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The flavivirus NS5 harbors a methyltransferase (MTase) in its N-terminal ≈ 265 residues and an RNA-dependent RNA polymerase (RdRP) within the C-terminal part. One of the major interests and challenges in NS5 is to understand the interplay between RdRP and MTase as a unique natural fusion protein in viral genome replication and cap formation. Here, we report the first crystal structure of the full-length flavivirus NS5 from Japanese encephalitis virus. The structure completes the vision for polymerase motifs F and G, and depicts defined intra-molecular interactions between RdRP and MTase. Key hydrophobic residues in the RdRP-MTase interface are highly conserved in flaviviruses, indicating the biological relevance of the observed conformation. Our work paves the way for further dissection of the inter-regulations of the essential enzymatic activities of NS5 and exploration of possible other conformations of NS5 under different circumstances.

We introduce a novel parameterization of supernova neutrino energy spectra with a clear physical motivation. Its central parameter, τ(t), quantifies the characteristic thermal-diffusion area during the explosion. When applied to the historic SN 1987A data, this parameterization yields statistically significant fits and provides robust constraints on the unobserved low-energy portion of the spectrum. Beyond this specific application, we demonstrate the model’s power on a suite of 3D core-collapse supernova simulations, finding that the temporal evolution of τ(t) distinctly separates successful from failed explosions. Furthermore, we constrain the progenitor mass of SN 1987A to approximately 19 solar masses by applying a smoothed isotonic regression, while noting the sensitivity of this estimate to observational uncertainties. Moreover, in these simulations, τ(t) and the gravitational-wave strain amplitude display a strong, synergistic coevolution, directly linking the engine’s energetic evolution to its geometric asymmetry. This implies that the thermodynamic state of the explosion is not only imprinted on the escaping neutrino flux but also recorded in the shape of the energy spectrum. Our framework therefore offers a valuable tool for decoding the detailed core dynamics and multimessenger processes of future Galactic supernovae.

We use the Modules for Experiments in Stellar Astrophysics (MESA) code to calculate the yields of 7 Li in the ejecta of classical novae, occurring on the surface of carbon-oxygen (CO) and oxygen-neon-magnesium (ONeMg) white dwarfs (WDs). Taking the masses and the mass accretion rates of WDs as input parameters, this article presents a grid showing the yield of 7 Li from classical novae, including a total of 79 models. Under similar input parameters, the 7 Li yields in our models are consistent with previous ones in the literature. 7 Li yields recently inferred spectroscopically from classical nova V1369 Cen are then compared with the theoretical values obtained in this work. Using the grid as its basis and population synthesis as its method, this paper estimates the amount of 7 Li produced by classical novae compared to the total 7 Li in the Galaxy. Our simulations suggest that novae can eject about 10 − 9 M of 7 Li every year. Hence, one may estimate that approximately 10% of 7 Li in the Galaxy originates from classical novae, which is significantly higher than the 7 Li produced by asymptotic giant branch stars.

De novo viral RNA-dependent RNA polymerases (RdRPs) utilize their priming element (PE) to facilitate accurate initiation. Upon transition to elongation, the PE has to retreat from the active site to give room to the template—product RNA duplex. However, PE conformational change upon this transition and the role of PE at elongation both remain elusive. Here, we report crystal structures of RdRP elongation complex (EC) from dengue virus serotype 2 (DENV2), demonstrating a dramatic refolding of PE that allows establishment of interactions with the RNA duplex backbone approved to be essential for EC stability. Enzymology data from both DENV2 and hepatitis C virus (HCV) RdRPs suggest that critical transition of the refolding likely occurs after synthesis of a 4- to 5-nucleotide (nt) product together providing a key basis in understanding viral RdRP transition from initiation to elongation.

Background Prostate cancer is one of the most common adult malignancies in men, and nearly all patients with metastatic prostate cancer can develop and receive resistance to primary androgen deprivation therapy (ADT), a state known as metastatic castration-resistant prostate cancer (mCRPC). Recent reports demonstrated the great breakthroughs made by the chimeric antigen receptor T (CAR-T) cell therapy, which is significantly different from traditional T cells therapies. In spite of the progress of CAR-T technology in the treatment of lymphoma, leukemia, and other blood system tumor, there are still many difficulties in the treatment of solid tumors by CAR-T technology. Methods In this report, we designed a panel of IL23mAb-PSMA-CARs, including PSMA-CAR, IL23mAb-T2A-PSMA-CAR, IL23mAb-PSMA-CAR, and PSMA-CAR (soluble IL23mAb). And we studied the function of these CARs in mice model. Results Co-culture experiments with different CAR T cells have normal lysis function in vitro. The duo-CAR T cells co-expressing the IL-23mAb and PSMA-mAb had a significant higher population than the rest three different CAR T cells in co-culturing experiments at day 28, 35 and 42. A panel of cytokines were differentially secreted at higher amounts in IL23mAb-T2A-PSMA-CAR T cells than CAR T cells in other groups. In NOD/SCID IL-2 gamma (NSG) mice model, IL23mAb-T2A-PSMA-CAR T cells functioned significantly better than CAR T cells from the other groups and eradicated the tumor from these mice starting at day 14 post T cells injection and regained the body weight immediately. In IL23mAb-T2A-PSMA-CAR mice, CD45RO+ CD8+ T cells and CD127+ CD4+ CAR T cells were significantly increased. RNA sequencing revealed a difference expression pattern of genes in IL23mAb-T2A-PSMA-CAR mice. A reverse infusion experiment under the same model further proved the tumor eradication function of IL23mAb-T2A-PSMA-CAR T cells. Conclusions We found that IL-23mAb combined PSMA CARs worked better than PSMA CAR only in Prostate Cancer Eradication, and we further discussed the mechanisms among different IL-23mAb combined PSMA CARs in Prostate Cancer Eradication.

We have investigated the variable stars in the field surrounding NGC 2355 based on the time-series photometric observation data. More than 3000 CCD frames were obtained in the V band spread over 13 nights with the Nanshan One-meter Wide-field Telescope. We have detected 88 variable stars, containing 72 new variable stars and 16 known variable stars. By analyzing these light curves, we classified the variable stars as follows: 26 eclipsing binaries, 52 pulsating stars, four rotating variables, and six unclear type-variable stars for which their periods are much longer than the time baseline chosen. Employing Gaia DR2 parallax, kinematics, and photometry, the cluster memberships of these variable stars were also analyzed for NGC 2355. In addition to the 11 variable members reported by Cantat-Gaudin et al. (2018), we identify four more variable member candidates located at the outer region of NGC 2355 and showed homogeneity in space positions and kinematic properties with the cluster members. The main physical parameters of NGC 2355 estimated from the two-color and color–magnitude diagrams are log(age/yr) = 8.9, E(B − V) = 0.24 mag, and [Fe/H] = −0.07 dex.

The human AAA+ ATPase CLPB (SKD3) is a protein disaggregase in the mitochondrial intermembrane space (IMS) and functions to promote the solubilization of various mitochondrial proteins. Loss-of-function CLPB mutations are associated with a few human diseases with neutropenia and neurological disorders. Unlike canonical AAA+ proteins, CLPB contains a unique ankyrin repeat domain (ANK) at its N-terminus. How CLPB functions as a disaggregase and the role of its ANK domain are currently unclear. Herein, we report a comprehensive structural characterization of human CLPB in both the apo- and substrate-bound states. CLPB assembles into homo-tetradecamers in apo-state and is remodeled into homo-dodecamers upon substrate binding. Conserved pore-loops (PLs) on the ATPase domains form a spiral staircase to grip and translocate the substrate in a step-size of 2 amino acid residues. The ANK domain is not only responsible for maintaining the higher-order assembly but also essential for the disaggregase activity. Interactome analysis suggests that the ANK domain may directly interact with a variety of mitochondrial substrates. These results reveal unique properties of CLPB as a general disaggregase in mitochondria and highlight its potential as a target for the treatment of various mitochondria-related diseases.

BackgroundThe prevalence of kidney stones (KSs) has been increasing globally, and their association with cardiovascular disease and metabolic syndrome suggests a shared underlying pathophysiology. However, the impact of different stages of cardiovascular-kidney-metabolic (CKM) syndrome on KS prevalence remains unclear.ObjectiveThis study aimed to investigate the association between the stages of CKM syndrome and the prevalence of KS in a nationally representative sample of adults in the USA.MethodsA total of 15 568 participants aged ≥20 years were included in the National Health and Nutrition Examination Survey 2007–2020 fasting subsample. CKM syndrome stages (0–4) were defined based on the 2023 American Heart Association Presidential Advisory on CKM Health. The KS history was determined using self-reported data. Multivariable logistic regression models were used to assess the association between the CKM syndrome stage and KS prevalence.ResultsOf the 15 568 participants, 1501 (9.64%) reported a history of KS. The KS prevalence increased progressively with advancing CKM stage, rising from 5.10% in stage 0 to 16.55% in stage 4 (p<0.001). In the fully adjusted model, the ORs for KS were 1.18 (95% CI 0.83–1.68) for stage 1, 1.72 (95% CI 1.28 to 2.32) for stage 2, 2.00 (95% CI 1.29 to 3.10) for stage 3 and 2.36 (95% CI 1.64 to 3.40) for stage 4, compared with stage 0 (P for trend <0.001). Stratified analyses revealed no significant interactions between age, sex, race/ethnicity or other subgroups.ConclusionThis study demonstrated a significant stepwise increase in KS prevalence with the advancing stages of CKM syndrome. These findings highlight the importance of monitoring and managing CKM syndromes to mitigate the risks of KS.

Heterogeneity of tumor cells and the tumor microenvironment (TME) is significantly associated with clinical outcomes and treatment responses in patients with urothelial carcinoma (UC). Comprehensive profiling of the cellular diversity and interactions between malignant cells and TME may clarify the mechanisms underlying UC progression and guide the development of novel therapies. This study aimed to extend our understanding of intra-tumoral heterogeneity and the immunosuppressive TME in UC and provide basic support for the development of novel UC therapies. Seven patients with UC were included who underwent curative surgery at our hospital between July 2020 and October 2020. We performed single-cell RNA sequencing (scRNA-seq) analysis in seven tumors with six matched adjacent normal tissues and integrated the results with two public scRNA-seq datasets. The functional properties and intercellular interactions between single cells were characterized, and the results were validated using multiplex immunofluorescence staining, flow cytometry, and bulk transcriptomic datasets. All statistical analyses were performed using the R package with two-sided tests. Wilcoxon-rank test, log-rank test, one-way analysis of variance test, and Pearson correlation analysis were used properly. Unsupervised t-distributed stochastic neighbor embedding clustering analysis identified ten main cellular subclusters in urothelial tissues. Of them, seven urothelial subtypes were noted, and malignant urothelial cells were characterized with enhanced cellular proliferation and reduced immunogenicity. CD8 + T cell subclusters exhibited enhanced cellular cytotoxicity activities along with increased exhaustion signature in UC tissues, and the recruitment of CD4 + T regulatory cells was also increased in tumor tissues. Regarding myeloid cells, coordinated reprogramming of infiltrated neutrophils, M2-type polarized macrophages, and LAMP3 + dendritic cells contribute to immunosuppressive TME in UC tissues. Tumor tissues demonstrated enhanced angiogenesis mediated by KDR + endothelial cells and RGS5 + /ACTA2 + pericytes. Through deconvolution analysis, we identified multiple cellular subtypes may influence the programmed death-ligand 1 (PD-L1) immunotherapy response in patients with UC. Our scRNA-seq analysis clarified intra-tumoral heterogeneity and delineated the pro-tumoral and immunosuppressive microenvironment in UC tissues, which may provide novel therapeutic targets.

Neutron stars are ideal astrophysical laboratories for testing theories of the de Haas-van Alphen effect and diamagnetic phase transition which is associated with magnetic domain formation. The \"magnetic interaction\" between delocalized magnetic moments of electrons (the Shoenberg effect), can result in an effect of the diamagnetic phase transition into domains of alternating magnetization (Condon's domains). Associated with the domain formation are prominent magnetic field oscillation and anisotropic magnetic stress which may be large enough to fracture the crust of magnetar with a super-strong field. Even if the fracture is impossible as in \"low-field\" magnetar, the depinning phase transition of domain wall (DW) motion driven by low field rate (mainly due to the Hall effect) in the randomly perturbed crust can result in a catastrophically variation of magnetic field. This intermittent motion, similar to the avalanche process, makes the Hall effect be dissipative. These qualitative consequences about magnetized electron gas are consistent with observations of magnetar emission, and especially the threshold critical dynamics of driven DW can partially overcome the difficulties of \"low-field\" magnetar bursts and the heating mechanism of transient, or \"outbursting\" magnetar.