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The nonlocal Cahn-Hilliard equation with nonlocal diffusion operator is more suitable for the simulation of microstructure phase transition than the local Cahn-Hilliard equation. In this paper, based on the exponential semi-implicit scalar auxiliary variable method, the highly efficient and accurate schemes (in time) with unconditional energy stability for solving the nonlocal Cahn-Hilliard equation are proposed. On the one hand, we have demonstrated the unconditional energy stability and mass conservation for the nonlocal Cahn-Hilliard equation with its high-order numerical schemes in the continuous and discrete level carefully and rigorously. On the other hand, in order to reduce the calculation and storage cost in numerical simulation, we use the fast solver based on fast Fourier transform and conjugate gradient approach for spatial discretization. Some numerical simulations involving the Gaussian kernel are presented and show the stability, accuracy, efficiency and unconditional energy stability of the proposed schemes. • We establish and analyze the unconditionally energy stable schemes from first- to fourth-order based on ESI-SAV approach for general NCH equation. • The proposed schemes are high-order accurate, easy-to-implement, and unconditionally energy stable. • We use a fast solver based on fast Fourier transform and conjugate gradient approach for spatial discretization of nonlocal terms to reduce the calculation and storage cost. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is rising steadily in incidence, and more effective methods are needed for early detection and image-guided surgery. Glypican-3 (GPC3) is a cell surface biomarker that is overexpressed in early-stage cancer but not in cirrhosis. An IRDye800-labeled 12-mer amino acid sequence was identified, and specific binding to GPC3 was validated in vitroand in orthotopically implanted HCC tumors in vivo. Over 4-fold greater binding affinity and 2-fold faster kinetics were measured by comparison with previous GPC3 peptides. Photoacoustic images showed peak tumor uptake at 1.5 h post-injection and clearance within ∼24 h. Laparoscopic and whole-body fluorescence images showed strong intensity from tumor versus adjacent liver with about a 2-fold increase. Immunofluorescence staining of human liver specimens demonstrated specific binding to HCC versus cirrhosis with 79% sensitivity and 79% specificity, and normal liver with 81% sensitivity and 84% specificity. The near-infrared peptide is promising for early HCC detection in clinical trials.

ABSTRACTRotavirus vaccination is the most effective means to prevent rotavirus gastroenteritis, but its coverage in China is not ideal. We aimed to explore parental preferences for rotavirus vaccination for their children under 5years old to improve vaccination coverage. A Discrete Choice Experiment was conducted online on 415 parents with at least one child under 5years old in 3 cities. Five attributes including vaccine effectiveness, protection duration, risk of mild side-effects, out-of-pocket costs, and time required for vaccination were identified. Each attribute was set at three levels. Mixed-logit models were used to measure parental preferences and the relative importance of vaccine attributes. The optimal vaccination strategy was also explored. 359 samples were included in the analysis. The impacts of the vaccine attribute levels on vaccine choice were all statistically significant (p < .01), except for 1-hour vaccination time. The risk of mild side-effects was the most important factor influencing vaccination. The time required for vaccination was the least important attribute. The largest increase in vaccination uptake (74.45%) occurred with decreased the vaccine risk of mild side-effects from 1/10 to 1/50. The predicted vaccination uptake of the optimal vaccination scenario was 91.79%. When deciding about vaccination, parents preferred the rotavirus vaccination with lower risk of mild side-effects, higher effectiveness, longer protection duration, 2-hour vaccination time and lower cost. The authorities should support enterprises to develop vaccines with lower side-effects, higher effectiveness and longer protection duration in the future. We call for appropriate government subsidies for the rotavirus vaccine.

The AP2/ERF transcription factors (TFs) regulate various processes of plant growth, development, and response to environmental stimuli. Although they have been extensively documented in many plants, little is known about stress responsive APETALA2/ethylene response factor (AP2/ERF) genes in sweetpotato (Ipomoea batatasL.). In this study, 20 putative AP2/ERF genes, named IbERF1, IbERF2, and IbERF5–IbERF23were identified based on the salt‐treated RNA‐seq data from two sweetpotato cultivars with different salt tolerance. Phylogenetic analysis and sequence characterization identified that all the screened IbERF proteins contained a conserved AP2 domain, which belonged to dehydration‐responsive element binding proteins (DREB; 7 members) or ERF (13 members) subfamily. The systematic expression analysis of 12 mainly salt‐induced IbERFsby quantitative real‐time polymerase chain reaction (qRT‐PCR) revealed that most IbERFs were remarkably increased by multiple abiotic stresses, such as NaCl, dehydration, and cold stress. Furthermore, varying degrees of upregulation were also detected in the expression of most IbERFs when treated with hormone abscisic acid, jasmonic acid, and salicylic acid. The expression profiles of IbERFs corroborate their involvement in diverse biological processes. In addition, the IbERF5, which was exclusively upregulated by the treatments, was identified as a nuclear protein without transcriptional activation activity. Collectively, the data of stress responsive IbERFs will provide valuable knowledge for further functional studies of IbERFs in sweetpotato stress tolerance.

NAC (NAM, ATAF, and CUC) transcription factors function as the nodes of regulatory networks in response to various biotic and abiotic stresses. Although they have been widely studied in many species, no knowledge concerning salt‐stress‐responsive NAC genes is available in sweetpotato (Ipomoea batatasL.). In the present study, 12 novel putative NAC genes, designated as IbNAC1Land IbNAC3through IbNAC13, were isolated on the basis of the salt‐stress‐treated RNA sequencing data of two sweetpotato cultivars (‘XuShu 22’ and ‘XuShu 32’) with different levels of salt tolerance. Motif compositions showed that all the IbNAC proteins except IbNAC9 contain five conserved subdomains in the NAC domain region that characterizes the NAC gene family. Furthermore, systematic expression analysis and function evaluation of these IbNACgenes were conducted using quantitative real‐time polymerase chain reaction. The results showed that the expression of most IbNACgenes was exclusively induced by multiple abiotic stresses, including NaCl, dehydration, cold, and heat. Varying degrees of induction were also observed in the transcription levels of these IbNACs, except IbNAC10, when treated with various hormones, including abscisic acid, 1‐aminocyclopropane‐1‐carboxylate, gibberellic acid, and jasmonic acid. Cumulatively, the data of stress‐responsive IbNACgenes in the present study will provide valuable information for further exploring the crucial and diverse roles of IbNACgenes in sweetpotato stress tolerance.

Targeted phototherapy and multi-modal imaging can effectively improve the therapeutic efficacy and reduce the side effects of theranostics. Herein, we constructed novel biocompatible cyanine dye IR808-conjugated hyaluronic acid nanoparticles (HAIR NPs) for photothermal therapy (PTT) with near-infrared fluorescence (FL) and photoacoustic (PA) dual-modal imaging. The nanoparticles formed stable nanostructures under aqueous conditions with uniform size distribution. The HAIR NPs were rapidly taken up by the human lung cancer cells A549 viaCD44 (the hyaluronic acid receptor on the surface of tumor cells) receptor-mediated endocytosis. Upon laser irradiation, the HAIR NPs enabled good near-infrared fluorescence imaging and photoacoustic imaging in tumor-bearing mice. In addition, the tight nanostructure arising from the covalent link between HA and IR808 could significantly improve the light-thermal conversion efficiency of IR808. Under a low dose of laser power, the HAIR NPs presented more effective photothermal therapy for the suppression of tumor growth than free IR808 in vitroand in vivo. Overall, these results indicate that the HAIR NPs may be an extremely promising nanoplatform in cancer theranostics for targeted PTT under FL and PA dual-modal imaging.

ABSTRACTTargeting PD1/PDL1 with blocking antibodies for cancer therapy has shown promising benefits in the clinic, but only approximately 20–30% of patients develop durable clinical responses to the treatment. Bispecific antibodies (BsAbs) that combine PD1/PDL1 blockade with the modulation of another immune checkpoint target may have greater potential to enhance immune checkpoint blockade therapy. In this study, we identified an anti-PD1 monoclonal antibody, 609A, whose heavy chain can pair with a variety of light chains from different antibodies while maintaining its PD1 binding/blocking activity. Taking advantage of this property and using a linear F(ab’)2format, we successfully produced a series of tetravalent IgG-like BsAbs that simultaneously target PD1 and other immune checkpoint targets, including PDL1 and CTLA4. The BsAbs exhibited superior bioactivities in vitro and in vivo compared to their respective parental mAbs. Importantly, the BsAbs demonstrated the desired IgG-like physicochemical properties in terms of high-level expression, ease of purification to homogeneity, good stability and in vivo pharmacokinetics. In summary, we describe a novel and flexible plug-and-play platform to engineer IgG-like BsAbs with excellent development potential for clinical applications.

•The anti-PD1 x anti-EGFR bispecific antibody (BsAb) exhibited all in-vitro bioactivities comparable to that of the parental mAbs and showed anti-tumor efficacies of each of the two arms on par with the mAbs in-vivo.•The anti-PD1 x anti-EGFR bispecific antibody (BsAb) retained full ADCC towards cancer cells but not to T cells. Thus the BsAb is capable of killing tumor cells via ADCC while sparing T cells for T cell-induced anti-tumor immunity.•The anti-PD1 x anti-EGFR bispecific antibody (BsAb) exhibited significantly stronger tumor cell killing effects in the presence of PBMC relative to that of combination of cetuximab with an anti-PD1 mAb, 609A.