epitaxial Semiconductor-Ferromagnetic Insulator InAs/EuS Interfaces: Band Alignment and Magnetic Structure.

Hybrid semiconductor-ferromagnetic insulator heterostructures are interesting due to their tunable electronic transport, self-sustained stray field, and local proximitized magnetic exchange. In this work, we present lattice-matched hybrid epitaxy of semiconductor-ferromagnetic insulator InAs/EuS heterostructures and analyze the atomic-scale structure and their electronic and magnetic characteristics. The Fermi level at the InAs/EuS interface is found to be close to the InAs conduction band and in the band gap of EuS, thus preserving the semiconducting properties. Both neutron and X-ray reflectivity measurements show that the overall ferromagnetic component is mainly localized in the EuS thin film with a suppression of the Eu moment in the EuS layer nearest the InAs and magnetic moments outside the detection limits on the pure InAs side. This work presents a step toward realizing defect-free semiconductor-ferromagnetic insulator epitaxial hybrids for spin-lifted quantum and spintronic applications without external magnetic fields.