Glycogen accumulation and phase separation drives liver tumor initiation.

Glucose consumption is generally increased in tumor cells to support tumor growth. Interestingly, we report that glycogen accumulation is a key initiating oncogenic event during liver malignant transformation. We found that glucose-6-phosphatase (G6PC) catalyzing the last step of glycogenolysis is frequently downregulated to augment glucose storage in pre-malignant cells. Accumulated glycogen undergoes liquid-liquid phase separation, which results in the assembly of the Laforin-Mst1/2 complex and consequently sequesters Hippo kinases Mst1/2 in glycogen liquid droplets to relieve their inhibition on Yap. Moreover, G6PC or another glycogenolysis enzyme-liver glycogen phosphorylase (PYGL) deficiency in both human and mice results in glycogen storage disease along with liver enlargement and tumorigenesis in a Yap-dependent manner. Consistently, elimination of glycogen accumulation abrogates liver growth and cancer incidence, whereas increasing glycogen storage accelerates tumorigenesis. Thus, we concluded that cancer-initiating cells adapt a glycogen storing mode, which blocks Hippo signaling through glycogen phase separation to augment tumor incidence.

Kinases Mst1 and Mst2 positively regulate phagocytic induction of reactive oxygen species and bactericidal activity.

Mitochondria need to be juxtaposed to phagosomes for the synergistic production of ample reactive oxygen species (ROS) in phagocytes to kill pathogens. However, how phagosomes transmit signals to recruit mitochondria has remained unclear. Here we found that the kinases Mst1 and Mst2 functioned to control ROS production by regulating mitochondrial trafficking and mitochondrion-phagosome juxtaposition. Mst1 and Mst2 activated the GTPase Rac to promote Toll-like receptor (TLR)-triggered assembly of the TRAF6-ECSIT complex that is required for the recruitment of mitochondria to phagosomes. Inactive forms of Rac, including the human Rac2(D57N) mutant, disrupted the TRAF6-ECSIT complex by sequestering TRAF6 and substantially diminished ROS production and enhanced susceptibility to bacterial infection. Our findings demonstrate that the TLR-Mst1-Mst2-Rac signaling axis is critical for effective phagosome-mitochondrion function and bactericidal activity.

Effective Manipulation of a Colossal Second-Order Transverse Response in an Electric-Field-Tunable Graphene Moiré System.

The second-order nonlinear transport illuminates a frequency-doubling response emerging in quantum materials with a broken inversion symmetry. The two principal driving mechanisms, the Berry curvature dipole and the skew scattering, reflect various information including ground-state symmetries, band dispersions, and topology of electronic wave functions. However, effective manipulation of them in a single system has been lacking, hindering the pursuit of strong responses. Here, we report on the effective manipulation of the two mechanisms in a single graphene moiré superlattice, AB-BA stacked twisted double bilayer graphene. Most saliently, by virtue of the high tunability of moiré band structures and scattering rates, a record-high second-order transverse conductivity ∼ 510 µm S V-1 is observed, which is orders of magnitude higher than any reported values in the literature. Our findings establish the potential of electrically tunable graphene moiré systems for nonlinear transport manipulations and applications.

MEN1 deficiency stabilizes PD-L1 and promotes tumor immune evasion of lung cancer.

Multiple Endocrine Neoplasia 1 gene (MEN1), which is known to be a tumor suppressor gene in lung tissues, encodes a 610 amino acid protein menin. Previous research has proven that MEN1 deficiency promotes the malignant progression of lung cancer. However, the biological role of this gene in the immune microenvironment of lung cancer remains unclear. In this study, we found that programmed cell death-ligand 1 (PD-L1) is upregulated in lung-specific KrasG12D mutation-induced lung adenocarcinoma in mice, after Men1 deficiency. Simultaneously, CD8+ and CD3+ T cells are depleted, and their cytotoxic effects are suppressed. In vitro, PD-L1 is inhibited by the overexpression of menin. Mechanistically, we found that MEN1 inactivation promotes the deubiquitinating activity of COP9 signalosome subunit 5 (CSN5) and subsequently increases the level of PD-L1.

Ultrahigh extinction ratio and a low power silicon thermo-optic switch.

The silicon thermo-optic switch (TOS) is one of the most fundamental and crucial blocks in large-scale silicon photonic integrated circuits (PICs). An energy-efficient silicon TOS with ultrahigh extinction ratio can effectively mitigate cross talk and reduce power consumption in optical systems. In this Letter, we demonstrate a silicon TOS based on cascading Mach-Zehnder interferometers (MZIs) with spiral thermo-optic phase shifters. The experimental results show that an ultrahigh extinction ratio of 58.8 dB is obtained, and the switching power consumption is as low as 2.32 mW/π without silicon air trench. The rise time and fall time of the silicon TOS are about 10.8 and 11.2 µs, respectively. Particularly, the figure of merit (FOM) has been improved compared with previously reported silicon TOS. The proposed silicon TOS may find potential applications in optical switch arrays, on-chip optical delay lines, etc.

Angiotensin II type-2 receptor signaling facilitates liver injury repair and regeneration via inactivation of Hippo pathway.

The angiotensin II type 2 receptor (AT2R) is a well-established component of the renin-angiotensin system and is known to counteract classical activation of this system and protect against organ damage. Pharmacological activation of the AT2R has significant therapeutic benefits, including vasodilation, natriuresis, anti-inflammatory activity, and improved insulin sensitivity. However, the precise biological functions of the AT2R in maintaining homeostasis in liver tissue remain largely unexplored. In this study, we found that the AT2R facilitates liver repair and regeneration following acute injury by deactivating Hippo signaling and that interleukin-6 transcriptionally upregulates expression of the AT2R in hepatocytes through STAT3 acting as a transcription activator binding to promoter regions of the AT2R. Subsequently, elevated AT2R levels activate downstream signaling via heterotrimeric G protein Gα12/13-coupled signals to induce Yap activity, thereby contributing to repair and regeneration processes in the liver. Conversely, a deficiency in the AT2R attenuates regeneration of the liver while increasing susceptibility to acetaminophen-induced liver injury. Administration of an AT2R agonist significantly enhances the repair and regeneration capacity of injured liver tissue. Our findings suggest that the AT2R acts as an upstream regulator in the Hippo pathway and is a potential target in the treatment of liver damage.

Epigallocatechin-3-gallate Alleviates Ethanol-Induced Endothelia Cells Injury Partly through Alteration of NF-κB Translocation and Activation of the Nrf2 Signaling Pathway.

Ethanol (alcohol) is a risk factor that contributes to non-communicable diseases. Chronic abuse of ethanol is toxic to both the heart and overall health, and even results in death. Ethanol and its byproduct acetaldehyde can harm the cardiovascular system by impairing mitochondrial function, causing oxidative damage, and reducing contractile proteins. Endothelial cells are essential components of the cardiovascular system, are highly susceptible to ethanol, either through direct or indirect exposure. Thus, protection against endothelial injury is of great importance for persons who chronic abuse of ethanol. In this study, an in vitro model of endothelial injury was created using ethanol. The findings revealed that a concentration of 20.0 mM of ethanol reduced cell viability and Bcl-2 expression, while increasing cell apoptosis, intracellular reactive oxygen species (ROS) levels, mitochondrial depolarization, and the expression of Bax and cleaved-caspase-3 in endothelial cells. Further study showed that ethanol promoted nuclear translocation of nuclear factor kappa B (NF-κB), increased the secretion of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6 in the culture medium, and inhibited nuclear factor-erythroid 2-related factor 2 (Nrf2) signaling pathway. The aforementioned findings suggest that ethanol has a harmful impact on endothelial cells. Nevertheless, the application of epigallocatechin-3-gallate (EGCG) to the cells can effectively mitigate the detrimental effects of ethanol on endothelial cells. In conclusion, EGCG alleviates ethanol-induced endothelial injury partly through alteration of NF-κB translocation and activation of the Nrf2 signaling pathway. Therefore, EGCG holds great potential in safeguarding individuals who chronically abuse ethanol from endothelial dysfunction.

Deep-learning-based radiomics of intratumoral and peritumoral MRI images to predict the pathological features of adjuvant radiotherapy in early-stage cervical squamous cell carcinoma.

BACKGROUND: Surgery combined with radiotherapy substantially escalates the likelihood of encountering complications in early-stage cervical squamous cell carcinoma(ESCSCC). We aimed to investigate the feasibility of Deep-learning-based radiomics of intratumoral and peritumoral MRI images to predict the pathological features of adjuvant radiotherapy in ESCSCC and minimize the occurrence of adverse events associated with the treatment. METHODS: A dataset comprising MR images was obtained from 289 patients who underwent radical hysterectomy and pelvic lymph node dissection between January 2019 and April 2022. The dataset was randomly divided into two cohorts in a 4:1 ratio.The postoperative radiotherapy options were evaluated according to the Peter/Sedlis standard. We extracted clinical features, as well as intratumoral and peritumoral radiomic features, using the least absolute shrinkage and selection operator (LASSO) regression. We constructed the Clinical Signature (Clinic_Sig), Radiomics Signature (Rad_Sig) and the Deep Transformer Learning Signature (DTL_Sig). Additionally, we fused the Rad_Sig with the DTL_Sig to create the Deep Learning Radiomic Signature (DLR_Sig). We evaluated the prediction performance of the models using the Area Under the Curve (AUC), calibration curve, and Decision Curve Analysis (DCA). RESULTS: The DLR_Sig showed a high level of accuracy and predictive capability, as demonstrated by the area under the curve (AUC) of 0.98(95% CI: 0.97-0.99) for the training cohort and 0.79(95% CI: 0.67-0.90) for the test cohort. In addition, the Hosmer-Lemeshow test, which provided p-values of 0.87 for the training cohort and 0.15 for the test cohort, respectively, indicated a good fit. DeLong test showed that the predictive effectiveness of DLR_Sig was significantly better than that of the Clinic_Sig(P < 0.05 both the training and test cohorts). The calibration plot of DLR_Sig indicated excellent consistency between the actual and predicted probabilities, while the DCA curve demonstrating greater clinical utility for predicting the pathological features for adjuvant radiotherapy. CONCLUSION: DLR_Sig based on intratumoral and peritumoral MRI images has the potential to preoperatively predict the pathological features of adjuvant radiotherapy in early-stage cervical squamous cell carcinoma (ESCSCC).

Reconstruction of TNF-α with specific isoelectric point released from SPIONs basing on variable charge to enhance pH-sensitive controlled-release.

The clinical application of tumor necrosis factor-α (TNF-α) is limited by its short half-life, subeffective concentration in the targeted area and severe systemic toxicity. In this study, the recombinant polypeptide S4-TNF-α was constructed and coupled with chitosan-modified superparamagnetic iron oxide nanoparticles (S4-TNF-α-SPIONs) to achieve pH-sensitive controlled release and active tumor targeting activity. The isoelectric point (pI) of S4-TNF-α was reconstructed to approach the pH of the tumor microenvironment. The negative-charge S4-TNF-α was adsorbed to chitosan-modified superparamagnetic iron oxide nanoparticles (CS-SPIONs) with a positive charge through electrostatic adsorption at physiological pH. The acidic tumor microenvironment endowed S4-TNF-α with a zero charge, which accelerated S4-TNF-α release from CS-SPIONs. Our studies showed that S4-TNF-α-SPIONs displayed an ideal pH-sensitive controlled release capacity and improved antitumor effects. Our study presents a novel approach to enhance the pH-sensitive controlled-release of genetically engineered drugs by adjusting their pI to match the pH of the tumor microenvironment.

Aromatic Ketones as Mild Presodiating Reagents toward Cathodes for High-Performance Sodium-Ion Batteries.

Chemical presodiation (CP) is an effective strategy to enhance energy density of sodium ion batteries. However, the sodiation reagents reported so far are basically polycyclic aromatic hydrocarbons (PAHs) wth low reductive potential (~0.1 V vs. Na+ /Na), which could easily cause over-sodiation and structural deterioration of the presodiated cathodes. In this work, Aromatic ketones (AKs) are rationally designed as mild presodiating reagents by introducing a carbonyl group (C=O) into PAHs to balance the conjugated and inductive effect. As the representatives, two compounds 9-Fluorenoneb (9-FN) and Benzophenone (BP) manifest favorable equilibrium potential of 1.55 V and 1.07 V (vs. Na+ /Na), respectively. Note that 9-FN demonstrates versatile presodiating capability toward multiple Na uptake hosts (tunneled Na0.44 MnO2 , layered Na0.67 Ni0.33 Mn0.67 O2 , polyanionic Na4 Fe2.91 (PO4 )2 P2 O7 , Na3 V2 (PO4 )3 and Na3 V2 (PO4 )2 F3 ), enabling greatly improved initial charging capacity of the cathode to balance the irrevisible capacity of the anode. Our results indicate that the Aromatic ketones are competitive presodiating cathodic reagents for high-performance sodium-ion batteries, and will inspire more studies and application attempts in the future.

Comprehensive analysis on the regulation of differentially expressed of mRNA and ncRNA in different ovarian stages of ark shell Scapharca broughtonii.

BACKGROUND: Ovarian development is an important prerequisite and basis for animal reproduction. In many vertebrates, it is regulated by multiple genes and influenced by sex steroid hormones and environmental factors. However, relative information is limited in shellfish. To explore the biological functions and molecular mechanisms of mRNA and non-coding RNA that regulate ovarian development in Scapharca broughtonii, we performed whole transcriptome sequencing analysis on ovaries at three developmental stages. Furthermore, the biological processes involved in the differential expression of mRNA and ncRNA were analyzed. RESULTS: A total of 11,342 mRNAs, 6897 lncRNAs, 135 circRNAs, and 275 miRNAs were differentially expressed. By mapping the differentially expressed RNAs from the three developmental stages of Venn diagram, multiple groups of shared mRNAs and lncRNAs were found to be associated with ovarian development, with some mRNA and ncRNA functions associated with steroid hormone. In addition, we constructed and visualized the lncRNA/circRNA-miRNA-mRNA network based on ceRNA targeting relationships. CONCLUSIONS: These findings may facilitate our further understanding the mRNA and ncRNAs roles in the regulation of shellfish reproduction.

Direct Observation of Vacancy-Cluster-Mediated Hydride Nucleation and the Anomalous Precipitation Memory Effect in Zirconium.

Controlling the heterogeneous nucleation of new phases is of importance in tuning the microstructures and properties of materials. However, the role of vacancy-a popular defect in materials that is hard to be resolved under conventional electron microscopy-in the heterogeneous phase nucleation remains intriguing. Here, this work captures direct in situ experimental evidences that vacancy clusters promote the heterogeneous hydride nucleation and cause the anomalous precipitation memory effect in zirconium. Both interstitial and vacancy dislocation loops form after hydride dissolution. Interestingly, hydride reprecipitation only occurs on those vacancy loop decorated sites during cooling. Atomistic simulations reveal that hydrogen atoms are preferentially segregated at individual vacancy and vacancy clusters, which assist hydride nucleation, and stimulate the unusual memory effect during hydride reprecipitation. The finding breaks the traditional view on the sequence of heterogeneous nucleation sites and sheds light on the solid phase transformation related to vacancy-sensitive alloying elements.

Tissue fibrosis induced by radiotherapy: current understanding of the molecular mechanisms, diagnosis and therapeutic advances.

Cancer remains the leading cause of death around the world. In cancer treatment, over 50% of cancer patients receive radiotherapy alone or in multimodal combinations with other therapies. One of the adverse consequences after radiation exposure is the occurrence of radiation-induced tissue fibrosis (RIF), which is characterized by the abnormal activation of myofibroblasts and the excessive accumulation of extracellular matrix. This phenotype can manifest in multiple organs, such as lung, skin, liver and kidney. In-depth studies on the mechanisms of radiation-induced fibrosis have shown that a variety of extracellular signals such as immune cells and abnormal release of cytokines, and intracellular signals such as cGAS/STING, oxidative stress response, metabolic reprogramming and proteasome pathway activation are involved in the activation of myofibroblasts. Tissue fibrosis is extremely harmful to patients' health and requires early diagnosis. In addition to traditional serum markers, histologic and imaging tests, the diagnostic potential of nuclear medicine techniques is emerging. Anti-inflammatory and antioxidant therapies are the traditional treatments for radiation-induced fibrosis. Recently, some promising therapeutic strategies have emerged, such as stem cell therapy and targeted therapies. However, incomplete knowledge of the mechanisms hinders the treatment of this disease. Here, we also highlight the potential mechanistic, diagnostic and therapeutic directions of radiation-induced fibrosis.

ß-arrestin2 deficiency ameliorates S-100-induced autoimmune hepatitis in mice by inhibiting infiltration of monocyte-derived macrophage and attenuating hepatocyte apoptosis.

Autoimmune hepatitis (AIH) is a progressive hepatitis syndrome characterized by high transaminase levels, interface hepatitis, hypergammaglobulinemia, and the presence of autoantibodies. Misdiagnosis or delayed treatment of AIH can lead to cirrhosis or liver failure, which poses a major risk to human health. ß-Arrestin2, a key scaffold protein for intracellular signaling pathways, has been found to be involved in many autoimmune diseases such as Sjogren's syndrome and rheumatoid arthritis. However, whether ß-arrestin2 plays a role in AIH remains unknown. In the present study, S-100-induced AIH was established in both wild-type mice and ß-arrestin2 knockout (Arrb2 KO) mice, and the experiments identified that liver ß-arrestin2 expression was gradually increased, and positively correlated to serum ANA, ALT and AST levels during AIH progression. Furthermore, ß-arrestin2 deficiency ameliorated hepatic pathological damage, decreased serum autoantibody and inflammatory cytokine levels. ß-arrestin2 deficiency also inhibited hepatocyte apoptosis and prevented the infiltration of monocyte-derived macrophages into the damaged liver. In vitro experiments revealed that ß-arrestin2 knockdown suppressed the migration and differentiation of THP-1 cells, whereas ß-arrestin2 overexpression promoted the migration of THP-1 cells, which was regulated by the activation of the ERK and p38 MAPK pathways. In addition, ß-arrestin2 deficiency attenuated TNF-α-induced primary hepatocyte apoptosis by activating the Akt/GSK-3ß pathway. These results suggest that ß-arrestin2 deficiency ameliorates AIH by inhibiting the migration and differentiation of monocytes, decreasing the infiltration of monocyte-derived macrophages into the liver, thereby reducing inflammatory cytokines-induced hepatocytes apoptosis. Therefore, ß-arrestin2 may act as an effective therapeutic target for AIH.

Rapid and efficient extraction of Zn from wasted Zn-rich paint residue by indirect bioleaching and successive production of high-purity ZnCO3/ZnO by precipitation.

Waste zinc-rich paint residue (WZPR) represents a typical hazardous waste containing both toxic organic substances and heavy metals. The extraction of Zn from WZPR by traditional direct bioleaching has been attracting attention owing to its eco-friendliness, energy conservation and low cost. However, a long bioleaching time and a low Zn release cast a shadow on the reputed bioleaching. To shorten the bioleaching time, the spent medium (SM) process was first used to free Zn from WZPR in this study. The results showed that the SM process had a much higher performance in Zn extraction. Zn removals of 100% and 44.2% (8.6 g/L and 15.2 g/L in the released concentration) were gained within 24 h under pulp densities of 2.0% and 8.0%, respectively, being over 1000 times of the release performance of Zn by previously reported direct bioleaching. On the one hand, the biogenic H+ in SM attacks ZnO to liberate Zn (Ⅱ) via quick acid dissolution. On the other hand, the biogenic Fe3+ not only highly oxidizes Zn0 in WZPR to generate and release Zn2+ but also intensely hydrolyzes to produce H+ to attack ZnO for further dissolution of Zn2+. Both biogenic H+ and Fe3+ contribute to over 90% of Zn extraction as the leading indirect bioleaching mechanism. Due to the high concentration of released Zn2+ and fewer impurity, the bioleachate was used to successfully produce high-purity ZnCO3/ZnO using a simple precipitation, thus achieving the high-value recycling of Zn in WZPR.

Microbial response behavior to powdered activated carbon in high-solids anaerobic digestion of kitchen waste: Metabolism and functional prediction analysis.

Anaerobic digestion (AD) can not only treat organic waste, but also recycle energy. However, high-solids AD of kitchen waste usually failed due to excessive acidification. In this study, the effect of activated carbon (AC) on kitchen waste AD performance was investigated under high-solids conditions (total solids contents = 15%). The results showed that efficiencies of acidogenesis and methanogenesis were promoted in presence of moderate concentration (50 g/L > AC >5 g/L), but high concentration (AC >70 g/L) weakened AD performance. Moreover, AC addition enhanced the methane production rate from 66.0 mL/g VS to 231.50 mL/g VS, i.e., up to 250.7%. High-throughput sequencing results demonstrated that the abundance of electroactive DMER64 increased from less than 1%-29.7% (20 g/L AC). As AC gradually increased，aceticlastic methanogenesis changed to hydrogenotrophic pathway. Predicted functional analysis indicated that AC can enhance abundances of energy and inorganic ion metabolism, resulting in high methane production.

Facile manufacture of high-purity CuSO4 from waste Cu-containing paint residue using combined processes of H2SO4 leaching and extraction stripping.

Waste copper-containing paint residue (WCPR) represents a typical hazardous waste containing both toxic organic substances and toxic heavy metals, but there are few reports on the recycling of heavy metals. The recovery of Cu from WCPR by H2SO4 leaching-extraction-stripping has the advantages of eco-friendliness, simplicity of operation, and high value-added product. The results show that under the optimal conditions, the leaching rate of Cu in WCPR is 94.31% (18.02 g/L), while the extraction and stripping rates of Cu in the leaching solution are 99.46 and 95.32%, respectively. Due to the high concentration of Cu2+ with fewer impurities in the stripping solution, the stripping solution is heated, evaporated, cooled, and crystallized to successfully produce high-purity dark blue CuSO4 crystal, accomplishing the high-value recycling of Cu in WCPR. In addition, the leach residue of WCPR contains acrylic resin and SiO2, which can be used in cement kilns for incineration, thus realizing the overall recycling and utilization of WCPR.

Digital Gonioscopy Based on Three-dimensional Anterior-Segment OCT: An International Multicenter Study.

PURPOSE: To develop and evaluate the performance of a 3-dimensional (3D) deep-learning-based automated digital gonioscopy system (DGS) in detecting 2 major characteristics in eyes with suspected primary angle-closure glaucoma (PACG): (1) narrow iridocorneal angles (static gonioscopy, Task I) and (2) peripheral anterior synechiae (PAS) (dynamic gonioscopy, Task II) on OCT scans. DESIGN: International, cross-sectional, multicenter study. PARTICIPANTS: A total of 1.112 million images of 8694 volume scans (2294 patients) from 3 centers were included in this study (Task I, training/internal validation/external testing: 4515, 1101, and 2222 volume scans, respectively; Task II, training/internal validation/external testing: 378, 376, and 102 volume scans, respectively). METHODS: For Task I, a narrow angle was defined as an eye in which the posterior pigmented trabecular meshwork was not visible in more than 180° without indentation in the primary position captured in the dark room from the scans. For Task II, PAS was defined as the adhesion of the iris to the trabecular meshwork. The diagnostic performance of the 3D DGS was evaluated in both tasks with gonioscopic records as reference. MAIN OUTCOME MEASURES: The area under the curve (AUC), sensitivity, and specificity of the 3D DGS were calculated. RESULTS: In Task I, 29.4% of patients had a narrow angle. The AUC, sensitivity, and specificity of 3D DGS on the external testing datasets were 0.943 (0.933-0.953), 0.867 (0.838-0.895), and 0.878 (0.859-0.896), respectively. For Task II, 13.8% of patients had PAS. The AUC, sensitivity, and specificity of 3D DGS were 0.902 (0.818-0.985), 0.900 (0.714-1.000), and 0.890 (0.841-0.938), respectively, on the external testing set at quadrant level following normal clinical practice; and 0.885 (0.836-0.933), 0.912 (0.816-1.000), and 0.700 (0.660-0.741), respectively, on the external testing set at clock-hour level. CONCLUSIONS: The 3D DGS is effective in detecting eyes with suspected PACG. It has the potential to be used widely in the primary eye care community for screening of subjects at high risk of developing PACG.

Correlated Insulators, Density Wave States, and Their Nonlinear Optical Response in Magic-Angle Twisted Bilayer Graphene.

The correlated insulator (CI) states and the recently discovered density wave (DW) states in magic-angle twisted bilayer graphene (TBG) have stimulated intense research interest. However, to date, the nature of these "featureless" correlated states with zero Chern numbers are still elusive and lack a characteristic experimental signature. Thus, an experimental probe to identify the characters of these featureless CI and DW states is urgently needed. In this Letter, we theoretically study the correlated insulators and density wave states at different integer and fractional fillings of the flat bands in magic-angle TBG based on extended unrestricted Hartree-Fock calculations including the Coulomb screening effects from the remote bands. We further investigate the nonlinear optical response of the various correlated states and find that the nonlinear optical conductivities can be used to identify the nature of these CI and DW states at most of the fillings. Therefore, we propose that a nonlinear optical response can serve as a promising experimental probe for unveiling the nature of the CI and DW states observed in magic-angle TBG.

Spin-Polarized Nematic Order, Quantum Valley Hall States, and Field-Tunable Topological Transitions in Twisted Multilayer Graphene Systems.

We theoretically study the correlated insulator states, quantum anomalous Hall (QAH) states, and field-induced topological transitions between different correlated states in twisted multilayer graphene systems. Taking twisted bilayer-monolayer graphene and twisted double-bilayer graphene as examples, we show that both systems stay in spin-polarized, C_{3z}-broken insulator states with zero Chern number at 1/2 filling of the flat bands under finite displacement fields. In some cases these spin-polarized, nematic insulator states are in the quantum valley Hall (QVH) phase by virtue of the nontrivial band topology of the systems. The spin-polarized insulator state is quasidegenerate with the valley polarized state if only the dominant intravalley Coulomb interaction is included. Such quasidegeneracy can be split by atomic on-site interactions such that the spin-polarized, nematic state become the unique ground state. Such a scenario applies to various twisted multilayer graphene systems at 1/2 filling, thus can be considered as a universal mechanism. Moreover, under vertical magnetic fields, the orbital Zeeman splittings and the field-induced change of charge density in twisted multilayer graphene systems would compete with the atomic Hubbard interactions, which can drive transitions from spin-polarized zero-Chern-number states to valley-polarized QAH states with small onset magnetic fields.