Lung-Targeted Transgene Expression of Nanocomplexed Ad5 Enhances Immune Response in the Presence of Preexisting Immunity

Recombinant adenovirus serotype 5(Ad5)vector has been widely applied in vaccine development targeting infectious diseases,such as Ebola virus disease and coronavirus disease 2019(COVID-19).However,the high prevalence of preexisting anti-vector immunity compromises the immunogenicity of Ad5-based vaccines.Thus,there is a substantial unmet need to minimize preexisting immunity while improving the insert-induced immunity of Ad5 vectors.Herein,we address this need by utilizing biocompatible nanoparticles to modulate Ad5–host interactions.We show that positively charged human serum albumin nanoparticles((+)HSAnp),which are capable of forming a complex with Ad5,significantly increase the transgene expression of Ad5 in both coxsackievirus–adenovirus receptor-positive and-negative cells.Furthermore,in charge-and dose-dependent manners,Ad5/(+)HSAnp complexes achieve robust(up to227-fold higher)and long-term(up to 60 days)transgene expression in the lungs of mice following intranasal instillation.Importantly,in the presence of preexisting anti-Ad5 immunity,complexed Ad5-based Ebola and COVID-19 vaccines significantly enhance antigen-specific humoral response and mucosal immunity.These findings suggest that viral aggregation and charge modification could be leveraged to engineer enhanced viral vectors for vaccines and gene therapies.

A cross-species co-functional gene network underlying leaf senescence

The complex leaf senescence process is governed by various levels of transcriptional and translational regulation.Several features of the leaf senescence process are similar across species,yet the extent to which the molecular mechanisms underlying the process of leaf senescence are conserved remains unclear.Currently used experimental approaches permit the identification of individual pathways that regulate various physiological and biochemical processes;however,the large-scale regulatory network underpinning intricate processes like leaf senescence cannot be built using these methods.Here,we discovered a series of conserved genes involved in leaf senescence in a common horticultural crop(Solanum lycopersicum),a monocot plant(Oryza sativa),and a eudicot plant(Arabidopsis thaliana)through analyses of the evolutionary relationships and expression patterns among genes.Our analyses revealed that the genetic basis of leaf senescence is largely conserved across species.We also created a multi-omics workf low using data from more than 10000 samples from 85 projects and constructed a leaf senescence-associated co-functional gene network with 2769 conserved,high-confidence functions.Furthermore,we found that the mitochondrial unfolded protein response(UPR^(mt))is the central biological process underlying leaf senescence.Specifically,UPR^(mt) responds to leaf senescence by maintaining mitostasis through a few cross-species conserved transcription factors(e.g.NAC13)and metabolites(e.g.ornithine).The co-functional network built in our study indicates that UPR^(mt) figures prominently in cross-species conserved mechanisms.Generally,the results of our study provide new insights that will aid future studies of leaf senescence.

磁响应性碳量子点的制备

碳量子点(CQDs)因为具有良好生物相容性和独特光学特性常被用作光催化剂、荧光探针、生物传感器、药物载体等。本文研究了用4种不同碳源体系经水热法制备水溶性CQDs,通过透射电镜(TEM)、荧光光谱(PL)及X射线衍射仪(XRD)等方法表征,结果表明:以明胶-柠檬酸复合体系为碳源,当加入适量Fe(II)、Fe(III)离子(nFe(II):nFe(III) = 1:2),可合成平均粒径约3 nm、储存稳定且具有磁响应性的CQDs,其荧光量子产率可高达50.29%。

空气加速器结构对熔喷气流场的影响

为降低熔喷纤维的直径,设计了带有空气加速器的新型模头,考察了空气加速器结构对其下方流场的影响。借助Fluent软件对新型模头的气流场进行了数值计算,分析了流场中空气速度和空气温度的分布规律。研究结果表明,空气加速器结构对流场性能有很大的影响。当空气加速器间距减小、空气加速器高度增加、空气加速器倾角减小、空气加速器侧面为内圆弧状时,纺丝线上的空气速度峰值增大、空气温度提高。综合对比,在空气加速器半间距为10mm、空气加速器高度为30 mm、空气加速器倾角为60°、空气加速器侧面为内圆弧状的条件下,新型模头下方流场中的气流速度极值最大、气流温度更高。

Lithium-Ion Battery Screening by K-Means with DBSCAN for Denoising

Batteries are often packed together to meet voltage and capability needs.However,due to variations in raw materials,different ages of equipment,and manual operation,there is inconsistency between batteries,which leads to reduced available capacity,variability of resistance,and premature failure.Therefore,it is crucial to pack similar batteries together.The conventional approach to screening batteries is based on their capacity,voltage and internal resistance,which disregards how batteries perform during manufacturing.In the battery discharge process,real time discharge voltage curves(DVCs)are collected as a set of unlabeled time series,which reflect how the battery voltage changes.However,few studies have focused on DVC based battery screening.In this paper,we provide an effective approach for battery screening.First,we apply interpolation on DVCs and give a method to transform them into slope sequences.Then,we use density-based spatial clustering of applications with noise(DBSCAN)for denoising and treat the remaining data as input to the K-means algorithm for screening.Finally,we provide the experimental results and give our evaluation.It is proved that our method is effective.

To jump or not to jump:momentum of jumps in crude oil price volatility prediction

A well-documented finding is that explicitly using jumps cannot efficiently enhance the predictability of crude oil price volatility.To address this issue,we find a phenomenon,“momentum of jumps”(MoJ),that the predictive ability of the jump component is persistent when forecasting the oil futures market volatility.Specifically,we propose a strategy that allows the predictive model to switch between a benchmark model without jumps and an alternative model with a jump component according to their recent past forecasting performance.The volatility data are based on the intraday prices of West Texas Intermediate.Our results indicate that this simple strategy significantly outperforms the individual models and a series of competing strategies such as forecast combinations and shrinkage methods.A mean–variance investor who targets a constant Sharpe ratio can realize the highest economic gains using the MoJ-based volatility forecasts.Our findings survive a wide variety of robustness tests,including different jump measures,alternative volatility measures,various financial markets,and extensive model specifications.

The effects of various chemotherapy regimens on the expression of PCNA and human breast cancer xenograft (MCF-7) transplanted in nude mice

Objective: To investigate the antitumor activity of different combination regimens to human breast cancer xeno-graft (MCF-7) transplanted in nude mice and the effects on the expression of PCNA, and to evaluate the value of PCNA as predictive factor for the response of chemotherapy and individualized treatment. Methods: (1) 88 nude mice models of human breast cancer xenograft (MCF-7) were established, and then were randomly divided into control group and 10 chemotherapy groups (each group, n = 8). Among them, the mice of 5 chemotherapy groups were treated intraperitoneally/orally by 5 com-bination chemotherapy regimens (CMF, CAF, NP, TP, Xeloda) respectively at 1/3 LD10 dosage schedule (dose lethal to 10% of the mice), and that in another 5 chemotherapy groups were treated at 2/3 LD10 dosage schedule. Control animals were administered intraperitoneally with normal saline. (2) The body weight of nude mice and transplanted tumor growth were ob-served and recorded, then inhibition rate of tumor growth was calculated. (3) The pathological features of transplanted tumor were studied under microscope. The expression of proliferating cell nuclear antigen (PCNA) was comparatively studied in chemotherapy group and control group by SP immunohistochemical method and flow cytometry analysis. Results: (1) Body weight, tumor weight and inhibition rate of tumor growth of athymic mice bearing cancer: Body weights and tumor weights of nude mice in every 2/3 LD10 chemotherapy group were significantly lower than those of the control group (P < 0.05), and the inhibition rates of tumor growth were 83.1%, 75.5%, 84.6%, 87.9% and 91.0%, respectively. Body weights of athymic mice in every 1/3 LD10 chemotherapy group were lower than that of the control (P < 0.05). The results showed that the 2/3 LD10 chemotherapy groups could reflect the effect of combination chemotherapy on the nude mice and the clinical dependability was better. So the data of 2/3 LD10 chemotherapy groups were appropriated for successive study. (2) Immunohistochemical studies: The expressions of PCNA in every chemotherapy group were significantly lower than that of the control (P < 0.05). Moreover, the expression of PCNA in NP group was significantly lower than those of CMF, CAF, TP and Xeloda groups (P < 0.05), while the expressions of TP and Xeloda groups were significantly lower than those of CMF and CAF groups (P < 0.05). (3) FCM analysis: FI values of PCNA in every chemotherapy group were significantly lower than that of the control (P < 0.05). FI values of PCNA in TP and Xeloda groups were significantly lower than those of CMF and CAF groups (P < 0.05), while the value of NP group was significantly lower than that of CMF group (P < 0.05). (4) Relationship between PCNA expression and pathologic response: The expression of PCNA was significantly correlated with pathological therapeutic response of transplanted breast carcinoma (P = 0.001). Conclusion: In vivo chemosensitivity testing with 2/3 LD10 dosage combinations in nude mice bearing cancer can reflect the effects of chemotherapeutics and affects of organism exactly. Various chemotherapy regimens all can decrease the expression of PCNA in breast cancer. The PCNA can be regarded as the factor to judge the response to chemotherapy, and it become possibly one of the prospective factors in the selection of chemotherapy regimen and play a rule in individualized therapy in the clinic.

An emerging antibacterial nanovaccine for enhanced chemotherapy by selectively eliminating tumor-colonizing bacteria

Fusobacterium nucleatum(F.nucleatum),an oral anaerobe,is prevalent in colorectal cancer and is closely related to increased cancer cell growth,metastasis,and poor treatment outcomes.Bacterial vaccines capable of selectively eliminating bacteria present a promising approach to targeting intratumor F.nucleatum,thereby enhancing cancer treatment.Although adjuvants have been employed to enhance the immune response,the vaccine’s effectiveness is constrained by inadequate T-cell activation necessary for eradicating intracellular pathogens.In this study,we developed a minimalistic,biomimetic nanovaccine by integrating highly immunostimulatory adjuvant cholesterol-modified CpG oligonucleotides into the autologously derived F.nucleatum membranes.Compared to the traditional vaccines consisting of inactivated bacteria and Alum adjuvant,the nanovaccine coupled with bacterial membranes and adjuvants could remarkably improve multiple antigens and adjuvant co-delivery to dendritic cells,maximizing their ability to achieve effective antigen presentation and strong downstream immune progress.Notably,the nanovaccine exhibits outstanding selective prophylactic and therapeutic effects,eliminating F.nucleatum without affecting intratumoral and gut microbiota.It significantly enhances chemotherapy efficacy and reduces cancer metastasis in F.nucleatum-infected colorectal cancer.Overall,this work represents the rational application of bacterial nanovaccine and provides a blueprint for future development in enhancing the antitumor effect against bacterial-infected cancer.

Active-transporting of charge-reversal Cu(Ⅱ)-doped mesoporous silica nanoagents for antitumor chemo/chemodynamic therapy

Fe-based Fenton agents can generate highly reactive and toxic hydroxyl radicals(·OH)in the tumor microenvironment(TME)for chemodynamic therapy(CDT)with high specificity.However,the low pH environment and insufficient endogenous hydrogen peroxide(H_(2)O_(2))of the highly efficient Fenton reaction limits its practical application in clinic.Here,a Cu(Ⅱ)-doped mesoporous silica nanoagent(Cu-MSN)with excellent dispersity was successfully developed.After loaded with doxorubicin(DOX)and ascorbate(AA),Cu-MSN@DA was coated with active targeting ligand folic acid(FA),dimethyl maleic an-hydride(DMMA)and carboxymethyl chitosan(CMC)to obtain an active transporting nanoagent(FCDC@Cu-MSN@DA)with tunable charge-reversal property,which is more adaptable to the pH value of TME than Fe-based Fenton agents,and can self-supply exogenous H_(2)O_(2)by ascorbate to produce more toxic·OH to trigger the apoptosis of cancer cells.Meanwhile,the high level of glutathione(GSH)in TME can reduce Cu(Ⅱ)to Cu(I)by Fenton-like reaction,increasing the generation rate of·OH and relieving tumor antioxidant ability.The supply of exogenous H_(2)O_(2)significantly enhanced the synergistic effect of CDT by oxidative damage.Together with DOX-induced cell apoptosis,this novel nanoagent FCDC@Cu-MSN@DA can achieve maximum therapeutic efficacy,creating a new model of safe and effective tumor treatment with high specificity.

Malignant ovarian tumors during pregnancy:Diagnostic evaluation,optimal treatment,and future perspective

To the Editor:Malignant ovarian tumors during pregnancy(MOTP)rank second after cervical cancer among gynecological malignancies diagnosed during pregnancy,and most women today hope to maintain pregnancy and preserve fertility,which complicates oncologic treatment,as all potential complications and prognoses should be carefully considered for both the mother and fetus.A coordinated approach from a multidisciplinary team involving gynecological oncologists,obstetricians,and pathologists is recommended.

A causal multiomics study discriminates the early immune features of Ad5-vectored Ebola vaccine recipients

The vaccine-induced innate immune response is essential for the generation of an antibody response.To date,how Ad5-vectored vaccines are influenced by preexisting anti-Ad5 antibodies during activation of the early immune response remains unclear.Here,we investigated the specific alterations in GP1,2-specific IgG-related elements of the early immune response at the genetic,molecular,and cellular levels on days 0,1,3,and 7 after Ad5-EBOV vaccination.In a causal multiomics analysis,distinct early immune responses associated with GP1,2-specific IgG were observed in Ad5-EBOV recipients with a low level of preexisting anti-Ad5 antibodies.This study revealed the correlates of the Ad5-EBOV-induced IgG response and provided mechanistic evidence for overcoming preexisting Ad5 immunity during the administration of Ad5-vectored vaccines.

Side-chain engineering for regulating structure and properties of a novel visible-light-driven perylene diimide-based supramolecular photocatalyst

Systematic and in-depth explorations of the effects of side-chain modulation on the molecular assembly,optoelectronic properties,and photocatalytic properties of supramolecular systems,as well as the kinetics of charge separation and migration in these systems,are rare.In this study,a novel supramolecular photocatalyst with an alkoxy side chain(S-EPDI)was successfully developed through subtle design of the short and linear alkoxyl side chains,affording a phenol degradation efficiency approximately four times that of the counterpart with an alkyl side chain(S-APDI).Notably,combined density functional theory(DFT)calculations,absorption spectroscopy,and other characterizations revealed that the perylene diimide(PDI)molecular units,throughπ-πstacking,formed a unique rotationally offset stacked supramolecular structure,exhibiting a significant dipole moment.This gave rise to the formation of a larger inherent electric field within S-EPDI compared to S-APDI.Moreover,the study quantitatively demonstrated that a stronger inherent electric field and lower rate of surface charge recombination facilitate efficient separation of the photogenerated carriers.Therefore,the side-chain molecular engineering method employed in this study offers an effective approach for modulating the kinetics of charge migration.

The host microbiota is associated with the occurrence and development of esophageal squamous cell carcinoma

DearEditor,Microecology is an emerging research area,particularly that of the digestive system(Marchesi et al.,2016;Wang et al.,2018).The intestinal microbiota contains a rich and complex microbial ecosystem that is in dynamic balance,the disruption of which can result in disease(Yatsunenko et al.,2012;Li et al.,2017;He et al.,2018).For example,studies have found that the esophagus has a variety of colonizing bacteria that may be related to esophageal cancer.

Dehydroepiandrosterone Inhibited the Bone Resorption through the Upregulation of OPG/RANKL

The plasma level of dehydroepiandrosterone （DHEA） is decreases gradually along with aging. The beneficial effects of DHEA as an anti-aging steroid, such as the stimulatory effect on immune system, anti-diabetes mellitus, antl-atherosclerosis, anti.dementia, anti-obesity and anti-osteoporosis have been demonstrated in experiment both in vitro and in vivo. It is important to investigate the effective mechanism of DHEA in therapeutics for postmenopausal osteoporosis. Having isolated and cultured osteoblasts （OBs） and osteoclasts （OCs）, we analysed the effect of DHEA on osteoblastic viability, regulation of DHEA on the expression of osteoprotegerin （OPG）/receptor activator of NF-κB Ugand （RANKL） mRNA in OBs, and then observed the action of DHEA on bone resorption of OCs in the presence or absence of OBs. The results showed that DHEA improved viability of OBs within the concentration range of 10^-8-10^-6 M, especially at the concentration of 10^-7 M. DHEA could apparently increase the ratio of OPG/RANKL mRNA in OBs. In the presence of OBs, DHEA could decrease the number and area of absorption lacuna of specula. We concluded, therefore, only in the presence of OBs, DHEA could inhibit the bone resorption of OCs, which may be mediated by OPG/RANKL of OBs.

Antenna-assisted picosecond control of nanoscale phase transition in vanadium dioxide

Nanoscale devices in which the interaction with light can be configured using external control signals hold great interest for next-generation optoelectronic circuits.Materials exhibiting a structural or electronic phase transition offer a large modulation contrast with multi-level optical switching and memory functionalities.In addition,plasmonic nanoantennas can provide an efficient enhancement mechanism for both the optically induced excitation and the readout of materials strategically positioned in their local environment.Here,we demonstrate picosecond all-optical switching of the local phase transition in plasmonic antenna-vanadium dioxide(VO_(2))hybrids,exploiting strong resonant field enhancement and selective optical pumping in plasmonic hotspots.Polarization-and wavelength-dependent pump–probe spectroscopy of multifrequency crossed antenna arrays shows that nanoscale optical switching in plasmonic hotspots does not affect neighboring antennas placed within 100 nm of the excited antennas.The antenna-assisted pumping mechanism is confirmed by numerical model calculations of the resonant,antenna-mediated local heating on a picosecond time scale.The hybrid,nanoscale excitation mechanism results in 20 times reduced switching energies and 5 times faster recovery times than a VO_(2) film without antennas,enabling fully reversible switching at over two million cycles per second and at local switching energies in the picojoule range.The hybrid solution of antennas and VO_(2) provides a conceptual framework to merge the field localization and phase-transition response,enabling precise,nanoscale optical memory functionalities.

Strontium modulates osteogenic activity of bone cement composed of bioactive borosilicate glass particles by activating Wnt/β-catenin signaling pathway

There is a need for synthetic grafts to reconstruct large bone defects using minimal invasive surgery.Our previous study showed that incorporation of Sr into bioactive borate glass cement enhanced the osteogenic capacity in vivo.However,the amount of Sr in the cement to provide an optimal combination of physicochemical properties and capacity to stimulate bone regeneration and the underlying molecular mechanism of this stimulation is yet to be determined.In this study,bone cements composed of bioactive borosilicate glass particles substituted with varying amounts of Sr(0 mol%to 12 mol%SrO)were created and evaluated in vitro and in vivo.The setting time of the cement increased with Sr substitution of the glass.Upon immersion in PBS,the cement degraded and converted more slowly to HA(hydroxyapatite)with increasing Sr substitution.The released Sr2+modulated the proliferation,differentiation,and mineralization of hBMSCs(human bone marrow mesenchymal stem cells)in vitro.Osteogenic characteristics were optimally enhanced with cement(designated BG6Sr)composed of particles substituted with 6mol%SrO.When implanted in rabbit femoral condyle defects,BG6Sr cement supported better peri-implant bone formation and bone-implant contact,comparing to cements substituted with 0mol%or 9mol%SrO.The underlying mechanism is involved in the activation of Wnt/β-catenin signaling pathway in osteogenic differentiation of hBMSCs.These results indicate that BG6Sr cement has a promising combination of physicochemical properties and biological performance for minimally invasive healing of bone defects.

Study on Wall Temperature Distribution of Oscillating Tube

The wall temperature distribution and heat transfer process of the oscillating tube have been investigated in thispaper using both numerical simulation and experimental method. The wall temperature of oscillating tube increasesrapidly in the inlet and then decreases slowly, moreover, the rally phenomenon of wall temperature nearthe closed end is observed. With the increase of jet flow frequency, the highest wall temperature increases and thelocation of that moves towards the inlet. The velocity of pressure wave in the oscillating tube almost remainsconstant even its intensity changes. The quantity of heat transfer between the gas and inner wall of the oscillatingtube determines the wall temperature of every location, and the pressure wave disturbance can cause the heattransfer quantity change. Each pressure wave has its own disturbance range. The wall temperature distribution canbe explained by the change of pressure wave intensity and its disturbance time. Besides, the step and rally of walltemperature are discussed, which shows that the conditions of heat transfer can be improved due to intersection orreflection of pressure waves.

Comparative characterization of antibody responses induced by Ad5-vectored spike proteins of emerging SARS-CoV-2 VOCs

Highly divergent SARS-CoV-2 variants have continuously emerged and spread around the world,and updated vaccines and innovative vaccination strategies are urgently needed to address the global SARS-COV2 pandemic.Here,we established a series of Ad5-vectored SARS-CoV-2 variant vaccines encoding multiple spike proteins derived from the Alpha,Beta,Gamma,Epsilon,Kappa,Delta and Omicron lineages and analyzed the antibody immune responses induced by single-dose and prime-boost vaccination strategies against emerging SARS-CoV-2 variants of concern(VOCs).Single-dose vaccination with SARS-CoV-2 variant vaccines tended to elicit the optimal self-matched neutralizing effects,and Ad5-B.1.351 produced more broad-spectrum cross-neutralizing antibodies against diverse variants.In contrast,prime-boost vaccination further strengthened and broadened the neutralizing antibody responses against highly divergent SARS-CoV-2 variants.The heterologous administration of Ad5-B.1.617.2 and Ad5-B.1.429 to Ad5-WT-primed mice resulted in superior antibody responses against most VOCs.In particular,the Omicron spike could only stimulate self-matched neutralizing antibodies with infrequent cross-reactivities to other variants used in single-dose vaccination strategies;moreover,with prime-boost regimens,this vaccine elicited an optimal specific neutralizing antibody response to Omicron,and prompted cross-antibody responses against other VOCs that were very similar to those obtained with Ad5-WT booster.Overall,this study delineated the unique characteristics of antibody responses to the SARS-CoV-2 VOC spikes with the single-dose or prime-boost vaccination strategies and provided insight into the vaccine development of next SARS-CoV-2 VOCs.

Corrigendum to“Strontium modulates osteogenic activity of bone cement composed of bioactive borosilicate glass particles by activating Wnt/β-catenin signaling pathway”[Bioact.Mater.5(2020)334-347]

The authors regret that the printed version of the above article contained a number of errors which were not identified during the proofing stage.The correct and final version follows.The authors would like to apologies for any inconvenience caused.The authors regret:1.“…and the underlying molecular mechanism of this simulation is yet to be determined”,Page 335,needs to be corrected to“and the underlying molecular mechanism of this stimulation is yet to be determined”.

Investors’perspective on forecasting crude oil return volatility:Where do we stand today?

In this paper,we review studies of oil volatility prediction from a new perspective:that of investors who require economic evaluations of forecasting performance.Our results indicate that no single volatility model outperforms all of the competing models,of which GARCH and realized volatility models are the most popular.Most studies evaluate forecasting performance using two criteria:value at risk and hedging effectiveness.Parameter instability and model uncertainty are technical issues that affect out-of-sample performance.Most studies assess volatility forecasts from the perspectives of portfolio management and derivative pricing.Whether oil volatility can predict economic variables and the asset pricing implications of oil volatility for financial markets are important topics that require attention.