Single Molecular Nanomedicines Based on Macrocyclic Carrier-Drug Conjugates for Concentration-Independent Encapsulation and Precise Activation of Drugs.

Nanomedicines often rely on noncovalent self-assembly and encapsulation for drug loading and delivery. However, challenges such as reproducibility issues due to the multicomponent nature, off-target activation caused by premature drug release, and complex pharmacokinetics arising from assembly dissociation have hindered their clinical translation. In this study, we introduce an innovative design concept termed single molecular nanomedicine (SMNM) based on macrocyclic carrier-drug conjugates. Through the covalent linkage of two chemotherapy drugs to a hypoxia-cleavable macrocyclic carrier, azocalix[4]arene, we obtained two self-included complexes to serve as SMNMs. The intramolecular inclusion feature of the SMNMs has not only demonstrated comprehensive shielding and protection for the drugs but also effectively prevented off-target drug leakage, thereby significantly reducing their side effects and enhancing their antitumor therapeutic efficacy. Additionally, the attributes of being a single component and molecularly dispersed confer advantages such as ease of preparation and good reproducibility for SMNMs, which is desirable for clinical applications.

An angel or a devil? Current view on the role of CD8+ T cells in the pathogenesis of myasthenia gravis.

BACKGROUND: Myasthenia gravis (MG) and the experimental autoimmune MG (EAMG) animal model are characterized by T-cell-induced and B-cell-dominated autoimmune diseases that affect the neuromuscular junction. Several subtypes of CD4+ T cells, including T helper (Th) 17 cells, follicular Th cells, and regulatory T cells (Tregs), contribute to the pathogenesis of MG. However, increasing evidence suggests that CD8+ T cells also play a critical role in the pathogenesis and treatment of MG. MAIN BODY: Herein, we review the literature on CD8+ T cells in MG, focusing on their potential effector and regulatory roles, as well as on relevant evidence (peripheral, in situ, cerebrospinal fluid, and under different treatments), T-cell receptor usage, cytokine and chemokine expression, cell marker expression, and Treg, Tc17, CD3+CD8+CD20+ T, and CXCR5+ CD8+ T cells. CONCLUSIONS: Further studies on CD8+ T cells in MG are necessary to determine, among others, the real pattern of the Vß gene usage of autoantigen-specific CD8+ cells in patients with MG, real images of the physiology and function of autoantigen-specific CD8+ cells from MG/EAMG, and the subset of autoantigen-specific CD8+ cells (Tc1, Tc17, and IL-17+IFN-γ+CD8+ T cells). There are many reports of CD20-expressing T (or CD20 + T) and CXCR5+ CD8 T cells on autoimmune diseases, especially on multiple sclerosis and rheumatoid arthritis. Unfortunately, up to now, there has been no report on these T cells on MG, which might be a good direction for future studies.

Bioinformatic prediction of the stereoselectivity of modular polyketide synthase: an update of the sequence motifs in ketoreductase domain.

Polyketides are a major class of natural products, including bioactive medicines such as erythromycin and rapamycin. They are often rich in stereocenters biosynthesized by the ketoreductase (KR) domain within the polyketide synthase (PKS) assembly line. Previous studies have identified conserved motifs in KR sequences that enable the bioinformatic prediction of product stereochemistry. However, the reliability and applicability of these prediction methods have not been thoroughly assessed. In this study, we conducted a comprehensive bioinformatic analysis of 1,762 KR sequences from cis-AT PKSs to reevaluate the residues involved in conferring stereoselectivity. Our findings indicate that the previously identified fingerprint motifs remain valid for KRs in ß-modules from actinobacteria, but their reliability diminishes for KRs from other module types or taxonomic origins. Additionally, we have identified several new motifs that exhibit a strong correlation with the stereochemical outcomes of KRs. These updated fingerprint motifs for stereochemical prediction not only enhance our understanding of the enzymatic mechanisms governing stereocontrol but also facilitate accurate stereochemical prediction and genome mining of polyketides derived from modular cis-AT PKSs.

Anti-mesothelin CAR-T immunotherapy in patients with ovarian cancer.

Recently, chimeric antigen receptor T cell (CAR-T) therapy has received increasing attention as an adoptive cellular immunotherapy that targets tumors. However, numerous challenges remain for the effective use of CAR-T to treat solid tumors, including ovarian cancer, which is an aggressive and metastatic cancer with a poor therapeutic response. We screened for an effective anti-MSLN single-chain Fv antibody with comparable binding activity and non-off-target properties using human phage display library. A second-generation of anti-MSLN CAR was designed and generated. We demonstrated the efficacy of our anti-MSLN CAR-T cells for ovarian cancer treatment in an in vitro experiment to kill ovarian tumor cell lines. The anti-MSLN CAR-T cells impeded MSLN-positive tumor growth concomitant with a significant increase in cytokine levels compared with the control. Then, we demonstrated the efficacy of anti-MSLN CAR-T cells in an in vivo experiment against ovarian cancer cell-derived xenografts. Furthermore, we herein report three cases with ovarian cancer who were treated with autologous anti-MSLN CAR-T cells and evaluate the safety and effectiveness of adoptive cell therapy. In this investigator-initiated clinical trials, no patients experienced cytokine release syndrome or neurological symptoms over 2 grads. Disease stabilized in two patients, with progression-free survival times of 5.8 and 4.6 months. Transient CAR expression was detected in patient blood after infusion each time. The tumor partially subsided, and the patient's condition was relieved. In conclusion, this work proves the efficacy of the anti-MSLN CAR-T treatment strategy in ovarian cancer and provides preliminary data for the development of further clinical trials.

Hypoxia and Matrix Metalloproteinase 13-Responsive Hydrogel Microspheres Alleviate Osteoarthritis Progression In Vivo.

The occurrence of osteoarthritis (OA) is highly associated with the inflammatory hypoxic microenvironment. Yet currently no attention has been paid to fabricating hypoxia-responsive platforms for OA treatment. Herein, an injectable hydrogel microsphere system (HAM-SA@HCQ) focusing on the hypoxic inflamed joint is prepared with methacrylate-modified sulfonated azocalix[4]arene (SAC4A-MA), methacrylated hyaluronic acid (HA-MA), and dithiol-terminated matrix metalloproteinase 13 (MMP-13) sensitive peptide via a microfluidic device and photo crosslinking technique, followed by encapsulation of the anti-inflammatory drug hydroxychloroquine (HCQ) through host-guest interaction. Owing to the hydrophobic deep cavity, phenolic units, and azo bonds of SAC4A-MA, the hydrogel microspheres show strong drug loading capacity, prominent reactive oxygen species (ROS) scavenging capability, and specific hypoxia-responsive drug release ability. In the OA tissue microenvironment, the hydrogel microspheres undergo degradation by excessive MMP-13 and release HCQ under the hypoxia condition, which synergizes with the ROS-scavenging calixarene to inhibit the inflammatory response of macrophages. After being injected into the OA-inflamed joint, the HAM-SA@HCQ can significantly attenuate the oxidative stress, downregulate the expression of hypoxia-induced factor-1α and inflammatory cytokines, and prevent the cartilage from being destroyed.

Synergistic Interplay of Dual-Active-Sites on Metallic Ni-MOFs Loaded with Pt for Thermal-Photocatalytic Conversion of Atmospheric CO2 under Infrared Light Irradiation.

Infrared light driven photocatalytic reduction of atmospheric CO2 is challenging due to the ultralow concentration of CO2 (0.04 %) and the low energy of infrared light. Herein, we develop a metallic nickel-based metal-organic framework loaded with Pt (Pt/Ni-MOF), which shows excellent activity for thermal-photocatalytic conversion of atmospheric CO2 with H2 even under infrared light irradiation. The open Ni sites are beneficial to capture and activate atmospheric CO2 , while the photogenerated electrons dominate H2 dissociation on the Pt sites. Simultaneously, thermal energy results in spilling of the dissociated H2 to Ni sites, where the adsorbed CO2 is thermally reduced to CO and CH4 . The synergistic interplay of dual-active-sites renders Pt/Ni-MOF a record efficiency of 9.57 % at 940 nm for converting atmospheric CO2 , enables the procurement of CO2 to be independent of the emission sources, and improves the energy efficiency for trace CO2 conversion by eliminating the capture media regeneration and molecular CO2 release.

An Antitumor Dual-Responsive Host-Guest Supramolecular Polymer Based on Hypoxia-Cleavable Azocalix[4]arene.

The exploitation of specific guests which can respond to external stimuli is the main approach for the construction of stimuli-responsive supramolecular polymers (SPs) based on host-guest interactions. Most functional guests, however, fail to manifest stimuli-responses. Herein, a hypoxia-responsive dimeric azocalixarene (D-SAC4A) with outstanding hosting properties was used as the macrocyclic building block for the preparation of host stimuli-responsive SPs. Since azocalixarenes can also be compatible with stimuli-responsive guests, an antitumor drug, camptothecin (CPT), was chosen and linked via a disulfide-containing linker to afford a glutathione (GSH)-responsive ditropic guest (D-CPT). A unique dual-responsive SP was obtained by 1 : 1 mixing of D-SAC4A and D-CPT in water, which further assembled into SP nanoparticles (DSPNs). DSPNs displayed outstanding stability against dilution and biological interferants, as well as precise CPT-release under GSH and hypoxia conditions. In vitro and in vivo experiments demonstrated the good biosafety and tumor-suppressive effects of DSPNs.

Fundamental linewidth of an AlN microcavity Raman laser.

Raman lasing can be a promising way to generate highly coherent chip-based lasers, especially in high-quality (high-Q) crystalline microcavities. Here, we measure the fundamental linewidth of a stimulated Raman laser in an aluminum nitride (AlN)-on-sapphire microcavity with a record Q-factor up to 3.7 million. An inverse relationship between fundamental linewidth and emission power is observed. A limit of the fundamental linewidth, independent of Q-factor, due to Raman-pump-induced Kerr parametric oscillation is derived.

Pure quartic solitons in dispersion-engineered aluminum nitride micro-cavities.

Pure quartic soliton (PQS) is a new class of solitons demonstrated in recent years and provides innovations in nonlinear optics and its applications. Generating PQSs in micro-cavities offers a novel way to achieve coherent microcombs, presenting a promising application potential. Here we numerically investigate the PQS generation in a dispersion-engineered aluminum nitride (AlN) micro-cavity. To support PQS, a well-designed shallow-trench waveguide structure is adopted, which is feasible to be fabricated. The structure exhibits a dominant fourth-order dispersion reaching up to -5.35×10-3 ps4/km. PQSs can be generated in this AlN micro-cavity in the presence of all-order-dispersion and stimulated Raman scattering. Spectral recoil and soliton self-frequency shift are observed in the PQS spectrum. Furthermore, we find that due to the narrow Raman gain spectrum of crystalline AlN, the PQS evolves directly to chaos rather than turning into a breather. The threshold pump power with which the PQS turns into chaos is also theoretically calculated, which squares with the simulation results.

Raman pure quartic solitons in Kerr microresonators.

Pure quartic solitons (PQSs) are a unique class of solitons advantageous for developing promising applications due to their broad and flat-top spectrum, as well as the distinctive energy scaling law. Here we investigate the characteristics and dynamics of the PQS in the presence of the Raman effect based on Kerr microresonators. Stimulated Raman scattering leads to reduced pulse peak power, self-frequency shifts, and distortion of the symmetry pulse shape of the PQS. Besides, dynamical evolution of the Raman PQS, especially the breathing state, is investigated. We discover the appearance of an intermediate stable state between the existence region of breathers and chaos in the parameter space, which has not been discovered yet in other soliton regimes. A stability analysis is performed to investigate the spatial dynamics in the context of the Raman PQS.

Self-frequency shift of AlN-on-sapphire Kerr solitons.

We study the self-frequency shift of continuously pumped Kerr solitons in AlN-on-sapphire microcavities with Raman gain bandwidths narrower than the cavity free-spectral range. Solitons are generated in ∼230GHz microcavities via high-order mode dispersion engineering. The dependence of the self-frequency shift on soliton pulse width is measured and differs from amorphous material microcavities. Our measurement and simulation reveal the impact of frequency detuning between the cavity resonances and Raman gain peaks, as well as the importance of all three Raman gain peaks. The interplay between the Raman effect and dispersive wave recoil and a potential quiet point are also observed.

Evaluation of Dissipation Behavior, Residues, and Dietary Risk Assessment of Fludioxonil in Cherry via QuEChERS Using HPLC-MS/MS Technique.

The chemical fungicide fludioxonil is widely used to control post-harvest fungal disease in cherries. This study was implemented to investigate the dissipation behaviours and residues of fludioxonil on cherries. A reliable and efficient analytical method was established. Cherry samples from four product areas were analyzed by QuEChERS and HPLC-MS/MS methods with acceptable linearity (R2 > 0.99), accuracy (recoveries of 81-94%), and precision (relative standard deviation of 2.5-11.9%). The limits of quantification (LOQs) and limits of detection (LODs) of cherries were 0.01 mg/kg and 0.005 mg/kg. The dissipation of fludioxonil on cherries followed first order kinetics with half-lives of 33.7-44.7 days. The terminal residues of fludioxonil were all lower than 5.00 mg/kg, which is the MRL recommended by the European Commission. According to Chinese dietary patterns and terminal residue distributions, the risk quotient (RQs) of fludioxonil was 0.61%, revealing that the evaluated cherries exhibited an acceptably low dietary risk to consumers.

Short to mid-term outcome of total hip arthroplasty with cementless implants in patients younger than 25 years old.

BACKGROUND: Total hip arthroplasty (THA) was once reserved for old patients with hip arthritis but has become more common in very young patients (≤25 years old) diagnosed with various joint disease that were not relieved with conservative treatment. The purpose of this study was to evaluate short to mid-term outcome of THA in patients younger than 25 years old. METHOD: This retrospective study included 45 patients younger than 25 years (mean age 21.8 ± 2.14 years) who underwent THA. The surgical indications, implant selection, leg length discrepancy, medication history, radiographic outcome, survival and clinical results including the modified Harris hip score (mHHS) and SF-36 score were assessed. RESULT: The mean follow-up period recorded for patients was 7.82 years (range 5-12 years). The most common diagnosis was avascular necrosis (37.7%) followed by ankylosing spondylitis (24.4%), developmental dysplasia of the hip (17.7%) and rheumatoid arthritis (8.8%). The preoperative leg length discrepancy (LLD), which ranged from 0.5-7 cm significantly improved after surgery ranging from 0-1 cm. The mean preoperative mHHS was 32.44 ± 18.90 compared with the postoperative score of 94.54 ± 5.81 (p < 0.001). The preoperative p-value of SF-36 was lower compared to the postoperative value in all subgroups of SF-36 (p < 0.001). At the latest follow-up there were no radiological signs of loosening and all the implants were classified as well-integrated. CONCLUSION: At present total hip arthroplasty is considered to be safe and a good solution for young patients below 25 years suffering from end-stage joint disease; however, longer follow-up is required to evaluate the long-term function and outcome of the prosthesis in order to restore the normal lifestyle of the patients.

The Biosynthetic Gene Cluster of Pyrazomycin-A C-Nucleoside Antibiotic with a Rare Pyrazole Moiety.

Pyrazomycin is a rare C-nucleoside antibiotic containing a naturally occurring pyrazole ring, the biosynthetic origin of which has remained obscure for decades. In this study we report the identification of the gene cluster responsible for pyrazomycin biosynthesis in Streptomyces candidus NRRL 3601, revealing that the StrR-family regulator PyrR is the cluster-situated transcriptional activator governing pyrazomycin biosynthesis. Furthermore, our results from in vivo reconstitution and stable-isotope feeding experiments provide support for the hypothesis that PyrN is a new nitrogen-nitrogen bond-forming enzyme that catalyzes the linkage of the ϵ-NH2 nitrogen atom of l-N6 -OH-lysine and the α-NH2 nitrogen atom of l-glutamic acid. This study lays the foundation for further genetic and biochemical characterization of pyrazomycin pathway enzymes involved in constructing the characteristic pyrazole ring.

Non-Hermitian Skin Effect and Chiral Damping in Open Quantum Systems.

One of the unique features of non-Hermitian Hamiltonians is the non-Hermitian skin effect, namely, that the eigenstates are exponentially localized at the boundary of the system. For open quantum systems, a short-time evolution can often be well described by the effective non-Hermitian Hamiltonians, while long-time dynamics calls for the Lindblad master equations, in which the Liouvillian superoperators generate time evolution. In this Letter, we find that Liouvillian superoperators can exhibit the non-Hermitian skin effect, and uncover its unexpected physical consequences. It is shown that the non-Hermitian skin effect dramatically shapes the long-time dynamics, such that the damping in a class of open quantum systems is algebraic under periodic boundary conditions but exponential under open boundary conditions. Moreover, the non-Hermitian skin effect and non-Bloch bands cause a chiral damping with a sharp wave front. These phenomena are beyond the effective non-Hermitian Hamiltonians; instead, they belong to the non-Hermitian physics of full-fledged open quantum dynamics.

Non-Hermitian Topological Invariants in Real Space.

The topology of non-Hermitian systems is drastically shaped by the non-Hermitian skin effect, which leads to the generalized bulk-boundary correspondence and non-Bloch band theory. The essential part in formulations of bulk-boundary correspondence is a general and computable definition of topological invariants. In this Letter, we introduce a construction of non-Hermitian topological invariants based directly on real-space wave functions, which provides a general and straightforward approach for determining non-Hermitian topology. As an illustration, we apply this formulation to several representative models of non-Hermitian systems, efficiently obtaining their topological invariants in the presence of non-Hermitian skin effect. Our formulation also provides a dual picture of the non-Bloch band theory based on the generalized Brillouin zone, offering a unique perspective of bulk-boundary correspondence.

Excitation of direction-tunable surface plasmon polaritons by using a rectangular array of silver nanodisks.

Use of dipole-like localized surface plasmons (LSPs) induced on a rectangular array of silver nanodisks to excite directional surface plasmon polaritons (SPPs) on a flat silver film is demonstrated. By modifying the spectral resonance of the LSPs, an effective coupling of the incident light into the SPPs has been achieved at operational wavelength of λ0 = 628 nm. The maximum SPP intensity exceeds 25% of the incident intensity. Meanwhile, owing to the angle-dependent spatial distribution of the LSPs and the constructive interference between columns or rows of the array, the excited SPPs are supported to propagate in two orthogonal channels with a width of 1756 nm. Moreover, the propagation of the SPPs is tunable by rotating the polarization direction of the incident light between angles of 0 and π/2. This approach of launching direction-tunable SPPs shows great potential in applications of integrated plasmonic circuits.

Edge States and Topological Invariants of Non-Hermitian Systems.

The bulk-boundary correspondence is among the central issues of non-Hermitian topological states. We show that a previously overlooked "non-Hermitian skin effect" necessitates redefinition of topological invariants in a generalized Brillouin zone. The resultant phase diagrams dramatically differ from the usual Bloch theory. Specifically, we obtain the phase diagram of the non-Hermitian Su-Schrieffer-Heeger model, whose topological zero modes are determined by the non-Bloch winding number instead of the Bloch-Hamiltonian-based topological number. Our work settles the issue of the breakdown of conventional bulk-boundary correspondence and introduces the non-Bloch bulk-boundary correspondence.

Non-Hermitian Chern Bands.

The relation between chiral edge modes and bulk Chern numbers of quantum Hall insulators is a paradigmatic example of bulk-boundary correspondence. We show that the chiral edge modes are not strictly tied to the Chern numbers defined by a non-Hermitian Bloch Hamiltonian. This breakdown of conventional bulk-boundary correspondence stems from the non-Bloch-wave behavior of eigenstates (non-Hermitian skin effect), which generates pronounced deviations of phase diagrams from the Bloch theory. We introduce non-Bloch Chern numbers that faithfully predict the numbers of chiral edge modes. The theory is backed up by the open-boundary energy spectra, dynamics, and phase diagram of representative lattice models. Our results highlight a unique feature of non-Hermitian bands and suggest a non-Bloch framework to characterize their topology.