Search

Intravenous thrombolysis with recombinant tissue plasminogen activator (rtPA) is the primary treatment for ischemic stroke. However, rtPA treatment can substantially increase blood‐brain barrier (BBB) permeability and susceptibility to hemorrhagic transformation. Herein, the mechanism underlying the side effects of rtPA treatment is investigated and demonstrated that ferroptosis plays an important role. The ferroptosis inhibitor, liproxstatin‐1 (Lip) is proposed to alleviate the side effects. A well‐designed macrocyclic carrier, glucose‐modified azocalix[4]arene (GluAC4A), is prepared to deliver Lip to the ischemic site. GluAC4A bound tightly to Lip and markedly improved its solubility. Glucose, modified at the upper rim of GluAC4A, imparts BBB targeting to the drug delivery system owing to the presence of glucose transporter 1 on the BBB surface. The responsiveness of GluAC4A to hypoxia due to the presence of azo groups enabled the targeted release of Lip at the ischemic site. GluAC4A successfully improved drug accumulation in the brain, and Lip@GluAC4A significantly reduced ferroptosis, BBB leakage, and neurological deficits induced by rtPA in vivo. These findings deepen the understanding of the side effects of rtPA treatment and provide a novel strategy for their effective mitigation, which is of great significance for the treatment and prognosis of patients with ischemic stroke. [ABSTRACT FROM AUTHOR]

Tertiary lymphoid structure (TLS) can predict the prognosis and sensitivity of tumors to immune checkpoint inhibitors (ICIs) therapy, whether it can be noninvasively predicted by radiomics in hepatocellular carcinoma with liver transplantation (HCC‐LT) has not been explored. In this study, it is found that intra‐tumoral TLS abundance is significantly correlated with recurrence‐free survival (RFS) and overall survival (OS). Tumor tissues with TLS are characterized by inflammatory signatures and high infiltration of antitumor immune cells, while those without TLS exhibit uncontrolled cell cycle progression and activated mTOR signaling by bulk and single‐cell RNA‐seq analyses. The regulators involved in mTOR signaling (RHEB and LAMTOR4) and S‐phase (RFC2, PSMC2, and ORC5) are highly expressed in HCC with low TLS. In addition, the largest cohort of HCC patients is studied with available radiomics data, and a classifier is built to detect the presence of TLS in a non‐invasive manner. The classifier demonstrates remarkable performance in predicting intra‐tumoral TLS abundance in both training and test sets, achieving areas under receiver operating characteristic curve (AUCs) of 92.9% and 90.2% respectively. In summary, the absence of intra‐tumoral TLS abundance is associated with mTOR signaling activation and uncontrolled cell cycle progression in tumor cells, indicating unfavorable prognosis in HCC‐LT. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease associated with B‐cell hyperactivity. Telitacicept is a transmembrane activator, calcium modulator, and cyclophilin ligand interactor‐Fc fusion protein, which can neutralize both B‐cell lymphocyte stimulator and a proliferation‐inducing ligand. Patients with active SLE who received telitacicept were prospectively followed at month 1, 3, 6, 9, and 12 after telitacicept initiation. Thirty‐seven participants were involved and followed for 6.00 [3.00, 6.00] months. SRI‐4 rate at month 6 was 44.7%. The median dosage of prednisone was decreased by 43.8% (from 10 to 5.62 mg/d) at month 6. The anti‐dsDNA level was significantly decreased, while complement levels were significantly increased at month 6 from baseline. Continuously significant reductions in serum immunoglobin (Ig)G IgA, and IgM levels were also observed. Patients experienced significant decreases in the numbers of total and naive B cells, whereas memory B cells and T cell populations did not change. The number of NK cells was significantly increased during the follow‐up. At month 6, 58.3% (14 out of 24) patients experienced improved fatigue accessed by FACIT–Fatigue score exceeding the minimum clinically important difference of 4. Most adverse events were mild, but one each case of severe hypogammaglobulinemia, psychosis with suicidal behavior, and B‐cell lymphoma were occurred. In our first prospective real‐world study, telitacicept treatment led to a significant clinical and laboratory improvement of disease activity, as well as fatigue amelioration in patients with SLE. Safety profile was favorable overall, but more studies are greatly needed. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID‐19), caused by SARS‐CoV‐2, have profoundly affected human health. Booster COVID‐19 vaccines have demonstrated significant efficacy in reducing infection and severe cases. However, the effects of booster COVID‐19 vaccines on key immune cell subsets and their responses in rheumatoid arthritis (RA) are not well understood. By using single‐cell RNA sequencing (scRNA‐seq) combined with scTCR/BCR‐seq analysis, a total of 8 major and 27 minor cell clusters were identified from paired peripheral blood mononuclear cells (PBMCs) which were collected 1 week before and 4 weeks after booster vaccination in stable RA patients. Booster vaccination only had limited impact on the composition and proportions of PBMCs cell clusters. CD8+ cytotoxic T cells (CD8+T_CTL) showed a trend toward an increase after vaccination, while naive B cells and conventional dendritic cells (cDCs) showed a trend toward a decrease. Transcriptomic changes were observed after booster vaccination, primarily involving T/B cell receptor signaling pathways, phagosome, antigen processing and presenting, and viral myocarditis pathways. Interferon (IFN) and pro‐inflammatory response gene sets were slightly upregulated across most major cell subpopulations in COVID‐19 booster‐vaccinated RA individuals. Plasma neutralizing antibody titers significantly increased after booster COVID‐19 vaccination (p = 0.037). Single‐cell TCR/BCR analysis revealed increased B cell clone expansion and repertoire diversity postvaccination, with no consistent alterations in T cells. Several clonotypes of BCRs and TCRs were identified to be significantly over‐represented after vaccination, such as IGHV3‐15 and TRBV28. Our study provided a comprehensive single‐cell atlas of the peripheral immune response and TCR/BCR immune repertoire profiles to inactivated SARS‐CoV‐2 booster vaccination in RA patients, which helps us to understand vaccine‐induced immune responses better. [ABSTRACT FROM AUTHOR]

Cysteine and glycine‐rich protein 2 (Csrp2) has emerged as a key factor in controlling the phenotypic modulation of smooth muscle cells. The phenotypic transition of airway smooth muscle cells (ASMCs) is a pivotal step in developing airway remodeling during the onset of asthma. However, whether Csrp2 mediates the phenotypic transition of ASMCs in airway remodeling during asthma onset is undetermined. This work aimed to address the link between Csrp2 and the phenotypic transition of ASMCs evoked by platelet‐derived growth factor (PDGF)‐BB in vitro. The overexpression or silencing of Csrp2 in ASMCs was achieved through adenovirus‐mediated gene transfer. The expression of mRNA was measured by quantitative real‐time‑PCR. Protein levels were determined through Western blot analysis. Cell proliferation was detected by EdU assay and Calcein AM assays. Cell cycle distribution was assessed via fluorescence‐activated cell sorting assay. Cell migration was evaluated using the scratch‐wound assay. The transcriptional activity of Yes‐associated protein (YAP)/transcriptional coactivator with PDZ‐binding motif (TAZ) was measured using the luciferase reporter assay. A decline in Csrp2 level occurred in PDGF‐BB‐stimulated ASMCs. Increasing Csrp2 expression repressed the PDGF‐BB‐evoked proliferation and migration of ASMCs. Moreover, increasing Csrp2 expression impeded the phenotypic change of PDGF‐BB‐stimulated ASMCs from a contractile phenotype into a synthetic/proliferative phenotype. On the contrary, the opposite effects were observed in Csrp2‐silenced ASMCs. The activity of YAP/TAZ was elevated in PDGF‐BB‐stimulated ASMCs, which was weakened by Csrp2 overexpression or enhanced by Csrp2 silencing. The YAP/TAZ activator could reverse Csrp2‐overexpression‐mediated suppression of the PDGF‐BB‐evoked phenotypic switching of ASMCs, while the YAP/TAZ suppressor could dimmish Csrp2‐silencing‐mediated enhancement on PDGF‐BB‐evoked phenotypic switching of ASMCs. In summary, Csrp2 serves as a determinant for the phenotypic switching of ASMCs. Increasing Csrp2 is able to impede PDGF‐BB‐evoked phenotypic change of ASMCs from a synthetic phenotype into a synthetic/proliferative phenotype through the effects on YAP/TAZ. This work implies that Csrp2 may be a key player in airway remodeling during the onset of asthma. Significance statement: This study reported that Csrp2 plays a crucial role in the phenotypic transition of ASMCs. Overexpression of Crsp2 repressed the phenotypic change of PDGF‐BB‐stimulated ASMCs from a contractile phenotype into a synthetic/proliferative phenotype through inhibition of YAP/TAZ. Given that the phenotypic transformation of ASMCs plays a critical role in the development of airway remodeling in asthma, the Crsp2‐regulated YAP/TAZ pathway may represent a critical mechanism for the pathogenesis of asthma. Therefore, therapeutic approaches target and promote Csrp2 expression may have potential applications in treatment of asthma in the future. [ABSTRACT FROM AUTHOR]

Due to the high carrier mobility and direct bandgap character, indium selenide (InSe) exhibits great advantages for advanced optoelectronic applications. However, the unique optical section rule in InSe weakens the light‐matter interaction when the electric field of illuminated light is perpendicular to the c‐axis of planar InSe flake. To overcome this constraint, ultramicrotome technique is introduced to achieve vertically aligned InSe ribbons, aiming to reconfigure the optical paths for improved optical absorption and device performance. The well‐designed InSe ribbons are acquired with uniform morphology, showing an integrated structure free of cracks or fragments. First, the structural symmetry, crystal orientation, and optical anisotropy of InSe ribbon are carefully revealed by polarization‐dependent Raman spectrum, second harmonic generation (SHG), and photoluminescence measurements. Then, the back focal plane (BFP) imaging of photoluminescence distinguishes the in‐plane and out‐of‐plane dipole emission of InSe ribbons and planar InSe flakes, respectively. Notably, the ribbon exhibits new PL peaks with energy lower than the exciton peak of InSe at low temperature, which is attributed to Se vacancies. The work by introducing vertically aligned InSe nanoribbons provides a new strategy to manipulate the light‐matter interactions and defect engineering for novel optoelectronics, which can be also extended to other 2D semiconductors. [ABSTRACT FROM AUTHOR]