Background and Aims
HBV‐pgRNA (pregenomic RNA) has been proposed for predicting the response of nucleos(t)ide analogue (NA) treatment, guiding discontinuation of NA therapy and monitoring the ...emergence of viral mutations. However, the contributions of HBV‐pgRNA to HCC remain open for study.
Approach and Results
Double‐center cohorts of serum samples with undetectable serum HBV‐DNA (below the lower limit of detection) were obtained from long‐term NA‐treated (≥48 weeks) HBV‐related HCC patients. The correlation between serum pgRNA concentration and the prognosis of HCC were analyzed. The role pgRNA played in HCC development was assessed both in vitro and in vivo. Our findings revealed that for patients who underwent long‐term NA therapy with undetectable serum HBV‐DNA, patients with high serum pgRNA expression had a poorer overall survival rate and higher cumulative recurrence rate after hepatectomy. Experiments demonstrated that pgRNA promotes proliferation, stemness, and tumorigenicity of HCC cells. Mechanistically, we found that pgRNA could up‐regulate the expression of insulin‐like growth factor 2 mRNA‐binding protein 3 (IGF2BP3), a well‐proven oncoprotein, at the posttranscriptional level. Furthermore, interferon (IFN)‐α‐2a could degrade the stability of pgRNA through increasing its N6‐methyladenosine (m6A) RNA modification. Collectively, our findings uncover that serum pgRNA could serve as a potential biomarker for predicting the prognosis and recurrence of HCC in patients who received long‐term NA therapy with undetectable serum HBV‐DNA; and the pgRNA‐IGF2BP3 axis plays an important role in the development of HBV‐related HCC. Moreover, IFN‐α‐2a could reduce the stability of pgRNA by increasing its m6A RNA modification level, thereby suppressing the development of HBV‐related HCC.
Conclusions
In conclusion, our studies reveal a significance and mechanism of HBV‐pgRNA in increasing stemness features and offer a potential prognostic marker and a therapeutic target for HBV‐related HCC.
Dopamine receptors, including D1- and D2-like receptors, are important therapeutic targets in a variety of neurological syndromes, as well as cardiovascular and kidney diseases. Here, we present five ...cryoelectron microscopy (cryo-EM) structures of the dopamine D1 receptor (DRD1) coupled to Gs heterotrimer in complex with three catechol-based agonists, a non-catechol agonist, and a positive allosteric modulator for endogenous dopamine. These structures revealed that a polar interaction network is essential for catecholamine-like agonist recognition, whereas specific motifs in the extended binding pocket were responsible for discriminating D1- from D2-like receptors. Moreover, allosteric binding at a distinct inner surface pocket improved the activity of DRD1 by stabilizing endogenous dopamine interaction at the orthosteric site. DRD1-Gs interface revealed key features that serve as determinants for G protein coupling. Together, our study provides a structural understanding of the ligand recognition, allosteric regulation, and G protein coupling mechanisms of DRD1.
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•Structures of DRD1-Gs in complex with catechol-based and non-catechol agonists•Key polar interaction network is involved in DRD1 activation•Specific features for agonists interaction and Gs coupling of DRD1 are determined•Structure of DRD1-Gs complexed with dopamine and positive allosteric modulator•Structural basis of allosteric regulation of DRD1 by LY3154207 is investigated
The cryo-EM structures of DRD1 coupled to its G protein, in complex with important agonists, elucidates the mechanism of G-protein-coupled selectivity and will facilitate future drug discovery and design.
•Metal Al was used as an electrical conductive coating material for LiNi0.5Mn1.5O4.•The uniform surface coating layer of metal Al was successfully achieved with adjusted thickness through a physical ...vapor deposition technology.•Al3+-doped LiNi0.5Mn1.5O4 can be easily obtained by further directly annealing of Al-coated LiNi0.5Mn1.5O4 in air.•The conductive Al-coating layer can greatly improve the rate performance and cycle stability of LiNi0.5Mn1.5O4.
In this work, spinel LiNi0.5Mn1.5O4 (LNMO) hollow microspheres are synthesized by an impregnation method using microsphere MnO2 as both the precursor and template. To enhance the electrical conductivity of LNMO, metal Al was employed for the first time as a coating material for LNMO. Though an Electron-beam Vapor Deposition approach, the surface of LNMO can be easily coated by a tight layer of Al nanoparticles with adjusted thickness. Further annealing the Al-coated sample at 800°C in air, the Al3+-doped LNMO can be obtained. The effects of Al-coating and Al3+-doping on the sample morphology and structure are investigated by SEM, TEM, XRD and FT-IR. The electrochemical properties of Al-coated LNMO and Al3+-doped LNMO are measured with comparison of bare LNMO by charge/discharge tests and electrochemical impedance spectroscopy (EIS). The results show that both Al-coating and Al3+-doping can greatly enhance the cycle performance and rate capability of LNMO. Especially for Al-coated LNMO, it shows the lowest battery impedance due to the existence of conductive Al coating layer, thus delivers the best rate performance among the three. The physical coating procedure used in this work may provide a new facile modification approach for other cathode materials.
Lactoferrin (lactotransferrin; Lf) is an iron-binding glycoprotein and one of the most important bioactivators in milk and other external secretions. It has numerous biological roles, including the ...regulation of iron absorption and modulation of immune responses, and has anti-microbial, anti-viral, antioxidant, anti-cancer, and anti-inflammatory activities. Lf regulates the quantity of iron absorbed in the intestine via its role in iron transport and can also chelate iron, directly or indirectly. Notably, it has been used as an adjuvant therapy for some intestinal diseases. It is now used in nutraceuticalsupplemented infant formula and other food products. This article reviews the content, distribution, physiologic functions and current applications of Lf, and aims to shed light on future prospects for additional applications of Lf.
Abstract
Most triple-negative breast cancer (TNBC) patients fail to respond to T cell-mediated immunotherapies. Unfortunately, the molecular determinants are still poorly understood. Breast cancer is ...the disease genetically linked to a deficiency in autophagy. Here, we show that autophagy defects in TNBC cells inhibit T cell-mediated tumour killing in vitro and in vivo. Mechanistically, we identify Tenascin-C as a candidate for autophagy deficiency-mediated immunosuppression, in which Tenascin-C is Lys63-ubiquitinated by Skp2, particularly at Lys942 and Lys1882, thus promoting its recognition by p62 and leading to its selective autophagic degradation. High Tenascin-C expression is associated with poor prognosis and inversely correlated with LC3B expression and CD8
+
T cells in TNBC patients. More importantly, inhibition of Tenascin-C in autophagy-impaired TNBC cells sensitizes T cell-mediated tumour killing and improves antitumour effects of single anti-PD1/PDL1 therapy. Our results provide a potential strategy for targeting TNBC with the combination of Tenascin-C blockade and immune checkpoint inhibitors.
More than 30% of patients with diffuse large B-cell lymphoma (DLBCL) experience treatment failure after first-line therapy. Neutrophil extracellular traps (NETs), a pathogen-trapping structure in ...tumor microenvironment, can promote the transition of autoimmunity to lymphomagenesis. Here, we investigate whether NETs play a novel role in DLBCL progression and its underlying mechanism.
NETs in DLBCL tumor samples and plasma were detected by immunofluorescence and ELISA, respectively. The correlation between NETs and clinical features were analyzed. The effects of NETs on cellular proliferation and migration and mechanisms were explored, and the mechanism of NET formation was also studied by a series of
and
assays.
Higher levels of NETs in plasma and tumor tissues were associated with dismal outcome in patients with DLBCL. Furthermore, we identified NETs increased cell proliferation and migration
and tumor growth and lymph node dissemination
. Mechanistically, DLBCL-derived IL8 interacted with its receptor (CXCR2) on neutrophils, resulting in the formation of NETs via Src, p38, and ERK signaling. Newly formed NETs directly upregulated the Toll-like receptor 9 (TLR9) pathways in DLBCL and subsequently activated NFκB, STAT3, and p38 pathways to promote tumor progression. More importantly, disruption of NETs, blocking IL8-CXCR2 axis or inhibiting TLR9 could retard tumor progression in preclinical models.
Our data reveal a tumor-NETs aggressive interaction in DLBCL and indicate that NETs is a useful prognostic biomarker and targeting this novel cross-talk represents a new therapeutic opportunity in this challenging disease.
Abstract The aim of this study was to develop a magnetic thermosensitive hydrogel as intravesical Bacillus Calmette–Guérin (BCG) delivery system, which was formulated with chitosan (CS), ...β-glycerophosphate (GP) and Fe3 O4 magnetic nanoparticle (Fe3 O4 -MNP). The gelation time and magnetic response of the gel system were investigated. The morphology of the gel was displayed by scanning electron microscope. Frozen section examination was creatively employed for exhibiting the structure of the gel and determining its intravesical residence time. The antitumor effect and local immune activity of BCG loaded magnetic gel were evaluated. The flowing solution of CS/GP under room temperature could gelate rapidly at body temperature both in vitro and in vivo. The magnetic injectable hydrogels significantly prolonged intravesical BCG residence time under an applied magnetic field. In comparison to traditional BCG therapy for superficial bladder tumor, BCG delivered by the gel system induced a stronger Th1 immune response and revealed higher antitumor efficacy.
Manipulating the collective molecular movements to implement macroscopic mechanical response of bulk material is attractive and challenging. Here, an organic‐inorganic hybrid single crystal is ...synthesized, which exhibits a giant macroscopic shape transformation with a remarkable thermal hysteretic feature. The colossal anisotropic shape change, which manifests as an abrupt elongation of ca. 9 % along the crystallographic c‐axis and a concomitant contraction of ca. 9 % in a perpendicular direction, is induced by a significant reorientation of imidazolium, accompanied with a substantial configurational variation in CuBr42− complex anions. The synergistic motions of both the molecular cations and anions engender a remarkable large thermal hysteresis (>30 K) in the shape transformation of the single crystal, implying that this material may play a role in alternating memory media. Furthermore, due to the stable crystal lattice, a single crystal that demonstrates naked‐eye detectable large shape transformation was used as a thermal actuator to spontaneously control an electric circuit by temperature variation.
Switch it up: A single crystal of CuII complex demonstrates an abrupt and reversible giant shape transformation with remarkable wide thermal hysteresis, as a consequence of synergetic actions of reorientation of molecular cations and geometric variation of complex anions. The giant shape deformation of single crystal can be used as a thermal actuator to spontaneously control a circuit by temperature variation.
Anthropogenic impacts on widespread global soil moisture (SM) drying in the root zone layer during 1948–2005 were evaluated based on the Global Land Data Assimilation System version 2 (GLDAS‐2) and ...global climate models from the Coupled Model Intercomparison Project Phase 5 using trend analysis and optimal fingerprint methods. Both methods show agreement that natural forcing alone cannot drive significant SM drying. There is a high probability (≥90%) that the anthropogenic climate change signal is detectable in global SM drying. Specifically, anthropogenic greenhouse gas forcing can lead to global SM drying by 2.1 × 10−3 m3/m3, which is comparable to the drying trend seen in Global Land Data Assimilation System version 2 (2.4 × 10−3 m3/m3) over the past 58 years. Global SM drying is expected to continue in the future, given continuous greenhouse gas emissions.
Plain Language Summary
Satellite observations and model simulations indicated widespread soil moisture (SM) drying in the root zone layer. Global‐scale SM drying has also been corroborated by meteorological drought indices. SM drying can accentuate the intensity of heat waves under global warming. Recent record‐breaking heat waves were amplified by SM drying, such as the 2003 European heat waves and 2010 Russia heat waves. The contributions of human activities to global‐scale SM changes have not been comprehensively evaluated. There is a high probability (≥90%) that the anthropogenic climate change signal in global SM drying is detectable. Specifically, anthropogenic greenhouse gas forcing can lead to global SM drying by 2.1 × 10–3 m3/m3, which is comparable to the drying trend seen in Global Land Data Assimilation System version 2 (2.4 × 10–3 m3/m3) over the past 58 years. Global SM drying is expected to continue in the future, given continuous greenhouse gas emissions.
Key Points
Global soil moisture drying can be explained by anthropogenic and greenhouse gas forcings
The anthropogenic climate change signal in global soil moisture drying is detectable
Global soil moisture drying is projected to continue under future climate scenarios with various greenhouse gas emissions
Identifying the structure sensitivity of catalysts in reactions, such as Fischer–Tropsch synthesis from CO and H2 over cobalt catalysts, is an important yet challenging issue in heterogeneous ...catalysis. Based on a first-principles kinetic study, we find for the first time that CO activation on hexagonal close-packed (HCP) Co not only has much higher intrinsic activity than that of face centered-cubic (FCC) Co but also prefers a different reaction route, i.e., direct dissociation with HCP Co but H-assisted dissociation on the FCC Co. The origin is identified from the formation of various denser yet favorable active sites on HCP Co not available for FCC Co, due to their distinct crystallographic structure and morphology. The great dependence of the activity on the crystallographic structure and morphology of the catalysts revealed here may open a new avenue for better, stable catalysts with maximum mass-specific reactivity.
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