Identification of Hydrolyzable Tannins (Punicalagin, Punicalin and Geraniin) as Novel inhibitors of Hepatitis B Virus Covalently Closed Circular DNA

The development of new agents to target HBV cccDNA is urgently needed because of the limitations of current available drugs for treatment of hepatitis B. By using a cell-based assay in which the production of HBeAg is in a cccDNA-dependent manner, we screened a compound library derived from Chinese herbal remedies for inhibitors against HBV cccDNA. Three hydrolyzable tannins, specifically punicalagin, punicalin and geraniin, emerged as novel anti-HBV agents. These compounds significantly reduced the production of secreted HBeAg and cccDNA in a dose-dependent manner in our assay, without dramatic alteration of viral DNA replication. Furthermore, punicalagin did not affect precore/core promoter activity, pgRNA transcription, core protein expression, or HBsAg secretion. By employing the cell-based cccDNA accumulation and stability assay, we found that these tannins significantly inhibited the establishment of cccDNA and modestly facilitated the degradation of preexisting cccDNA. Collectively, our results suggest that hydrolyzable tannins inhibit HBV cccDNA production via a dual mechanism through preventing the formation of cccDNA and promoting cccDNA decay, although the latter effect is rather minor. These hydrolyzable tannins may serve as lead compounds for the development of new agents to cure HBV infection

The properties of horizontal magnetic elements in quiet solar intranetwork

Using the data observed by the Solar Optical Telescope/Spectro-Polarimeter aboard the Hinode satellite, the horizontal and vertical fields are derived from the wavelength-integrated measures of Zeeman-induced linear and circular polarizations. The quiet intranetwork regions are pervaded by horizontal magnetic elements. We categorize the horizontal intranetwork magnetic elements into two types: one is the non-isolated element which is accompanied by the vertical magnetic elements during its evolution; another is the isolated element which is not accompanied by the vertical magnetic elements. We identify 446 horizontal intranetwork magnetic elements, among them 87 elements are isolated and 359 are non-isolated. Quantitative measurements reveal that the isolated elements have relatively weaker horizontal magnetic fields, almost equal size, and shorter lifetime comparing with the non-isolated elements. Most non-isolated horizontal intranetwork magnetic elements are identified to associate with the emergence of Omega-shaped flux loops. A few non-isolated elements seem to indicate scenarios of submergence of Omega loops or emergence of U-like loops. There is a positive correlation between the lifetime and the size for both the isolated and non-isolated HIFs. It is also found that there is also positive correlation between the lifetime and the magnetic flux density for non-isolated HIFs, but no correlation for isolated HIFs. Even though the horizontal elements show lower magnetic flux density, they could carry the total magnetic flux in the order of magnitude close to 10^25 Mx to the solar surface each day.Comment: 10 figures, 25 pages. ApJ, in pres

Solar Intranetwork Magnetic Elements: bipolar flux appearance

The current study aims to quantify characteristic features of bipolar flux appearance of solar intranetwork (IN) magnetic elements. To attack such a problem, we use the Narrow-band Filter Imager (NFI) magnetograms from the Solar Optical Telescope (SOT) on board \emph{Hinode}; these data are from quiet and an enhanced network areas. Cluster emergence of mixed polarities and IN ephemeral regions (ERs) are the most conspicuous forms of bipolar flux appearance within the network. Each of the clusters is characterized by a few well-developed ERs that are partially or fully co-aligned in magnetic axis orientation. On average, the sampled IN ERs have total maximum unsigned flux of several 10^{17} Mx, separation of 3-4 arcsec, and a lifetime of 10-15 minutes. The smallest IN ERs have a maximum unsigned flux of several 10^{16} Mx, separations less than 1 arcsec, and lifetimes as short as 5 minutes. Most IN ERs exhibit a rotation of their magnetic axis of more than 10 degrees during flux emergence. Peculiar flux appearance, e.g., bipole shrinkage followed by growth or the reverse, is not unusual. A few examples show repeated shrinkage-growth or growth-shrinkage, like magnetic floats in the dynamic photosphere. The observed bipolar behavior seems to carry rich information on magneto-convection in the sub-photospheric layer.Comment: 26 pages, 14 figure

An ancestral NB-LRR with duplicated 3'UTRs confers stripe rust resistance in wheat and barley.

Wheat stripe rust, caused by Puccinia striiformis f. sp. tritici (Pst), is a global threat to wheat production. Aegilops tauschii, one of the wheat progenitors, carries the YrAS2388 locus for resistance to Pst on chromosome 4DS. We reveal that YrAS2388 encodes a typical nucleotide oligomerization domain-like receptor (NLR). The Pst-resistant allele YrAS2388R has duplicated 3' untranslated regions and is characterized by alternative splicing in the nucleotide-binding domain. Mutation of the YrAS2388R allele disrupts its resistance to Pst in synthetic hexaploid wheat; transgenic plants with YrAS2388R show resistance to eleven Pst races in common wheat and one race of P. striiformis f. sp. hordei in barley. The YrAS2388R allele occurs only in Ae. tauschii and the Ae. tauschii-derived synthetic wheat; it is absent in 100% (n = 461) of common wheat lines tested. The cloning of YrAS2388R will facilitate breeding for stripe rust resistance in wheat and other Triticeae species

Single-cell ligand–receptor profiling reveals an immunotherapy-responsive subtype and prognostic signature in triple-negative breast cancer

BackgroundTriple-negative breast cancer (TNBC) is an aggressive form of cancer that lacks specific targeted therapies. Although ligand–receptor (LR) interactions play a crucial role in intercellular communication and contribute to tumor heterogeneity, their molecular details and potential as prognostic or predictive markers in TNBC have not been thoroughly investigated.MethodsWe analyzed single-cell RNA sequencing data to categorize TNBC into 12 subgroups and 10 distinct cell types. From this dataset, we identified LR pairs that exhibited significant intercellular crosstalk and evaluated their prognostic relevance in a METABRIC TNBC cohort (n = 298). Through consensus clustering of these LR pairs, two molecular subtypes were defined. Key LR genes were then selected using Lasso regression and stepwise multivariate analysis to build an LR-based prognostic scoring system (LR.score), which was validated using both the METABRIC and GSE58812 datasets (n = 107). Additionally, we performed siRNA-mediated knockdown of the CXCL9/CXCR3 axis in MDA-MB-231 cells, confirming the knockdown via RT-qPCR and Western blot. The functional impact was assessed through proliferation, colony formation, and wound healing assays.ResultsOne subtype (Clust1) demonstrated strong immune cell infiltration, higher immune scores, and enrichment in pathways such as epithelial–mesenchymal transition, angiogenesis, and KRAS signaling—indicative of a basal-like, immune-active phenotype. Among the LR pairs, the CXCL9–CXCR3 axis was identified as a key factor in immune cell recruitment and anti-tumor responses. Functionally, silencing the CXCL9/CXCR3 axis significantly diminished the proliferation, colony formation, and migratory capabilities of MDA-MB-231 cells. Moreover, a higher LR.score was correlated with poorer overall survival (HR = 1.69, 95% CI = 1.12–2.56, P < 0.05) and reduced response to immune checkpoint inhibitors (ICIs), while patients with lower LR.score showed increased sensitivity to ICIs, particularly in anti–PD-L1 cohorts.ConclusionThe LR.score serves as an independent prognostic factor and a reliable predictor of immunotherapy response in TNBC. Targeting crucial LR interactions, especially the CXCL9–CXCR3 axis, may enhance immunotherapeutic efficacy and refine prognostic evaluations, paving the way for improved treatment strategies in TNBC

Mendelian randomization shows causal effects of birth weight and childhood body mass index on the risk of frailty

BackgroundThe association between birth weight and childhood body mass index (BMI) and frailty has been extensively studied, but it is currently unclear whether this relationship is causal.MethodsWe utilized a two-sample Mendelian randomization (MR) methodology to investigate the causal effects of birth weight and childhood BMI on the risk of frailty. Instrumental variables (p < 5E-08) strongly associated with own birth weight (N = 298,142 infants), offspring birth weight (N = 210,267 mothers), and childhood BMI (N = 39,620) were identified from large-scale genomic data from genome-wide association studies (GWAS). The frailty status was assessed using the frailty index, which was derived from comprehensive geriatric assessments of older adults within the UK Biobank and the TwinGene database (N = 175,226).ResultsGenetically predicted one standard deviation (SD) increase in own birth weight, but not offspring birth weight (maternal-specific), was linked to a decreased frailty index (β per SD increase = −0.068, 95%CI = −0.106 to −0.030, p = 3.92E-04). Conversely, genetically predicted one SD increase in childhood BMI was associated with an elevated frailty index (β per SD increase = 0.080, 95%CI = 0.046 to 0.114, p = 3.43E-06) with good statistical power (99.8%). The findings remained consistent across sensitivity analyses and showed no horizontal pleiotropy (p > 0.05).ConclusionThis MR study provides evidence supporting a causal relationship between lower birth weight, higher childhood BMI, and an increased risk of frailty