Traditional Chinese medicine formulae: A complementary method for the treatment of polycystic ovary syndrome.

ETHNOPHARMACOLOGICAL RELEVANCE: Polycystic ovary syndrome (PCOS) is a prevalent female endocrine condition that significantly affects women of all age groups and is characterized by metabolic dysfunction. The efficacy of existing pharmaceutical interventions for the treatment of PCOS remains inadequate. With a rich history and cultural significance spanning thousands of years, Traditional Chinese Medicine (TCM) is extensively employed for treating a variety of ailments and can serve as a supplementary therapy for managing PCOS. Multiple clinical observations and laboratory tests have unequivocally demonstrated the substantial effectiveness and safety of TCM formulae in treating PCOS, and further investigations are currently in progress. AIM OF THE STUDY: To summarize the TCM formulae commonly employed in the clinical management of PCOS, examine their therapeutic benefits, investigate their mechanism of action, active constituents, and establish the correlation between efficacy, mechanism of action, and active constituents. MATERIALS AND METHODS: We conducted a comprehensive search on PubMed, Web of Science, and China national knowledge infrastructure (CNKI) using the following keywords: "Polycystic Ovary Syndrome", "Traditional Chinese Medicine Decoctions", "Traditional Chinese Medicine formulae", "Traditional Chinese Medicine", "Clinical Observation", "Mechanism", "Treatment", "Pharmacology", and various combinations of these terms. From January 1, 2006 until October 7, 2023, (inclusive). RESULTS: This paper summarized the clinical effectiveness, mechanism of action, and active components of 8 TCM formulae for the treatment of PCOS. Our research indicates that TCM formulae can potentially treat PCOS by enhancing the levels of hyperandrogenism and other endocrine hormones, decreasing insulin resistance and hyperinsulinemia, and controlling chronic low-grade inflammation, among other modes of action. In addition, we found an association between epigenetics and TCM formulae for the treatment of PCOS. CONCLUSION: TCM formulae have specific advantages in the treatment of Polycystic Ovary Syndrome (PCOS). They achieve therapeutic benefits by targeting several pathways and connections, attracting considerable interest and playing a vital role in the treatment of PCOS. TCM formulae can be used as an adjunctive therapy for the treatment of PCOS.

Research progress on composite material of bismuth vanadate catalyzing the decomposition of Quinolone antibiotics.

Since quinolone is a kind of synthetic broad-spectrum antibacterial drugs, with the widespread use of this class of antibiotics, the risk and harm to human health have been attendant to the sewage containing quinolones which are discharged into the environment. Photocatalysis is considered as a promising technology for antibiotic degradation for its strong redox properties and reaction rate. As a metal oxidizing substance, Bismuth vanadate (BiVO4) is such a popular and hot material for the degradation of organic pollutants recently due to its good photocatalytic activity and chemical stability. Numerous studies have confirmed that BiVO4 composites can overcome the shortcomings of pure BiVO4 and cleave the main structure of quinolone under photocatalytic conditions. This paper mainly outlines the research progress on the preparation of BiVO4 composites and the degradation of quinolone antibiotics from the perspective of improving the catalysis and degrading the efficiency mechanism of BiVO4 composites.

Imaging inter-valley coherent order in magic-angle twisted trilayer graphene.

Magic-angle twisted trilayer graphene (MATTG) exhibits a range of strongly correlated electronic phases that spontaneously break its underlying symmetries1,2. Here we investigate the correlated phases of MATTG using scanning tunnelling microscopy and identify marked signatures of interaction-driven spatial symmetry breaking. In low-strain samples, over a filling range of about two to three electrons or holes per moiré unit cell, we observe atomic-scale reconstruction of the graphene lattice that accompanies a correlated gap in the tunnelling spectrum. This short-scale restructuring appears as a Kekulé supercell-implying spontaneous inter-valley coherence between electrons-and persists in a wide range of magnetic fields and temperatures that coincide with the development of the gap. Large-scale maps covering several moiré unit cells further reveal a slow evolution of the Kekulé pattern, indicating that atomic-scale reconstruction coexists with translation symmetry breaking at a much longer moiré scale. We use auto-correlation and Fourier analyses to extract the intrinsic periodicity of these phases and find that they are consistent with the theoretically proposed incommensurate Kekulé spiral order3,4. Moreover, we find that the wavelength characterizing moiré-scale modulations monotonically decreases with hole doping away from half-filling of the bands and depends weakly on the magnetic field. Our results provide essential insights into the nature of the correlated phases of MATTG in the presence of strain and indicate that superconductivity can emerge from an inter-valley coherent parent state.

Light-Induced Giant Rashba Spin-Orbit Coupling at Superconducting KTaO3 (110) Heterointerfaces.

The 2D electron system (2DES) at the KTaO3 surface or heterointerface with 5d orbitals hosts extraordinary physical properties, including a stronger Rashba spin-orbit coupling (RSOC), higher superconducting transition temperature, and potential of topological superconductivity. Herein, a huge enhancement of RSOC under light illumination achieved at a superconducting amorphous-Hf0.5 Zr0.5 O2 /KTaO3 (110) heterointerfaces is reported. The superconducting transition is observed with Tc = 0.62 K and the temperature-dependent upper critical field reveals the interaction between spin-orbit scattering and superconductivity. A strong RSOC with Bso = 1.9 T is revealed by weak antilocalization in the normal state, which undergoes sevenfold enhancement under light illumination. Furthermore, RSOC strength develops a dome-shaped dependence of carrier density with the maximum of Bso = 12.6 T achieved near the Lifshitz transition point nc ≈ 4.1 × 1013 cm-2 . The highly tunable giant RSOC at KTaO3 (110)-based superconducting interfaces show great potential for spintronics.

FGL2-targeting T cells exhibit antitumor effects on glioblastoma and recruit tumor-specific brain-resident memory T cells.

Although tissue-resident memory T (TRM) cells specific for previously encountered pathogens have been characterized, the induction and recruitment of brain TRM cells following immune therapy has not been observed in the context of glioblastoma. Here, we show that T cells expressing fibrinogen-like 2 (FGL2)-specific single-chain variable fragments (T-αFGL2) can induce tumor-specific CD8+ TRM cells that prevent glioblastoma recurrence. These CD8+ TRM cells display a highly expanded T cell receptor repertoire distinct from that found in peripheral tissue. When adoptively transferred to the brains of either immunocompetent or T cell-deficient naïve mice, these CD8+ TRM cells reject glioma cells. Mechanistically, T-αFGL2 cell treatment increased the number of CD69+CD8+ brain-resident memory T cells in tumor-bearing mice via a CXCL9/10 and CXCR3 chemokine axis. These findings suggest that tumor-specific brain-resident CD8+ TRM cells may have promising implications for the prevention of brain tumor recurrence.

A Case Study of Chimeric Antigen Receptor T Cell Function: Donor Therapeutic Differences in Activity and Modulation with Verteporfin.

BACKGROUND: Chimeric antigen receptor (CAR) T cells have recently been demonstrated to extract and express cognate tumor antigens through trogocytosis. This process may contribute to tumor antigen escape, T cell exhaustion, and fratricide, which plays a central role in CAR dysfunction. We sought to evaluate the importance of this effect in epidermal growth factor receptor variant III (EGFRvIII) specific CAR T cells targeting glioma. METHODS: EGFRvIII-specific CAR T cells were generated from various donors and analyzed for cytotoxicity, trogocytosis, and in vivo therapeutic activity against intracranial glioma. Tumor autophagy resulting from CAR T cell activity was evaluated in combination with an autophagy inducer (verteporfin) or inhibitor (bafilomycin A1). RESULTS: CAR T cell products derived from different donors induced markedly divergent levels of trogocytosis of tumor antigen as well as PD-L1 upon engaging target tumor cells correlating with variability in efficacy in mice. Pharmacological facilitation of CAR induced-autophagy with verteporfin inhibits trogocytic expression of tumor antigen on CARs and increases CAR persistence and efficacy in mice. CONCLUSION: These data propose CAR-induced autophagy as a mechanism counteracting CAR-induced trogocytosis and provide a new strategy to innovate high-performance CARs through pharmacological facilitation of T cell-induced tumor death.

The W-Acidic Motif of Histidine Kinase WalK Is Required for Signaling and Transcriptional Regulation in Streptococcus mutans.

In Streptococcus mutans, we find that the histidine kinase WalK possesses the longest C-terminal tail (CTT) among all 14 TCSs, and this tail plays a key role in the interaction of WalK with its response regulator WalR. We demonstrate that the intrinsically disordered CTT is characterized by a conserved tryptophan residue surrounded by acidic amino acids. Mutation in the tryptophan not only disrupts the stable interaction, but also impairs the efficient phosphotransferase and phosphatase activities of WalRK. In addition, the tryptophan is important for WalK to compete with DNA containing a WalR binding motif for the WalR interaction. We further show that the tryptophan is important for in vivo transcriptional regulation and bacterial biofilm formation by S. mutans. Moreover, Staphylococcus aureus WalK also has a characteristic CTT, albeit relatively shorter, with a conserved W-acidic motif, that is required for the WalRK interaction in vitro. Together, these data reveal that the W-acidic motif of WalK is indispensable for its interaction with WalR, thereby playing a key role in the WalRK-dependent signal transduction, transcriptional regulation and biofilm formation.

Two distinct superconducting states controlled by orientations of local wrinkles in LiFeAs.

For iron-based superconductors, the phase diagrams under pressure or strain exhibit emergent phenomena between unconventional superconductivity and other electronic orders, varying in different systems. As a stoichiometric superconductor, LiFeAs has no structure phase transitions or entangled electronic states, which manifests an ideal platform to explore the pressure or strain effect on unconventional superconductivity. Here, we observe two types of superconducting states controlled by orientations of local wrinkles on the surface of LiFeAs. Using scanning tunneling microscopy/spectroscopy, we find type-I wrinkles enlarge the superconducting gaps and enhance the transition temperature, whereas type-II wrinkles significantly suppress the superconducting gaps. The vortices on wrinkles show a C2 symmetry, indicating the strain effects on the wrinkles. By statistics, we find that the two types of wrinkles are categorized by their orientations. Our results demonstrate that the local strain effect with different directions can tune the superconducting order parameter of LiFeAs very differently, suggesting that the band shifting induced by directional pressure may play an important role in iron-based superconductivity.

Demonstration of the role of cell wall homeostasis in Staphylococcus aureus growth and the action of bactericidal antibiotics.

Bacterial cell wall peptidoglycan is essential, maintaining both cellular integrity and morphology, in the face of internal turgor pressure. Peptidoglycan synthesis is important, as it is targeted by cell wall antibiotics, including methicillin and vancomycin. Here, we have used the major human pathogen Staphylococcus aureus to elucidate both the cell wall dynamic processes essential for growth (life) and the bactericidal effects of cell wall antibiotics (death) based on the principle of coordinated peptidoglycan synthesis and hydrolysis. The death of S. aureus due to depletion of the essential, two-component and positive regulatory system for peptidoglycan hydrolase activity (WalKR) is prevented by addition of otherwise bactericidal cell wall antibiotics, resulting in stasis. In contrast, cell wall antibiotics kill via the activity of peptidoglycan hydrolases in the absence of concomitant synthesis. Both methicillin and vancomycin treatment lead to the appearance of perforating holes throughout the cell wall due to peptidoglycan hydrolases. Methicillin alone also results in plasmolysis and misshapen septa with the involvement of the major peptidoglycan hydrolase Atl, a process that is inhibited by vancomycin. The bactericidal effect of vancomycin involves the peptidoglycan hydrolase SagB. In the presence of cell wall antibiotics, the inhibition of peptidoglycan hydrolase activity using the inhibitor complestatin results in reduced killing, while, conversely, the deregulation of hydrolase activity via loss of wall teichoic acids increases the death rate. For S. aureus, the independent regulation of cell wall synthesis and hydrolysis can lead to cell growth, death, or stasis, with implications for the development of new control regimes for this important pathogen.

Majorana zero modes in impurity-assisted vortex of LiFeAs superconductor.

The iron-based superconductor is emerging as a promising platform for Majorana zero mode, which can be used to implement topological quantum computation. One of the most significant advances of this platform is the appearance of large vortex level spacing that strongly protects Majorana zero mode from other low-lying quasiparticles. Despite the advantages in the context of physics research, the inhomogeneity of various aspects hampers the practical construction of topological qubits in the compounds studied so far. Here we show that the stoichiometric superconductor LiFeAs is a good candidate to overcome this obstacle. By using scanning tunneling microscopy, we discover that the Majorana zero modes, which are absent on the natural clean surface, can appear in vortices influenced by native impurities. Our detailed analysis reveals a new mechanism for the emergence of those Majorana zero modes, i.e. native tuning of bulk Dirac fermions. The discovery of Majorana zero modes in this homogeneous material, with a promise of tunability, offers an ideal material platform for manipulating and braiding Majorana zero modes, pushing one step forward towards topological quantum computation.

Opening of the Blood-Brain Barrier Using Low-Intensity Pulsed Ultrasound Enhances Responses to Immunotherapy in Preclinical Glioma Models.

PURPOSE: The blood-brain barrier (BBB) inhibits adequate dosing/penetration of therapeutic agents to malignancies in the brain. Low-intensity pulsed ultrasound (LIPU) is a safe therapeutic method of temporary BBB disruption (BBBD) to enhance chemotherapeutic delivery to the tumor and surrounding brain parenchyma for treatment of glioblastoma. EXPERIMENTAL DESIGN: We investigated if LIPU could enhance therapeutic efficacy of anti-PD-1 in C57BL/6 mice bearing intracranial GL261 gliomas, epidermal growth factor receptor variant III (EGFRvIII) chimeric antigen receptor (CAR) T cells in NSG mice with EGFRvIII-U87 gliomas, and a genetically engineered antigen-presenting cell (APC)-based therapy producing the T-cell attracting chemokine CXCL10 in the GL261-bearing mice. RESULTS: Mice treated with anti-PD-1 and LIPU-induced BBBD had a median survival duration of 58 days compared with 39 days for mice treated with anti-PD-1, and long-term survivors all remained alive after contralateral hemisphere rechallenge. CAR T-cell administration with LIPU-induced BBBD resulted in significant increases in CAR T-cell delivery to the CNS after 24 (P < 0.005) and 72 (P < 0.001) hours and increased median survival by greater than 129%, in comparison with CAR T cells alone. Local deposition of CXCL10-secreting APCs in the glioma microenvironment with LIPU enhanced T-cell glioma infiltration during the therapeutic window (P = 0.004) and markedly enhanced survival (P < 0.05). CONCLUSIONS: LIPU increases immune therapeutic delivery to the tumor microenvironment with an associated increase in survival and is an emerging technique for enhancing novel therapies in the brain.

Observation of magnetic adatom-induced Majorana vortex and its hybridization with field-induced Majorana vortex in an iron-based superconductor.

Braiding Majorana zero modes is essential for fault-tolerant topological quantum computing. Iron-based superconductors with nontrivial band topology have recently emerged as a surprisingly promising platform for creating distinct Majorana zero modes in magnetic vortices in a single material and at relatively high temperatures. The magnetic field-induced Abrikosov vortex lattice makes it difficult to braid a set of Majorana zero modes or to study the coupling of a Majorana doublet due to overlapping wave functions. Here we report the observation of the proposed quantum anomalous vortex with integer quantized vortex core states and the Majorana zero mode induced by magnetic Fe adatoms deposited on the surface. We observe its hybridization with a nearby field-induced Majorana vortex in iron-based superconductor FeTe0.55Se0.45. We also observe vortex-free Yu-Shiba-Rusinov bound states at the Fe adatoms with a weaker coupling to the substrate, and discover a reversible transition between Yu-Shiba-Rusinov states and Majorana zero mode by manipulating the exchange coupling strength. The dual origin of the Majorana zero modes, from magnetic adatoms and external magnetic field, provides a new single-material platform for studying their interactions and braiding in superconductors bearing topological band structures.

Regulation of tumor immune suppression and cancer cell survival by CXCL1/2 elevation in glioblastoma multiforme.

The invasiveness and high immune suppression of glioblastoma multiforme (GBM) produce poor survival of afflicted patients. Unfortunately, in the past decades, no therapeutic approach has remarkably improved the survival time of patients with GBM. Our analysis of the TCGA database and brain tumor tissue arrays indicated that CXCL1 and CXCL2 overexpression is closely associated with GBM's aggressiveness. Our results showed that elevation of CXCL1 or CXCL2 facilitated myeloid cell migration and simultaneously disrupted CD8+ T cell accumulation at tumor sites, causing accelerated tumor progression. Yet, blockade of CXCL1/2 significantly prevented myeloid-derived suppressor cell migration and thereby increased CD8+ T cell accumulation in vitro and in vivo. CXCL1/2 also promoted the paracrine factor S100A9 and further activated Erk1/2 and p70S60k, whereas blocking CXCL1/2 down-regulated these prosurvival factors. The combination of targeting CXCL1/2 and standard temozolomide chemotherapy improved upon the antitumor efficacy of chemotherapy alone, extending the overall survival time in GBM.

MiR-181 Family Modulates Osteopontin in Glioblastoma Multiforme.

MiRNAs can silence a wide range of genes, which may be an advantage for targeting heterogenous tumors like glioblastoma. Osteopontin (OPN) plays both an oncogenic role in a variety of cancers and can immune modulate macrophages. We conducted a genome wide profiling and bioinformatic analysis to identify miR-181a/b/c/d as potential miRNAs that target OPN. Luciferase assays confirmed the binding potential of miRNAs to OPN. Expression levels of miR-181a/b/c/d and OPN were evaluated by using quantitative real-time PCR and enzyme-linked immunosorbent assay in mouse and human glioblastomas and macrophages that showed these miRNAs were downregulated in Glioblastoma associated CD11b+ cells compared to their matched blood CD14b+ cells. miRNA mimicking and overexpression using lentiviruses showed that MiR-181a overexpression in glioblastoma cells led to decreased OPN production and proliferation and increased apoptosis in vitro. MiR-181a treatment of immune competent mice bearing intracranial glioblastoma demonstrated a 22% increase in median survival duration relative to that of control mice.

A new Majorana platform in an Fe-As bilayer superconductor.

Iron-chalcogenide superconductors have emerged as a promising Majorana platform for topological quantum computation. By combining topological band and superconductivity in a single material, they provide significant advantage to realize isolated Majorana zero modes. However, iron-chalcogenide superconductors, especially Fe(Te,Se), suffer from strong inhomogeneity which may hamper their practical application. In addition, some iron-pnictide superconductors have been demonstrated to have topological surface states, yet no Majorana zero mode has been observed inside their vortices, raising a question of universality about this new Majorana platform. In this work, through angle-resolved photoemission spectroscopy and scanning tunneling microscopy/spectroscopy measurement, we identify Dirac surface states and Majorana zero modes, respectively, for the first time in an iron-pnictide superconductor, CaKFe4As4. More strikingly, the multiple vortex bound states with integer-quantization sequences can be accurately reproduced by our model calculation, firmly establishing Majorana nature of the zero mode.

Radiation with STAT3 Blockade Triggers Dendritic Cell-T cell Interactions in the Glioma Microenvironment and Therapeutic Efficacy.

PURPOSE: Patients with central nervous system (CNS) tumors are typically treated with radiotherapy, but this is not curative and results in the upregulation of phosphorylated STAT3 (p-STAT3), which drives invasion, angiogenesis, and immune suppression. Therefore, we investigated the combined effect of an inhibitor of STAT3 and whole-brain radiotherapy (WBRT) in a murine model of glioma. EXPERIMENTAL DESIGN: C57BL/6 mice underwent intracerebral implantation of GL261 glioma cells, WBRT, and treatment with WP1066, a blood-brain barrier-penetrant inhibitor of the STAT3 pathway, or the two in combination. The role of the immune system was evaluated using tumor rechallenge strategies, immune-incompetent backgrounds, immunofluorescence, immune phenotyping of tumor-infiltrating immune cells (via flow cytometry), and NanoString gene expression analysis of 770 immune-related genes from immune cells, including those directly isolated from the tumor microenvironment. RESULTS: The combination of WP1066 and WBRT resulted in long-term survivors and enhanced median survival time relative to monotherapy in the GL261 glioma model (combination vs. control P < 0.0001). Immunologic memory appeared to be induced, because mice were protected during subsequent tumor rechallenge. The therapeutic effect of the combination was completely lost in immune-incompetent animals. NanoString analysis and immunofluorescence revealed immunologic reprograming in the CNS tumor microenvironment specifically affecting dendritic cell antigen presentation and T-cell effector functions. CONCLUSIONS: This study indicates that the combination of STAT3 inhibition and WBRT enhances the therapeutic effect against gliomas in the CNS by inducing dendritic cell and T-cell interactions in the CNS tumor.

Profiling of patients with glioma reveals the dominant immunosuppressive axis is refractory to immune function restoration.

In order to prioritize available immune therapeutics, immune profiling across glioma grades was conducted, followed by preclinical determinations of therapeutic effect in immune-competent mice harboring gliomas. T cells and myeloid cells were isolated from the blood of healthy donors and the blood and tumors from patients with glioma and profiled for the expression of immunomodulatory targets with an available therapeutic. Murine glioma models were used to assess therapeutic efficacy of agents targeting the most frequently expressed immune targets. In patients with glioma, the A2aR/CD73/CD39 pathway was most frequently expressed, followed by the PD-1 pathway. CD73 expression was upregulated on immune cells by 2-hydroxyglutarate in IDH1 mutant glioma patients. In murine glioma models, adenosine receptor inhibitors demonstrated a modest therapeutic response; however, the addition of other inhibitors of the adenosine pathway did not further enhance this therapeutic effect. Although adenosine receptor inhibitors could recover immunological effector functions in T cells, immune recovery was impaired in the presence of gliomas, indicating that irreversible immune exhaustion limits the effectiveness of adenosine pathway inhibitors in patients with glioma. This study illustrates vetting steps that should be considered before clinical trial implementation for immunotherapy-resistant cancers, including testing an agent's ability to restore immunological function in the context of intended use.

Anti-PD-1 Induces M1 Polarization in the Glioma Microenvironment and Exerts Therapeutic Efficacy in the Absence of CD8 Cytotoxic T Cells.

PURPOSE: Anti-programmed cell death protein 1 (PD-1) therapy has demonstrated inconsistent therapeutic results in patients with glioblastoma (GBM) including those with profound impairments in CD8 T-cell effector responses. EXPERIMENTAL DESIGN: We ablated the CD8α gene in BL6 mice and intercrossed them with Ntv-a mice to determine how CD8 T cells affect malignant progression in forming endogenous gliomas. Tumor-bearing mice were treated with PD-1 to determine the efficacy of this treatment in the absence of T cells. The tumor microenvironment of treated and control mice was analyzed by IHC and FACS. RESULTS: We observed a survival benefit in immunocompetent mice with endogenously arising intracranial glioblastomas after intravenous administration of anti-PD-1. The therapeutic effect of PD-1 administration persisted in mice even after genetic ablation of the CD8 gene (CD8-/-). CD11b+ and Iba1+ monocytes and macrophages were enriched in the glioma microenvironment of the CD8-/- mice. The macrophages and microglia assumed a proinflammatory M1 response signature in the setting of anti-PD-1 blockade through the elimination of PD-1-expressing macrophages and microglia in the tumor microenvironment. Anti-PD-1 can inhibit the proliferation of and induce apoptosis of microglia through antibody-dependent cellular cytotoxicity, as fluorescently labeled anti-PD-1 was shown to gain direct access to the glioma microenvironment. CONCLUSIONS: Our results show that the therapeutic effect of anti-PD-1 blockade in GBM may be mediated by the innate immune system, rather than by CD8 T cells. Anti-PD-1 immunologically modulates innate immunity in the glioma microenvironment-likely a key mode of activity.

Nearly quantized conductance plateau of vortex zero mode in an iron-based superconductor.

Majorana zero modes (MZMs) are spatially localized, zero-energy fractional quasiparticles with non-Abelian braiding statistics that hold promise for topological quantum computing. Owing to the particle-antiparticle equivalence, MZMs exhibit quantized conductance at low temperature. By using variable-tunnel-coupled scanning tunneling spectroscopy, we studied tunneling conductance of vortex bound states on FeTe0.55Se0.45 superconductors. We report observations of conductance plateaus as a function of tunnel coupling for zero-energy vortex bound states with values close to or even reaching the 2e 2/h quantum conductance (where e is the electron charge and h is Planck's constant). By contrast, no plateaus were observed on either finite energy vortex bound states or in the continuum of electronic states outside the superconducting gap. This behavior of the zero-mode conductance supports the existence of MZMs in FeTe0.55Se0.45.