LASS2 enhances chemosensitivity to cisplatin by inhibiting PP2A-mediated ß-catenin dephosphorylation in a subset of stem-like bladder cancer cells.

BACKGROUND: The benefits of first-line, cisplatin-based chemotherapy for muscle-invasive bladder cancer are limited due to intrinsic or acquired resistance to cisplatin. Increasing evidence has revealed the implication of cancer stem cells in the development of chemoresistance. However, the underlying molecular mechanisms remain to be elucidated. This study investigates the role of LASS2, a ceramide synthase, in regulating Wnt/ß-catenin signaling in a subset of stem-like bladder cancer cells and explores strategies to sensitize bladder cancer to cisplatin treatment. METHODS: Data from cohorts of our center and published datasets were used to evaluate the clinical characteristics of LASS2. Flow cytometry was used to sort and analyze bladder cancer stem cells (BCSCs). Tumor sphere formation, soft agar colony formation assay, EdU assay, apoptosis analysis, cell viability, and cisplatin sensitivity assay were used to investigate the functional roles of LASS2. Immunofluorescence, immunoblotting, coimmunoprecipitation, LC-MS, PCR array, luciferase reporter assays, pathway reporter array, chromatin immunoprecipitation, gain-of-function, and loss-of-function approaches were used to investigate the underlying mechanisms. Cell- and patient-derived xenograft models were used to investigate the effect of LASS2 overexpression and a combination of XAV939 on cisplatin sensitization and tumor growth. RESULTS: Patients with low expression of LASS2 have a poorer response to cisplatin-based chemotherapy. Loss of LASS2 confers a stem-like phenotype and contributes to cisplatin resistance. Overexpression of LASS2 results in inhibition of self-renewal ability of BCSCs and increased their sensitivity to cisplatin. Mechanistically, LASS2 inhibits PP2A activity and dissociates PP2A from ß-catenin, preventing the dephosphorylation of ß-catenin and leading to the accumulation of cytosolic phospho-ß-catenin, which decreases the transcription of the downstream genes ABCC2 and CD44 in BCSCs. Overexpression of LASS2 combined with a tankyrase inhibitor (XAV939) synergistically inhibits tumor growth and restores cisplatin sensitivity. CONCLUSIONS: Targeting the LASS2 and ß-catenin pathways may be an effective strategy to overcome cisplatin resistance and inhibit tumor growth in bladder cancer patients.

Sparstolonin B inhibits pancreatic adenocarcinoma through the NF-κB signaling pathway.

Pancreatic adenocarcinoma is a highly lethal malignant gastrointestinal tumor. Sparstolonin B is an isocoumarin whose anticancer activity has recently received increasing attention. This study aimed to investigate Sparstolonin B's potential antitumor effect on pancreatic adenocarcinoma. The effect of Sparstolonin B on pancreatic cancer target genes and molecular mechanism was predicted via network pharmacology; Sparstolonin B significantly decreased Panc-1 and SW1990 cell viability and effectively suppressed the proliferation, migration, and invasion of pancreatic cancer cells as shown by CCK-8, colony formation, and Transwell assays. Flow cytometry showed that it induced cell cycle arrest and apoptosis. Sparstolonin B also upregulated Bax levels but decreased those of MMP2 and Bcl-2, downregulated IκBα expression, and upregulated p65 and IκBα phosphorylation; however, it had no effect on total NF-κB p65 levels. The NF-κB pathway inhibitor QNZ reversed these effects. The treatment group (26 µmol/L) had reduced graft volume and weight and fewer Ki-67-positive cells than the control group. Therefore, Sparstolonin B can inhibit the growth and induce the apoptosis of pancreatic cancer cells via the NF-κB signaling pathway and may be a potential novel drug for pancreatic cancer treatment.

Advanced Glycation End Products Induced Mitochondrial Dysfunction of Chondrocytes through Repression of AMPKα-SIRT1-PGC-1α Pathway.

INTRODUCTION: Our previous studies have demonstrated advanced glycation end products (AGEs) was an important mediator in osteoarthritis (OA) which may induce mitochondrial dysfunction. AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and its downstream target peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) are the critical sensors that regulate mitochondrial biogenesis and have been recognized as therapeutic targets in OA. This study was designed to test whether AGEs caused mitochondrial dysfunction through modulation of AMPKα/SIRT1/PGC-1α. METHODS: We knocked down or overexpressed AMPKα, SIRT1, and PGC-1α by small interfering RNA or plasmid DNA transfection, respectively. Mitochondrial membrane potential (△Ψ) was detected by tetraethylbenzimidazolyl carbocyanine iodide (JC-1) fluorescence probe. RESULTS: The results showed that AGEs impaired △Ψ, intracellular ATP level, and mitochondrial DNA content, linked to decreased AMPKα, SIRT1, and PGC-1α expression in chondrocyte. AMPKα pharmacologic activation or overexpression of AMPKα, SIRT1, and PGC-1α reversed impairments of mitochondrial biogenesis, oxidative stress, and inflammation in AGEs-induced chondrocytes. However, AMPKα activation using AICAR had decreased capacity to increase each of those same effect readouts in AGEs-treated SIRT1-siRNA or PGC-1α-siRNA chondrocyte. CONCLUSION: Taken together, AGEs reduced the AMPKα/SIRT1/PGC-1α signaling in chondrocytes, leading to mitochondrial dysfunction as a result of increased oxidative stress, inflammation, and apoptosis. These results indicated that target AMPK may be as a novel therapeutic strategy for AGEs-related OA prevention.

Multivariate analysis of the factors affecting the prognosis of walled-off pancreatic necrosis after endoscopic ultrasound-guided drainage.

BACKGROUND AND AIMS: Endoscopic ultrasound (EUS)-guided drainage has become the treatment of choice for walled-off pancreatic necrosis (WOPN). However, no consensus exists on the most significant patient- and procedure-related factors that affect prognosis. The aim of the study is to investigate the correlation between patient- and procedure-related factors and post-procedure complications after EUS-guided drainage. METHODS: A retrospective analysis of the clinical characteristics of patients with WOPN who underwent EUS-guided drainage at our endoscopy center between November 2011 and August 2017 was performed. Chi-square analysis and binary logistic regression statistical methods were used to analyze the correlation between influencing factors and prognosis. RESULTS: A total of 85 patients (male/female, 50/35) with WOPN were included in the study. The average age was 44.95 years. The cyst diameter was 10.58 ± 4.78 cm. Multivariate analysis showed that WOPN with higher solid content (> 30%) increased the probability of endoscopic necrosectomy (OR 6.798; 95% CI 1.423, 32.470; p = 0.016). The use of a metal stent increased the probability of endoscopic necrosectomy (OR 3.503; 95% CI 1.251, 9.810; p = 0.017) and the length of hospitalization (OR 3.315; 95% CI 1.192, 9.215; p = 0.022). Female patients had a higher probability of requiring endoscopic necrosectomy (OR 2.683; 95% CI 1.027, 7.007; p = 0.044) and prolonged hospitalization (OR 2.675; 95% CI 1.065, 6.721; p = 0.036). CONCLUSION: The solid content of WOPN, type of stent, and sex of patients were associated with increased probability of endoscopic necrosectomy.

Antinuclear antibodies and interleukin responses in patients with Schistosoma japonicum infection.

Schistosomiasis poses a serious threat to public health, and the infection will develop into chronic and advanced late-stage disease if not treated. Apart from the clinical signs due to immune reactions to schistosome eggs trapped in host tissues, it also increases the risk for the development of autoimmunity reflected by dysfunctional, auto-reactive antibodies. Antinuclear antibodies (ANA) have been reported in schistosomiasis due to S. mansoni and S. haematobium. We demonstrate ANA in schistosomiasis japonica and explore the relationship between this infection and autoimmune disease by measuring ANA and interleukin (IL)-10, IL-12 and IL-17 responses in the sera of 125 Chinese patients with different stages of schistosomiasis japonica. The incidence rates of ANA in the patients with acute, chronic and late stages of schistosomiasis infection were 6.7%, 23.3% and 70.0%, respectively, with statistically significant differences between each stage (P = 0.000). IL-17 concentrations were high at the acute stage of schistosomiasis compared to the other stages of the disease (P = 0.000). This pattern was also seen for IL-10 and IL-12 concentrations (P = 0.01). IL concentrations in patients in the chronic and late stages of the disease were low and showed no difference compared to the healthy adults.

Reactive Oxygen Species-Responsive Nanoparticles Toward Extracellular Matrix Normalization for Pancreatic Fibrosis Regression.

Pancreatic fibrosis (PF) is primarily characterized by aberrant production and degradation modes of extracellular matrix (ECM) components, resulting from the activation of pancreatic stellate cells (PSCs) and the pathological cross-linking of ECM mediated by lysyl oxidase (LOX) family members. The excessively deposited ECM increases matrix stiffness, and the over-accumulated reactive oxygen species (ROS) induces oxidative stress, which further stimulates the continuous activation of PSCs and advancing PF; challenging the strategy toward normalizing ECM homeostasis for the regression of PF. Herein, ROS-responsive and Vitamin A (VA) decorated micelles (named LR-SSVA) to reverse the imbalanced ECM homeostasis for ameliorating PF are designed and synthesized. Specifically, LR-SSVA selectively targets PSCs via VA, thereby effectively delivering siLOXL1 and resveratrol (RES) into the pancreas. The ROS-responsive released RES inhibits the overproduction of ECM by eliminating ROS and inactivating PSCs, meanwhile, the decreased expression of LOXL1 ameliorates the cross-linked collagen for easier degradation by collagenase which jointly normalizes ECM homeostasis and alleviates PF. This research shows that LR-SSVA is a safe and efficient ROS-response and PSC-targeted drug-delivery system for ECM normalization, which will propose an innovative and ideal platform for the reversal of PF.

SLC25A28 Overexpression Promotes Adipogenesis by Reducing ATGL.

Adipose tissue dysfunction is seen among obese and type 2 diabetic individuals. Adipocyte proliferation and hypertrophy are the root causes of adipose tissue expansion. Solute carrier family 25 member 28 (SLC25A28) is an iron transporter in the inner mitochondrial membrane. This study is aimed at validating the involvement of SLC25A28 in adipose accumulation by tail vein injection of adenovirus (Ad)-SLC25A28 and Ad-green fluorescent protein viral particles into C57BL/6J mice. After 16 weeks, the body weight of the mice was measured. Subsequently, morphological analysis was performed to establish a high-fat diet (HFD)-induced model. SLC25A28 overexpression accelerated lipid accumulation in white and brown adipose tissue (BAT), enhanced body weight, reduced serum triglyceride (TG), and impaired serum glucose tolerance. The protein expression level of lipogenesis, lipolysis, and serum adipose secretion hormone was evaluated by western blotting. The results showed that adipose TG lipase (ATGL) protein expression was reduced significantly in white and BAT after overexpression SLC25A28 compared to the control group. Moreover, SLC25A28 overexpression inhibited the BAT formation by downregulating UCP-1 and the mitochondrial biosynthesis marker PGC-1α. Serum adiponectin protein expression was unregulated, which was consistent with the expression in inguinal white adipose tissue (iWAT). Remarkably, serum fibroblast growth factor (FGF21) protein expression was negatively related to the expansion of adipose tissue after administrated by Ad-SLC25A28. Data from the current study indicate that SLC25A28 overexpression promotes diet-induced obesity and accelerates lipid accumulation by regulating hormone secretion and inhibiting lipolysis in adipose tissue.

Effect of a 3D-printed reconstruction automated matching system for selecting the size of a left double-lumen tube: a study protocol for a prospective randomised controlled trial.

INTRODUCTION: Lung isolation is primarily accomplished using a double-lumen tube (DLT) or bronchial blocker. A precise and accurate size of the DLT is a prerequisite for ensuring its accurate placement. Three-dimensional (3D) reconstruction technology can be used to accurately reproduce tracheobronchial structures to improve the accuracy of DLT size selection. Therefore, we have developed automatic comparison software for 3D reconstruction based on CT data (3DRACS). In this study, we aimed to evaluate the efficiency of using 3DRACS to select the DLT size for endobronchial intubation in comparison with using the 'blind' DLT intubation method to determine the DLT size, which is based on height and sex. METHODS AND ANALYSIS: This is a prospective, single-centre, double-blind randomised controlled trial. In total, 200 patients scheduled for lung resection using a left DLT will be randomly allocated to the 3D group or the control group at a 1:1 ratio. A 3DRACS will be used for the 3D group to determine the size of the DLT, while in the case of the control group, the size of the DLT will be determined according to patient height and sex. The primary outcome is the success rate of placement of the left DLT without fibreoptic bronchoscopy (FOB). The secondary outcomes include the following: successful intubation time, degree of pulmonary atrophy, grade of airway injury, oxygenation during one-lung ventilation, postoperative sore throat and hoarseness, and number of times FOB is used. ETHICS AND DISSEMINATION: Ethical approval has been obtained from our local ethics committee (approval number: SCCHEC-02-2022-155). Written informed consent will be obtained from all participants before randomisation, providing them with clear instructions about the purpose of the study. The results will be disseminated through peer-reviewed publications and conferences. TRIAL REGISTRATION NUMBER: NCT06258954.

CTRP9 Promotes Brown Adipose Tissue Lipolysis in Mice Fed a High-Fat Diet.

BACKGROUND: This study aimed to elucidate the molecular mechanism through which C1q/tumor necrosis factor (TNF)-related protein 9 (CTRP9) acts in the formation and differentiation of brown adipose tissue (BAT). METHODS: Adenovirus particles encoding CTRP9 and green fluorescent protein were inoculated into the scapula of C57BL/6J mice and fed a high-fat diet for 8 weeks; the body weight, lipid droplet morphology, glucose tolerance, insulin tolerance, and protein expression levels were analyzed. In addition, CTRP9 adenovirus was transfected into brown preadipocytes, and differentiation was induced to identify the effect of CTRP9 overexpression on adipocyte differentiation. RESULTS: CTRP9 overexpression significantly increased the weight gain of mice. Additionally, the CTRP9 overexpression group exhibited significantly increased adipose tissue weight and glucose clearance rates and decreased insulin sensitivity and serum triglyceride levels compared to the control group. Furthermore, CTRP9 overexpression significantly upregulated the adipose triglyceride lipase (ATGL) and perilipin 1 protein expression levels in BAT. The cell experiment results confirmed that CTRP9 overexpression significantly inhibited the adipogenesis of brown adipocytes as evidenced by the downregulation of uncoupling protein 1, beta-3 adrenergic receptor, ATGL, and hormone-sensitive lipase mRNA levels and the significant suppression of uncoupling protein 1, ATGL, and perilipin 1 protein levels in brown adipocytes. CONCLUSIONS: The finding of this study demonstrated that CTRP9 promotes lipolysis by upregulating ATGL expression in vivo and inhibits the differentiation of brown preadipocytes in vitro.

A Large-Range and High-Sensitivity Fiber-Optic Fabry-Perot Pressure Sensor Based on a Membrane-Hole-Base Structure.

In the field of in situ measurement of high-temperature pressure, fiber-optic Fabry-Perot pressure sensors have been extensively studied and applied in recent years thanks to their compact size and excellent anti-interference and anti-shock capabilities. However, such sensors have high technological difficulty, limited pressure measurement range, and low sensitivity. This paper proposes a fiber-optic Fabry-Perot pressure sensor based on a membrane-hole-base structure. The sensitive core was fabricated by laser cutting technology and direct bonding technology of three-layer sapphire and develops a supporting large-cavity-length demodulation algorithm for the sensor's Fabry-Perot cavity. The sensor exhibits enhanced sensitivity, a simplified structure, convenient preparation procedures, as well as improved pressure resistance and anti-harsh environment capabilities, and has large-range pressure sensing capability of 0-10 MPa in the temperature range of 20-370 °C. The sensor sensitivity is 918.9 nm/MPa, the temperature coefficient is 0.0695 nm/(MPa∙°C), and the error over the full temperature range is better than 2.312%.

An Autologous Macrophage-Based Phenotypic Transformation-Collagen Degradation System Treating Advanced Liver Fibrosis.

In advanced liver fibrosis (LF), macrophages maintain the inflammatory environment in the liver and accelerate LF deterioration by secreting proinflammatory cytokines. However, there is still no effective strategy to regulate macrophages because of the difficulty and complexity of macrophage inflammatory phenotypic modulation and the insufficient therapeutic efficacy caused by the extracellular matrix (ECM) barrier. Here, AC73 and siUSP1 dual drug-loaded lipid nanoparticle is designed to carry milk fat globule epidermal growth factor 8 (MFG-E8) (named MUA/Y) to effectively inhibit macrophage proinflammatory signals and degrade the ECM barrier. MFG-E8 is released in response to the high reactive oxygen species (ROS) environment in LF, transforming macrophages from a proinflammatory (M1) to an anti-inflammatory (M2) phenotype and inducing macrophages to phagocytose collagen. Collagen ablation increases AC73 and siUSP1 accumulation in hepatic stellate cells (HSCs) and inhibits HSCs overactivation. Interestingly, complete resolution of liver inflammation, significant collagen degradation, and HSCs deactivation are observed in methionine choline deficiency (MCD) and CCl4 models after tail vein injection of MUA/Y. Overall, this work reveals a macrophage-focused regulatory treatment strategy to eliminate LF progression at the source, providing a new perspective for the clinical treatment of advanced LF.

Inhaled nanoparticles for treating idiopathic pulmonary fibrosis by inhibiting honeycomb cyst and alveoli interstitium remodeling.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with high mortality. The Food and Drug Administration-approved drugs, nintedanib and pirfenidone, could delay progressive fibrosis by inhibiting the overactivation of fibroblast, however, there was no significant improvement in patient survival due to low levels of drug accumulation and remodeling of honeycomb cyst and interstitium surrounding the alveoli. Herein, we constructed a dual drug (verteporfin and pirfenidone)-loaded nanoparticle (Lip@VP) with the function of inhibiting airway epithelium fluidization and fibroblast overactivation to prevent honeycomb cyst and interstitium remodeling. Specifically, Lip@VP extensively accumulated in lung tissues via atomized inhalation. Released verteporfin inhibited the fluidization of airway epithelium and the formation of honeycomb cyst, and pirfenidone inhibited fibroblast overactivation and reduced cytokine secretion that promoted the fluidization of airway epithelium. Our results indicated that Lip@VP successfully rescued lung function through inhibiting honeycomb cyst and interstitium remodeling. This study provided a promising strategy to improve the therapeutic efficacy for IPF.

Construction of a specialized integrated simulation platform for molecule screening based on scientific computing workflow engine.

Numerical simulation is an efficient tool for evaluation and prediction of material properties and behavior in many industrial domains such as the development of novel materials and medicines. For numerical studies of complex processes or systems with high fidelity, various data processing tools, modeling and simulation programs are typically involved, desiring an integrated platform that can effectively manage the collaboration of such software resources and the execution of the underlying simulation workflow for efficiency purpose. Such a platform could be practically built with a scientific computing workflow engine that focuses on the automatic scheduling and execution of a batch of interrelated computing tasks. In this work, the main procedures on construction of a specialized integrated simulation platform for material research based on a general purpose scientific computing workflow engine named HSWAP is introduced in detail, and its application to molecule screening process of energetic materials is demonstrated. Due to the flexibility and the extensibility of the platform, the work could be handily extended to the screening of other materials such as protein to find optimized protein structures or high entropy alloys to find the best configuration of component contents, as well as other application scenarios such as geometry optimizations of complex structures.

"Dominolike" Barriers Elimination with an Intratumoral Adenosine-Triphosphate-Supersensitive Nanogel to Enhance Cancer Chemoimmunotherapy.

Pathophysiological barriers in "cold" tumors seriously limit the clinical outcomes of chemoimmunotherapy. These barriers distribute in a spatial order in tumors, including immunosuppressive microenvironment, overexpressed chemokine receptors, and dense tumor mesenchyme, which require a sequential elimination in therapeutics. Herein, we reported a "dominolike" barriers elimination strategy by an intratumoral ATP supersensitive nanogel (denoted as BBLZ-945@PAC-PTX) for enhanced chemoimmunotherapy. Once it has reached the tumor site, BBLZ-945@PAC-PTX nanogel undergoes supersensitive collapse triggered by adenosine triphosphate (ATP) in perivascular regions and releases BLZ-945 conjugated albumin (BBLZ-945) to deplete tumor-associated macrophages (TAMs). Deeper spatial penetration of shrunk nanogel (PAC-PTX) could not only block CXCR4 on the cell membrane to decrease immunosuppressive cell recruitment but also internalize into tumor cells for tumor-killing and T cell priming. The strategy of "dominolike" barriers elimination in tumors enables immune cell infiltration for a potentiated immune response and offers a high-responsive treatment opinion for chemoimmunotherapy.

Electrohydrodynamic Printed Ultra-Micro AgNPs Thin Film Temperature Sensors Array for High-Resolution Sensing.

Current methods for thin film sensors preparation include screen printing, inkjet printing, and MEMS (microelectromechanical systems) techniques. However, their limitations in achieving sub-10 µm line widths hinder high-density sensors array fabrication. Electrohydrodynamic (EHD) printing is a promising alternative due to its ability to print multiple materials and multilayer structures with patterned films less than 10 µm width. In this paper, we innovatively proposed a method using only EHD printing to prepare ultra-micro thin film temperature sensors array. The sensitive layer of the four sensors was compactly integrated within an area measuring 450 µm × 450 µm, featuring a line width of less than 10 µm, and a film thickness ranging from 150 nm to 230 nm. The conductive network of silver nanoparticles exhibited a porosity of 0.86%. After a 17 h temperature-resistance test, significant differences in the performance of the four sensors were observed. Sensor 3 showcased relatively superior performance, boasting a fitted linearity of 0.99994 and a TCR of 937.8 ppm/°C within the temperature range of 20 °C to 120 °C. Moreover, after the 17 h test, a resistance change rate of 0.17% was recorded at 20 °C.

Active disturbance rejection control for nanopositioning: A robust U-model approach.

Hysteresis severely reduces positioning performance of a piezoelectric nanopositioning stage. Linear active disturbance rejection control (LADRC) is a practical solution to improve the positioning accuracy. However, the PD controller utilized in the LADRC is not effective enough to suppress the uncancelled total disturbance, and high-order pure integrators are difficult to be stabilized just by a PD controller. In this work, a robust U-model active disturbance rejection control (RUADRC) is proposed by incorporating the core idea of the U-model control and the Glover-McFarlane control. Then, the controlled plant can be dynamically transformed to a unit. Difficulties in stabilizing high-order pure integrators are decreased, the phase lag between the input and output of a controlled plant is reduced, and the closed-loop responses is sped up. In addition, the influence of both inaccurate total disturbance estimation and imperfect approximation is also minimized by the Glover-McFarlane control Closed-loop stability, steady-state tracking error, and the phase advantage of the RUADRC have been analysed. Theoretical results show that the RUADRC promises a timelier and more accurate positioning. Experimental results still confirm the advantages of the RUADRC over the LADRC on both reference tracking speed, accuracy and disturbance rejection ability.

An extended state observer based U-model control of the COVID-19.

The coronavirus disease 2019 (COVID-19) is a new, rapidly spreading and evolving pandemic around the world. The COVID-19 has seriously affected people's health or even threaten people's life. In order to contain the spread of the pandemic and minimize its impact on economy, the tried-and-true control theory is utilized. Firstly, the control problem is clarified. Then, by combining advantages of the U-model control and the extended state observer (ESO), an extended state observer-based U-model control (ESOUC) is proposed to generate a population restriction policy. Closed-loop stability of the regulation system is also proved Two examples are considered, and numerical simulation results show that the ESOUC can suppress the COVID-19 faster than the linear active disturbance rejection control, which benefits controlling the infectious disease and the economic recovery. The ESOUC may provide a feasible non-pharmaceutical intervention in the control of the COVID-19.

Sequential Nano-Penetrators of Capillarized Liver Sinusoids and Extracellular Matrix Barriers for Liver Fibrosis Therapy.

During liver fibrogenesis, liver sinusoidal capillarization and extracellular matrix (ECM) deposition construct dual pathological barriers to drug delivery. Upon capillarization, the vanished fenestrae in liver sinusoidal endothelial cells (LSECs) significantly hinder substance exchange between blood and liver cells, while excessive ECM further hinders the delivery of nanocarriers to activated hepatic stellate cells (HSCs). Herein, an efficient nanodrug delivery system was constructed to sequentially break through the capillarized LSEC barrier and the deposited ECM barrier. For the first barrier, LSEC-targeting and fenestrae-repairing nanoparticles (named HA-NPs/SMV) were designed on the basis of the modification with hyaluronic acid and the loading of simvastatin (SMV). For the second barrier, collagenase I and vitamin A codecorated nanoparticles with collagen-ablating and HSC-targeting functions (named CV-NPs/siCol1α1) were prepared to deliver siCol1α1 with the goal of inhibiting collagen generation and HSC activation. Our in vivo results showed that upon encountering the capillarized LSEC barrier, HA-NPs/SMV rapidly released SMV and exerted a fenestrae-repairing function, which allowed more CV-NPs/siCol1α1 to enter the space of Disse to degrade deposited collagen and finally to achieve higher accumulation in activated HSCs. Scanning electronic microscopy images showed the recovery of liver sinusoids, and analysis of liver tissue sections demonstrated that HA-NPs/SMV and CV-NPs/siCol1α1 had a synergetic effect. Our pathological barrier-normalization strategy provides an antifibrotic therapeutic regimen.

Uncovering a conserved vulnerability site in SARS-CoV-2 by a human antibody.

An essential step for SARS-CoV-2 infection is the attachment to the host cell receptor by its Spike receptor-binding domain (RBD). Most of the existing RBD-targeting neutralizing antibodies block the receptor-binding motif (RBM), a mutable region with the potential to generate neutralization escape mutants. Here, we isolated and structurally characterized a non-RBM-targeting monoclonal antibody (FD20) from convalescent patients. FD20 engages the RBD at an epitope distal to the RBM with a KD of 5.6 nM, neutralizes SARS-CoV-2 including the current Variants of Concern such as B.1.1.7, B.1.351, P.1, and B.1.617.2 (Delta), displays modest cross-reactivity against SARS-CoV, and reduces viral replication in hamsters. The epitope coincides with a predicted "ideal" vulnerability site with high functional and structural constraints. Mutation of the residues of the conserved epitope variably affects FD20-binding but confers little or no resistance to neutralization. Finally, in vitro mode-of-action characterization and negative-stain electron microscopy suggest a neutralization mechanism by which FD20 destructs the Spike. Our results reveal a conserved vulnerability site in the SARS-CoV-2 Spike for the development of potential antiviral drugs.