Waning humoral immune responses to inactivated SARS-CoV-2 vaccines in patients with severe liver disease

Dear Editor,The Coronavirus disease 2019(COVID-19)pandemic caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is still ongoing around the world.Patients with severe liver disease(SLD),such as compensated cirrhosis(CC),decompensated cirrhosis(DC)or hepatocellular carcinoma(HCC),are highly vulnerable and have worse outcomes from COVID-191.Vaccines are effective measure for the prevention of SARS-CoV-2 infection,severe disease,and mortality.Recent studies have preliminarily described the safety and immunogenicity of SARSCoV-2 vaccines in patients with nonalcoholic fatty liver disease(NAFLD)2,and in patients with chronic hepatitis B virus infection(CHB)3.However,data are limited on the safety and immunogenicity of inactivated vaccines against SARS-CoV-2 in SLD patients.Additionally,the memory B cells(MBCs)responses and immunological memory after vaccination in SLD patients is still unclear.Hence,we aim to explore the safety,antibody responses,and MBCs responses of inactivated vaccines(BBIBPCorV or CoronaVac)in SLD patients through a prospective observational study(NCT05007665).

Dynamic Humoral Immune Response to Primary and Booster Inactivated SARS-CoV-2 Vaccination in Patients with Cirrhosis

Background and Aims:Our aim was to determine the immune efficacy of a severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)booster vaccination in cirrhotic patients who had received the primary series.Methods:We performed a longitudinal assessment in 48 patients with cirrhosis,57 patients with chronic hepatitis B(CHB)and 68 healthy controls(HCs)to continuously track the dynamics of SARS-CoV-2 specific antibodies and memory B cells after receiving the primary series and booster dose at different times.A pseudovirus neutralization assay was used to determine neutralization against Omicron subvariants BA.2.12.1,BA.4 and BA.5 from serum samples collected from three cohorts.Results:Serum anti-receptor-binding domain(RBD)immunoglobulin(Ig)G and neutralizing antibody(NAb)levels in cirrhotic patients were elevated within 15–45 days after completing the primary series before rapidly declining and reaching a valley at around 165–195 days.After receiving the booster dose,both antibody levels were significantly increased to levels comparable to patients with CHB and HCs.Subgroup analysis showed that booster vaccination induced weaker antibody responses in patients with decompensated cirrhosis than in those with compensated cirrhosis.The SARS-CoV-2 memory B-cell response in cirrhotic patients was durable during follow-up regardless of the hepatic fibrocirrhosis grade.However,compared with the primary series,the booster dose did not result in an evident improvement of neutralization activity against the Omicron subvariants BA.2.12.1 and BA.4,and was followed by a significant decrease in the titer against BA.5.Conclusions:A booster dose elicited a robust and durable humoral response to the wild-type strain in cirrhotic patients but not the Omicron subvariants.Repeated vaccination of inactivated SARS-CoV-2 vaccine may not benefit cirrhotic patients in neutralization against newly circulating strains.

有限长管道中具有重力的冲击喷流的适定性

具有重力的冲击喷流问题在工程环境和自然界中非常常见,如喷泉和瀑布等.本文研究具有重力的定常不可压缩理想流体动力学中的冲击喷流问题,建立有限长管道中具有重力的冲击喷流的数学理论.本文证明对于给定有限长管道入口来流的初始速度和大气压力,存在光滑的冲击喷流使得自由边界光滑地连接到管道的尾点.进一步地,本文研究管道入口角点附近解的正则性、冲击喷流在下游的渐近行为以及参数的唯一性.

ROS-responsive and triple-synergistic mitochondria-targeted polymer micelles for efficient induction of ICD in tumor therapeutics

Immunogenic cell death(ICD)represents a modality of apoptosis distinguished by the emanation of an array of damage-related molecular signals.This mechanism introduces a novel concept in the field of contemporary tumor immunotherapy.The inception of reactive oxygen species(ROS)within tumor cells stands as the essential prerequisite and foundation for ICD induction.The formulation of highly efficacious photodynamic therapy(PDT)nanomedicines for the successful induction of ICD is an area of significant scientific inquiry.In this work,we devised a ROS-responsive and triple-synergistic mitochondria-targeted polymer micelle(CAT/CPT-TPP/PEG-Ce6,CTC)that operates with multistage amplification of ROS to achieve the potent induction of ICD.Utilizing an“all-in-one”strategy,we direct both the PDT and chemotherapeutic units to the mitochondria.Concurrently,a multistage cyclical amplification that caused by triple synergy strategy stimulates continuous,stable,and adequate ROS generation(domino effect)within the mitochondria of cells.Conclusively,influenced by ROS,tumor cell-induced ICD is effectively activated,remodeling immunogenicity,and enhancing the therapeutic impact of PDT when synergized with chemotherapy.Empirical evidence from in vitro study substantiates that CTC micelles can efficiently provoke ICD,catalyzing CRT translocation,the liberation of HMGB1 and ATP.Furthermore,animal trials corroborate that polymer micelles,following tail vein injection,can induce ICD,accumulate effectively within tumor tissues,and markedly inhibit tumor growth subsequent to laser irradiation.Finally,transcriptome analysis was carried out to evaluate the changes in tumor genome induced by CTC micelles.This work demonstrates a novel strategy to improve combination immunotherapy using nanotechnology.

Drug nanoclusters formed in confined nano-cages of CD-MOF: dramatic enhancement of solubility and bioavailability of azilsartan

Tremendous efforts have been devoted to the enhancement of drug solubility using nanotechnologies, but few of them are capable to produce drug particles with sizes less than a few nanometers. This challenge has been addressed here by using biocompatible versatile γ-cyclodextrin(γ-CD) metal-organic framework(CD-MOF) large molecular cages in which azilsartan(AZL) was successfully confined producing clusters in the nanometer range. This strategy allowed to improve the bioavailability of AZL in Sprague–Dawley rats by 9.7-fold after loading into CD-MOF. The apparent solubility of AZL/CD-MOF was enhanced by 340-fold when compared to the pure drug. Based on molecular modeling, a dual molecular mechanism of nanoclusterization and complexation of AZL inside the CD-MOF cages was proposed, which was confirmed by small angle X-ray scattering(SAXS) and synchrotron radiation-Fourier transform infrared spectroscopy(SR-FTIR) techniques. In a typical cage-like unit of CD-MOF, three molecules of AZL were included by the γ-CD pairs, whilst other three AZL molecules formed a nanocluster inside the 1.7 nm sized cavity surrounded by six γ-CDs. This research demonstrates a dual molecular mechanism of complexation and nanoclusterization in CD-MOF leading to significant improvement in the bioavailability of insoluble drugs.

Zinc-substituted hemoglobin with specific drug binding sites and fatty acid resistance ability for enhanced photodynamic therapy

Precisely designed protein-based nanodrugs, as a kind of colloidal drug system, have attracted significant attention in tumor therapy because of their refined drug loading ratio, controlled delivery efficacy and natural biocompatibility. However, most drugs are conjugated to the protein carriers randomly without specific binding sites. Moreover, such sites could easily be replaced by lipophilic molecules in the physiological environment and result in low delivery efficiency. With strong and specific binding locations especially comparatively narrow spatial binding sites and nonflexible structure, hemin (FePPIX)-free hemoglobin or apohemoglobin (apoHb), as a natural metalloporphyrin protein carrier, represents great potential in bioapplication. Therefore, we herein introduce a folate acid (FA) modified, zinc-substituted hemoglobin (ZnPHb-FA) as a naturally occurring protein matrix-based photosensitizer for cancer photodynamic therapy (PDT). Noncovalent inserted ZnPPIX molecules in apoHb possess an extremely stable property and significant recovered photoproperties with superior biocompatibility and phototoxicity, both in vitro and in vivo. This stability was verified by molecular docking analysis and calculation of binding constant, representing a total of five drug binding sites of apoHb for ZnPPIX molecules, four of which are energetically favorable (△G value of -11.9 kcal/mol), and one which is energetically acceptable (△G value of -9 kcal/mol). Folate acid modification has been shown to efficiently enhance the internalization and retention time of ZnPHb nanodrug. ZnPHb-FA is also an efficient depressor of hemin oxygenase-1 (HO-1), which could, in turn, lower the antioxidant ability of cancer cells by decreasing the production of biiirublin. Results in vitro and in vivo both indicated that the firmly combination of apoHb and ZnPPIX described here represents a novel and efficient protein nanodrug systems for cancer therapy.

FGF8-mediated signaling regulates tooth developmental pace during odontogenesis

The developing human and mouse teeth constitute an ideal model system to study the regulatory mechanism underlying organ growth control since their teeth share highly conserved and well-characterized developmental processes, and their developmental tempo varies notably. In the current study, we manipulated heterogenous recombination between human and mouse dental tissues and demonstrated that the dental mesenchyme dominates the tooth developmental tempo and FGF8 could be a critical player during this developmental process. Forced activation of FGF8 signaling in the dental mesenchyme of mice promoted cell proliferation, prevented cell apoptosis via p38 and perhaps PI3 K-Akt intracellular signaling,and impelled the transition of the cell cycle from G1-to S-phase in the tooth germ, resulting in the slowdown of the tooth developmental pace. Our results provide compelling evidence that extrinsic signals can profoundly affect tooth developmental tempo, and the dental mesenchymal FGF8 could be a pivotal factor in controlling the developmental pace in a non-cell-autonomous manner during mammalian odontogenesis.

Single-molecule DNA logic nanomachines based on origami

Nowadays,it is a truism that chemists,bioengineers and others must be schooled in cell and molecular biology,including knowledge of the cellular,elemental and molecular building blocks of living systems.Inspired by exquisite and efficient biomolecular machines in living cells,such as ATPases that catalyze the decomposition of ATP into ADP and free phosphate ion,researchers representing multiple disciplines are actively engaged in developing artificial nanostructures with well-defined geometry and nanoscale addressability.A successful outcome of these studies could lead to the development and clinical application of smart molecular machines for the drug delivery of theranostics in vivo.

Identification of new aptamer BC-3 targeting RPS7 from rapid screening for bladder carcinoma

Aptamers,short single DNA or RNA oligonucleotides,have shown immense application potential as molecular probes for the early diagnosis and therapy of cancer.However,conventional cell-SELEX technologies for aptamer discovery are time-consuming and laborious.Here we discovered a new aptamer BC-3 by using an improved rapid X-Aptamer selection process for human bladder carcinoma,for which there is no specific molecular probe yet.We show that BC-3 exhibited excellent affinity in bladder cancer cells but not normal cells.We demonstrate that BC-3 displayed high selectivity for tumor cells over their normal counterparts in vitro,in mice,and in patient tumor tissue specimens.Further endocytosis pathway analysis revealed that BC-3 internalized into bladder cancer cells via clathrin-mediated endocytosis.Importantly,we identified ribosomal protein S7(RPS7)as the binding target of BC-3 via an integrated methodology(mass spectrometry,colocalization assay,and immunoblotting).Together,we report that a novel aptamer BC-3 is discovered for bladder cancer and its properties in the disease are unearthed.Our findings will facilitate the discovery of novel diagnostic and therapeutic strategies for bladder cancer.

Photoresponsive Biomimetic Protocells for Near-Infrared-Light- Regulated Phototheranostics

Nature has created complex living systems with outstanding structure and remarkable function.Constructing biomimetic systems that rival living organisms has attracted considerable research inter-est in research fields of self-assembly and bionic sci-ence.

Synthesis and properties of binaphthyl chiral thermally activated delayed fluorescence molecules using thioxanthone as acceptor

The currently reported axial chiral molecules based on the 3,3'-substitution of the binaphthyl skeleton are limited by intrinsic fluorescence properties,resulting in generally low device efficiencies(EQE<5%)of related organic light emitting diodes(OLEDs).Herein,we designed and synthesized four pair of chiral binaphthyl enantiomers(R/S-1-R/S-4)adopting acceptor-donor-donor-acceptor(ADDA)structure by introducing different thioxanthone modification groups on the 3,3'-position of 2,2'-dimethoxy-1,1'-binaphthalene.Among them,emitter R/S-2 and R/S-4 obtained by enhancing intramolecular charge transfer exhibited TADF characteristics due to relatively small Est of 0.12eV and 0.17eV,and relatively moderate SOC matrix elements of 0.28 cm^(-1)and 0.10 cm^(-1)between the 1CT and 3LE states.The CD spectra of these enantiomers in diluted solutions showed perfect mirror images and reasonable gabs for small organic molecules(10^(-4)-10^(-3)).And the external quantum eficiencies(EQE)of 10.9%and 8.32%for device A and B based on emitter S-2 and S-4 were highest compared with currently reported axial chiral molecules based on the 3,3'-position substitution of binaphthyl skeleton,providing simple molecular design strategies to construct efficient CP-OLED device.

Sampling formulas for 2D quaternionic signals associated with various quaternion Fourier and linear canonical transforms

The main purpose of this paper is to study different types of sampling formulas of quaternionic functions,which are bandlimited under various quaternion Fourier and linear canonical transforms.We show that the quaternionic bandlimited functions can be reconstructed from their samples as well as the samples of their derivatives and Hilbert transforms.In addition,the relationships among different types of sampling formulas under various transforms are discussed.First,if the quaternionic function is bandlimited to a rectangle that is symmetric about the origin,then the sampling formulas under various quaternion Fourier transforms are identical.If this rectangle is not symmetric about the origin,then the sampling formulas under various quaternion Fourier transforms are different from each other.Second,using the relationship between the two-sided quaternion Fourier transform and the linear canonical transform,we derive sampling formulas under various quaternion linear canonical transforms.Third,truncation errors of these sampling formulas are estimated.Finally,some simulations are provided to show how the sampling formulas can be used in applications.

Dual-emission carbonized polymer dots for ratiometric sensing and imaging of L-lysine and pH in live cell and zebrafish

It is highly desired to accurately and selectively detect and image intracellular L-lysine and pH in biological systems because they could act as the biomarkers in certain abnormal conditions and may give us a warning of the occurrence of diseases.It has been attracted more focuses to design new ratiometric fluorescent probe for monitoring L-lysine and pH to improve detection accuracy.Carbonized polymer dots(CPDs),which possess carbon/polymer hybrid structure rather than pure carbon structure and constitute of a carbon core and large amounts of functional groups/polymer chains on the surface,rise up as a new type of fluorescent nanomaterials and especially display many advantages for bioanalysis.In this study,o-phenylenediamine(o-PD)and poly(styrene-co-maleic anhydride)(PSMA)are used as the precursors to synthesize the desired CPDs through one-step hydrothermal amide method.The prepared CPDs display two well-resolved fluorescence emission bands,i.e.,a very weak emission centered at 470 nm in blue region and a strong emission centered at 558 nm in yellow region.It is found that the two emissions are both responsive to L-lysine based on the surface passivation mechanism,whereas,only the yellow emission is responsive to pH due to the protonation/deprotonation process of the amino groups.Based on the different responsive behaviors,ratiometric detection and imaging of L-lysine and pH are achieved.The prepared ratiometric CPDs probe is successfully applied for L-lysine and pH sensing and imaging at two emission channels in live cell and zebrafish with satisfactory results.

Nearly 100% exciton utilization in highly efficient red OLEDs based on dibenzothioxanthone acceptor

Improving the utilization of excitons has always been an important topic for the development of electroluminescence devices.In this work,we designed and synthesized three red TADF emitters TPA-DBT12,TPA-DBT3 and DTPA-DBT by employing dibenzothioxanthone(DBT)acceptor framework to stabilize the locally excited triplet state to participate in the reverse intersystem crossing(RISC)process.The fast RISC process and singlet radiation decay process gave rise to evidently enhanced exciton utilization.All of the red OLEDs based on these materials showed maximum EQE over 11% and high exciton utilization close to 100%.This work not only extend the acceptor framework for red materials but also provide a new perspective for the design of highly efficient red TADF materials with 100% exciton utilization by managing locally excited triplet state.

DNA aptamer S11e recognizes fibrosarcoma and acts as a tumor suppressor

Fibrosarcoma is a serious malignant mesenchymal tumor with strong invasiveness,high recurrence,and poor prognosis.Currently,surgical resection is the main treatment for fibrosarcoma.However,due to the lack of specific biomarkers,the inability to accurately diagnose fibrosarcoma can lead to sub-optimal surgical outcomes and decreased survival.Here,we seek to address this translational barrier and we show that DNA aptamer S11e was able to recognize fibrosarcoma cells(HT1080)but not human embryonic lung fibroblast cells with Kd values in the nanomolar range.In addition,we found that S11e discerned tumors in HT1080 xenograft mouse models and tumor tissues from fibrosarcoma patients.Furthermore,we demonstrated that S11e internalized into HT1080 cells independent of the lysosome pathway and located in mitochondria.Moreover,we revealed that S11e promoted the apoptosis of HT1080 cells and inhibited HT1080 cell migration.Finally,we investigated the biologically functional cellular target of S11e using a mass spectrometry approach,and identified that Diablo/SMAC protein is a cellular binding protein of S11e,by interacting to which S11e inhibited HT1080 cell migration and invasion.Taken together,these results provide the evidence that S11e may be useful for early diagnosis,targeted therapy,and prognostication of fibrosarcoma.