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An unprecedented protocol for the synthesis of 1,2,4-oxadiazoles from carbamates has been developed by employing nitriles as both substrates and solvents. This one-pot procedure achieves the formation of C═N bonds via TFA-mediated [3+2] annulation. A series of 1,2,4-oxadiazoles are synthesized in moderate to good yields.

The gradual fusion of intelligent transportation systems with metaverse technologies is giving rise to vehicular metaverses, which blend virtual spaces with physical space. As indispensable components for vehicular metaverses, Vehicular Twins (VTs) are digital replicas of Vehicular Metaverse Users (VMUs) and facilitate customized metaverse services to VMUs. VTs are established and maintained in RoadSide Units (RSUs) with sufficient computing and storage resources. Due to the limited communication coverage of RSUs and the high mobility of VMUs, VTs need to be migrated among RSUs to ensure real-time and seamless services for VMUs. However, during VT migrations, physical-virtual synchronization and massive communications among VTs may cause identity and location privacy disclosures of VMUs and VTs. In this article, we study privacy issues and the corresponding defenses for VT migrations in vehicular metaverses. We first present four kinds of specific privacy attacks during VT migrations. Then, we propose a VMU-VT dual pseudonym scheme and a synchronous pseudonym change framework to defend against these attacks. Additionally, we evaluate average privacy entropy for pseudonym changes and optimize the number of pseudonym distribution based on inventory theory. Numerical results show that the average utility of VMUs under our proposed schemes is 33.8% higher than that under the equal distribution scheme, demonstrating the superiority of our schemes.

Lithium slag (LS) is a waste residue generated during lithium extraction, posing significant environmental challenge due to its extensive accumulation. This study proposes a method of utilizing thermally activated LS as the sole precursor for geopolymer synthesis. The thermal activation mechanism of LS was investigated using XRD, FTIR, ICP, and SEM techniques, while exploring the optimal composition for LS geopolymers(LSG). The research revealed that heating at 700 °C increased the amorphous content of LS from 15.9 % to 48.1 %, altering the chemical structure of its aluminosilicates and enhancing its leaching capacity in alkaline environments, thereby boosting its reactivity. The activator modulus and alkali equivalent were found to significantly influence the strength and microstructure of LSG. As the modulus increased from 1.0 to 1.4, geopolymer strength initially rose before declining, whereas strength progressively increased with alkali equivalent from 0.10 to 0.16. The geopolymer synthesized with a modulus of 1.2 and alkali equivalent of 0.16 exhibited the highest compressive strength of 53.1 MPa after 28 days. Test results indicated that the internal structure of LSG primarily comprised unreacted particles, N(C)-A-S-H gel, and microcracks. The increased alkali equivalent facilitated the dissolution of Si4+and Al3+within LS, intensifying geopolymerization to produce more N(C)-A-S-H gel, thereby densifying the structure and significantly enhancing compressive strength. This study elucidates the mechanism by which high-temperature calcination enhances LS reactivity, as well as the impact of activator on compressive strength and microstructural properties of LSG, offering new insights into the engineering applications of LS in high-performance cementitious materials.

Excessive acid deposition causes soil acidification, and changes the soil microhabitat, thus affecting the survival and reproduction of soil organisms. Folsomia candida(Collembola, Isotomidae), as a model organism, is widely used to assess the chemical toxicity in soil, and its avoidance response can indicate the environmental changes. In this study, we used Folsomia candidato assess the risks of acid deposition on soil ecosystems. Different pH (3.0, 3.5, 4.0, 4.5, 5.0, and 5.5) treatments were set up in petri dish experiments, and the avoidance behavior of Folsomia candidawas measured after 12, 24, and 48 h exposure to the pH conditions. The results indicated that (1) both the exposure duration and pH level influenced avoidance behavior of collembolan. (2) After 12 h exposure, most of the individuals showed avoidance behavior but without significant differences among the treatments. (3) After 24 h exposure, significant avoidance behavior was observed at pH 3.0, 3.5, and 4.0. (4) After 48 h exposure, avoidance behavior was found in all treatment conditions except for pH 5.5. This study clarified the direct responses of soil fauna to acid deposition, and indicated that both pH and length of exposure influenced the avoidance behavior of Folsomia candida. During the experimental period, the collembolan reacted negatively and showed consistent avoidance behavior at pH 3.0, 3.5, and 4.0. Reversed avoidance behavior was apparent between pH 4.5 and 5.0 and not observed at pH 5.5, indicating that the latter was the preferred pH environment.

Abstract The purpose of this study was to evaluate the properties of asphalt and its mixtures modified with Decarbomodiphenyl ether (EBPED), Antimony trioxide and zinc borate (ZB). Thermal analysis and [...]

Although ABSCISIC ACID INSENSITIVE 4 (ABI4) was initially demonstrated as a key positive regulator in the phytohormone abscisic acid (ABA) signaling cascade, multiple studies have now shown that it is actually involved in the regulation of several other cascades, including diverse phytohormone biogenesis and signaling pathways, various developmental processes (such as seed dormancy and germination, seedling establishment, and root development), disease resistance and lipid metabolism. Consistent with its versatile biological functions, ABI4 either activates or represses transcription of its target genes. The upstream regulators of ABI4 at both the transcription and post-transcription levels have also been documented in recent years. Consequently, a complicated network consisting of the direct target genes and upstream regulators of ABI4, through which ABI4 participates in several phytohormone crosstalk networks, has been generated. In this review, we summarize current understanding of the sophisticated ABI4-mediated molecular networks, mainly focusing on diverse phytohormone (including ABA, gibberellin, cytokinin, ethylene, auxin, and jasmonic acid) crosstalks. We also discuss the potential mechanisms through which ABI4 receives the ABA signal, focusing on protein phosphorylation modification events.

ABSTRACTLiver cancer (LC) is the third largest contributor to mortality related to malignancies worldwide. The study was directed toward exploring the effects of miR-223 on LC proliferation and apoptosis. Dual luciferase reporter assay (DLRA) was carried out to verify the direct relationship of TLR4 mRNA 3′-UTR and miR-223-3p. HepG2 cells subsequently were transfected with miR-223 mimics. MTT assay and flow cytometric assay were carried out to evaluate proliferation and cell death, respectively. Toll-like receptor 4 (TLR4) transcription and translation were examined via qRT-PCR and western blotting, respectively. We observed that the miR-223 expression in LC tissues was inhibited, accompanied by reinforced TLR4 expression. Excessive miR-223 expression noticeably inhibited cell growth and promoted apoptosis in HepG2 and Bel-7402 HCC cell lines. Additionally, knockdown of TLR4 expression could suppress cell growth and promote apoptosis in HepG2 and Bel-7402 HCC cell lines. Moreover, TLR4 expression was suppressed via miR-223 transfection. T DLRA verified that miR-223 directly targeted TLR4. TLR4 over-expression canceled the effects of miR-223 on LC proliferation and apoptosis. Collectively, our findings suggest that miR-223 is an inhibitor of malignancy and participates in the inhibition of malignancy generation and reinforcement of LC cell death by targeting TLR4.

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Pair approximation model is an effective tool to study epidemic spread on complex networks. It can more accurately capture the effects of network structure on the spreading process. That then helps us grasp the spreading laws of epidemics on networks and further make effective prevention and control measures. Vaccination, an important measure for prevention and control of infectious disease, has made great achievements in public health. In this paper we study vaccination strategies with the help of pair approximation epidemic model with demographics. We firstly introduce constant vaccination into SIR pair approximation model. The reproduction number and endemic prevalence of disease are investigated, the critical vaccination rate which can help to control disease transmission is also given. Considering the restriction of financial resources, it is necessary to control disease transmission simultaneously to reduce vaccination cost. To this end, we further investigate optimal vaccination of SIR pair approximation model by use of optimal control theory. The existence of optimal solution is established and optimality system is derived. Finally, a series of stochastic simulations on different initial networks are performed to demonstrate our theoretical models and some numerical simulations are provided to observe and analyze different vaccination strategies. [ABSTRACT FROM AUTHOR]

Immune tolerance induction (ITI) with aggressive infusion of factor VIII (FVIII) is the current strategy used to eradicate FVIII inhibitors and restore normal FVIII pharmacokinetics in inhibitor patients. Whether the use of FVIII products containing von Willebrand factor (VWF) will affect the efficacy of ITI is still controversial. In this study, we explored the impact of VWF on FVIII memory immune responses in hemophilia A (HA) mice. A T-cell proliferation assay and cytokine profile analysis were used to study FVIII-primed CD4+ T cells. When CD4+ T cells from primed FVIIInull mice were restimulated with recombinant human FVIII (rhF8) plus recombinant human VWF (rhVWF) in vitro, the percentages of daughter CD4+ T cells were significantly decreased compared with the groups cultured with rhF8 only. Levels of interferon-? and interleukin 10 were significantly lower in the rhF8 plus rhVWF groups than in the rhF8 groups. When memory B-cell pools from primed FVIIInull mice were cultured with rhF8 with or without rhVWF to induce differentiation of memory B cells into antibody-secreting cells (ASCs), the number of ASCs was significantly lower in the rhF8 plus VWF group than in the rhF8 group. When memory B-cell pools were transferred into NSGF8KO mice followed by rhF8 immunization with or without rhVWF, the titers of anti-F8 inhibitors and total immunoglobulin G were significantly higher in the rhF8 group than in the rhF8 plus rhVWF group, with an average difference of 2.23- and 2.04-fold. Together, our data demonstrate that VWF attenuates FVIII memory immune responses in HA mice.

Fluctuations of conserved quantities, such as baryon, electric charge, and strangeness number, are sensitive observables in relativistic heavy-ion collisions to probe the QCD phase transition and search for the QCD critical point. In this paper, we review the experimental measurements of the cumulants (up to fourth order) of event-by-event net-proton (proxy for net-baryon), net-charge and net-kaon (proxy for net-strangeness) multiplicity distributions in Au+Au collisions at $$\sqrt{{s}_{\text{NN}}}=7.7, 11.5, 14.5, 19.6, 27, 39, 62.4, 200$$ sNN=7.7,11.5,14.5,19.6,27,39,62.4,200 GeV from the first phase of beam energy scan program at the relativistic heavy-ion collider (RHIC). We also summarize the data analysis methods of suppressing the volume fluctuations, auto-correlations, and the unified description of efficiency correction and error estimation. Based on theoretical and model calculations, we will discuss the characteristic signatures of critical point as well as backgrounds for the fluctuation observables in heavy-ion collisions. The physics implications and the future second phase of the beam energy scan (2019–2020) at RHIC will also be discussed.

Platelets are a rich source of many cytokines and chemokines including transforming growth factor β 1 (TGF-β1). TGF-β1 is required to convert conventional CD4+T (Tconv) cells into induced regulatory T (iTreg) cells that express the transcription factor Foxp3. Whether platelet contents will affect Treg cell properties has not been explored. In this study, we show that unfractionated platelet lysates (pltLys) containing TGF-β1 efficiently induced Foxp3 expression in Tconv cells. The common Treg cell surface phenotype and in vitro suppressive activity of unfractionated pltLys-iTreg cells were similar to those of iTreg cells generated using purified TGF-β1 (purTGFβ-iTreg) cells. However, there were substantial differences in gene expression between pltLys-iTreg and purTGFβ-iTreg cells, especially in granzyme B, interferon γ, and interleukin-2 (a 30.99-, 29.18-, and 17.94-fold difference, respectively) as determined by gene microarray analysis. In line with these gene signatures, we found that pltLys-iTreg cells improved cell recovery after transfer and immune suppressive function compared with purTGFβ-iTreg cells in factor VIII (FVIII)–deficient (F8null, hemophilia A model) mice after recombinant human FVIII (rhF8) infusion. Acute antibody-mediated platelet destruction in F8nullmice followed by rhF8 infusion increased the number of Treg cells and suppressed the antibody response to rhF8. Consistent with these data, ex vivo proliferation of F8-specific Treg cells from platelet-depleted animals increased when restimulated with rhF8. Together, our data suggest that pltLys-iTreg cells may have advantages in emerging clinical applications and that platelet contents impact the properties of iTreg cells induced by TGF-β1.

Platelets are a rich source of many cytokines and chemokines including transforming growth factor ß 1 (TGF-ß1). TGF-ß1 is required to convert conventional CD4+ T (Tconv) cells into induced regulatory T (iTreg) cells that express the transcription factor Foxp3. Whether platelet contents will affect Treg cell properties has not been explored. In this study, we show that unfractionated platelet lysates (pltLys) containing TGF-ß1 efficiently induced Foxp3 expression in Tconv cells. The common Treg cell surface phenotype and in vitro suppressive activity of unfractionated pltLys-iTreg cells were similar to those of iTreg cells generated using purified TGF-ß1 (purTGFß-iTreg) cells. However, there were substantial differences in gene expression between pltLys-iTreg and purTGFß-iTreg cells, especially in granzyme B, interferon ?, and interleukin-2 (a 30.99-, 29.18-, and 17.94-fold difference, respectively) as determined by gene microarray analysis. In line with these gene signatures, we found that pltLys-iTreg cells improved cell recovery after transfer and immune suppressive function compared with purTGFß-iTreg cells in factor VIII (FVIII)–deficient (F8null, hemophilia A model) mice after recombinant human FVIII (rhF8) infusion. Acute antibody-mediated platelet destruction in F8null mice followed by rhF8 infusion increased the number of Treg cells and suppressed the antibody response to rhF8. Consistent with these data, ex vivo proliferation of F8-specific Treg cells from platelet-depleted animals increased when restimulated with rhF8. Together, our data suggest that pltLys-iTreg cells may have advantages in emerging clinical applications and that platelet contents impact the properties of iTreg cells induced by TGF-ß1.

Evidence shows that factor VIII (FVIII) ectopically expressed in platelets (2bF8) is therapeutic in FVIIInull mice even with anti-FVIII inhibitory antibodies (inhibitors). If current efforts to generate platelets in vitro succeed, genetically manipulated platelets containing FVIII may be used therapeutically in hemophilia A patients with inhibitors. One important concern is the immunogenicity of platelet-derived FVIII. To address this concern, we infused 2bF8 transgenic (2bF8Tg) platelets into naïve FVIIInull mice weekly for 8 weeks. No anti-FVIII antibodies were detected in the infused animals during the study course. We then explored whether platelet-derived FVIII is immunogenic in FVIIInull mice with inhibitors. The 2bF8Tg platelets were transfused into rhF8-primed FVIIInull mice, resulting in no augmentation of anti-FVIII antibodies. To investigate whether preconditioning affects the immune response, animals were sublethally irradiated and subsequently transfused with 2bF8Tg platelets. No anti-FVIII antibodies were detected in the recipients after platelet infusions. Following further challenge with rhF8, the inhibitor titer in this group was significantly lower than in naïve FVIIInull mice utilizing the same immunization protocol. Thus, our data demonstrate that infusion of platelets containing FVIII triggers neither primary nor memory anti-FVIII immune response in FVIIInull mice and that sublethal irradiation plus 2bF8Tg platelet infusion suppresses anti-FVIII immune response in FVIIInull mice.

A novel class of manganese-based dual-mode contrast agents (DMCAs) based on the core–shell structured manganese-loaded dual-mesoporous silica spheres (Mn-DMSSs) for simultaneous T1- and T2-weighted magnetic resonance imaging (MRI) has been successfully reported. The in vitro MR tests demonstrate that the Mn-based DMCAs display an excellent simultaneous T1-weighted and T2-weighted MR imaging effect with a noticeably high T1 relaxivity (r1) of 10.1 mM–1s–1and a moderately high T2 relaxivity (r2) of 169.7 mM–1s–1. The Mn-based DMCAs exhibit negligible cytotoxicity with >80% cell viability at a concentration of up to 200 μg/mL in human liver carcinoma (HepG2) and mouse macrophage (RAW264.7) cells after 24 h. Confocal laser scanning microscopy (CLSM) results show that the Mn-DMSSs were internalized via endocytosis and located in the cytoplasm but not in the nucleus. The in vivo experiment shows that the signals of rat liver increased by 29% under T1-weighted imaging mode and decreased by 28% under T2-weighted imaging mode in 5 min postinjection of Mn-DMSSs, which reveal that the novel Mn-loaded DMSSs can be used as both positive (T1-weighted) and negative (T2-weighted) MR contrast agents in further biomedical applications.

A series of optically active nanoparticles composed of helical substituted polyacetylene is prepared via emulsion polymerization. A specific organic solvent is required for solid substituted acetylene monomers to undergo emulsion polymerization. The effects of this organic solvent are investigated. Its amount is found to be decisive for obtaining stable polymer emulsions. The helical conformations of the substituted polyacetylenes in nanoparticle state are identified with the help of CD and UV‐vis spectra. A blue shift occurs in CD and UV‐vis spectra of some of the polyacetylene emulsions. The underlying driving force for the blue shift is discussed, and an emulsion polymerization mechanism is proposed.

Cross‐linked microspheres consisting of optically active helical substituted polyacetylenes are reported. For preparing the microspheres, substituted polyacetylene copolymers with pendent polymerizable CC bonds are first prepared and then used as macromonomers to copolymerize with acrylates via suspension polymerization, providing cross‐linked microspheres. The helical polymer segments render the microspheres with optical activity, whereas the acrylate‐based polymers afford the swelling property. CD and UV‐vis spectra demonstrate the optical activity of the microspheres. The microspheres preferably adsorb (R)‐(+)‐1‐phenylethylamine, (R)‐(+)‐N‐benzyl‐1‐phenylethylamine, and Boc‐D‐alanine, whereas released Boc‐L‐alanine rather more rapidly than its enantiomer.

So bleibt man in Form: Ein achirales Acetylen geht in chiralen Micellen aus [{(nbd)RhCl}2] (nbd=2,5‐Norbornadien) und Dodecylphenylalanin als chiralem Emulgator eine Helixsinn‐selektive Polymerisation ein, bei der optisch aktive helicale Polymere und Polymeremulsionen gebildet werden.

The preparation of nanoparticles consisting of chiral helical substituted polyacetylenes via emulsification of the preformed polymers is reported. Two types of helically substituted acetylenes were examined as model polymers: two chiral poly(N‐propargylamide)s and two achiral poly(N‐propargylamide)s. The four polymers were emulsified with SDS as emulsifier to form nanoparticles. The particle size can be modulated by varying the SDS concentration. A comparison between nanoparticle emulsion and the corresponding polymer solution demonstrated obvious blue shifts in the CD spectra of nanoparticle emulsions made from helical polymers with relatively not‐so‐bulky pendent groups, for which the possible mechanism was proposed.

Objectives: Natural killer (NK) cells are the first donor-derived lymphocytes to be reconstituted after transplantation and play a critical role in improving transplantation outcomes. Their surface receptor, killer cell immunoglobulin like receptor (KIR), can trigger the alloreactivity of NK cells and have been shown to be protective for acute and chronic graft-versus-host disease (aGVHD, cGVHD) while retaining graft-versus-leukemia (GVL) effect. However, different results have been reported about KIR matching models and KIR alleles based on patient, donor and transplant characteristics, resulting in significant controversy about the best donor selection strategy. Here, we investigated the potential influence of KIR matching and KIR alleles on GVHD prophylaxis, overall survival (OS) and relapse rate (RR) of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in acute myeloid leukemia (AML) patients. Methods：Data from 79 patients with AML treated with haplo-HSCT between May 2015 and May 2021 in the transplantation unit of the Fujian Medical University Union Hospital were retrospectively analyzed. The cohort included 49 male patients (62.0%) and 30 female (38.0%), with a median age of 25 years (1-68 years). KIR genotyping was performed by the PCR-SSO method. The amplicons were quantified on the Luminex 200 flow analyzer and analyzed using the Quick-Type for Lifecodes software for generating KIR data. HLA-A and -B alleles were typed by polymerase chain reaction using sequence-specific primers (PCR-SSP) (TBG, Taipei, Taiwan). HLA-C genotyping was determined by reverse hybridization with sequence specific oligonucleotides probes (rSSO) Line probe assay. Cox proportional hazards model and Kaplan-Meier survival curves were used for analysis. Results：At the time of transplantation, 49 cases (62.0%) were at CR1, while 30 (38.0%) were not. aGVHD occurred in 16 patients (20.3%) and recurrence arose in 10 patients (12.7%), 4 (5.1%) cases cGVHD was observed. After adjusting for age, disease-risk, disease-status, HLA-match, donor gender, conditioning regimen intensity and type of post-grafting GVHD prophylaxis, Cox regression analysis revealed that both KIR ligand-ligand mismatching (KLM) and KIR receptor-ligand matching (RLM) was associated with an decreased risk of aGVHD and relapse compared to KIR ligand-ligand matching and receptor-ligand matching group, respectively (aGVHD: KLM: p=0.047, RLM: p＜0.001; RR: KLM: p=0.049, RLM: p=0.017). Furthermore, RLM shows more accurate in prediction of relapse and aGVHD compared with KLM in both aGVHD and relapse. (aGHVD: p=0.009; RR: p=0.039). After taking activating KIR (aKIR) into consideration to compensate the defect of only inhibitory KIR (iKIR) dominant model, we found that patients with more donor activating KIRs can reach the lower incidence of aGVHD and relapse, and the benefit can gradually increase parallel with the increase in donor activating KIRs. (aGVHD：p=0.019；RR：p=0.037). Patients with both receptor-ligand mismatch and the most donor aKIRs can reach the lowest relapse, lowest incidence of aGVHD and best overall survival (OS). Conclusions: KIR-mismatch, both KLM and RLM significantly reduced the risk of aGVHD and relapse after halpo-HSCT in AML patients and RLM show more superiority in the prediction of HSCT outcome. The synergistic effects of receptor-ligand mismatch and more donor aKIRs can provide a better clinically applicable donor selection strategy to improve haplo-HSCT outcome in AML patients.

Poly(p-vinylphenol) (PVPh) is miscible with poly(N-methyl-3-piperidinemethyl methacrylate) (PM3PMA). The glass transition temperatures of the blends are higher than those calculated from a linear additivity rule. Fourier transform infrared spectroscopy shows the existence of hydrogen-bonding interactions between the hydroxyl groups of PVPh and the carbonyl groups of PM3PMA. In addition, X-ray photoelectron spectroscopy shows that the piperidine nitrogen atoms of PM3PMA also interact with the hydroxyl groups of PVPh as shown by the development of a high-binding-energy N 1s peak in each blend. In contrast, we have earlier reported that the piperidine nitrogen atoms of poly(N-methyl-4-piperidyl methacrylate) are not involved in hydrogen-bonding interactions with PVPh. To better understand the interactions in various blends, ab initio calculations were performed on hydrogen-bonded dimers of saturated monomers.

Poly(1-vinylimidazole) (PVI) forms complexes with poly(styrenesulfonic acid) and the zinc salt of poly(styrenesulfonate) (PSSA and PSSZn, respectively) in water/ethanol (2 : 1 v/v) solution, indicating the presence of strong interactions. Infrared spectroscopic measurements showed the existence of protonated imidazole groups in all the complexes. X-ray photoelectron spectroscopic studies showed the development of high-binding-energy N(1) 1s and N(3) 1s peaks, but the values of the binding energy shift of N(3) 1s are larger than those of N(1) 1s in all PVI/PSSA and PVI/PSSZn complexes, suggesting proton transfer from PSSA to imidazole N(3) atoms in the PVI/PSSA complexes, and coordination between Zn²⁺ and the imidazole N(3) atoms in the PVI/PSSZn complexes. Based on the values of the binding energy shift of the interacting nitrogen atoms, the strength of the coordination interaction in PVI/PSSZn complexes is weaker than the ionic interactions in the PVI/PSSA complexes. The development of a new S 2p spin-orbit split doublet at a low-binding-energy region reveals the existence of interactions between Zn²⁺ and the imidazole nitrogen atoms.

The miscibility of poly(1-vinylimidazole) (PVI) with some hydroxyl- and carboxyl-containing polymers was studied. Each of the binary blends or complexes of PVI with poly(p-vinylphenol) (PVPh), poly(2-hydroxypropyl methacrylate) (PHPMA) and poly(acrylic acid) (PAA) showed a single glass transition temperature (Tg), indicating miscibility. However, PVI is immiscible with poly(styrene-co-allyl alcohol) (SAA) and poly(hydroxyether of bisphenol-A) (Phenoxy) as shown by the appearance of two Tg's in each of the blends. Based on the frequency shifts of the hydroxyl band of the hydroxyl-containing polymers, the intensities of hydrogen bonding interactions between PVI and hydroxyl-containing polymers are in the order PVPh > PHPMA > SAA and Phenoxy. PVI interacts with PAA via ionic interaction.

The effects of support materials on catalytic performance were investigated in catalytic removal of toluene. And the Mn–Ce binary oxides as active components were supported on ZrO2, SiO2, γ-Al2O3and TiO2support materials. Many techniques, including X-ray diffraction (XRD), Brunauer–Emmett–Teller method (BET), X-ray photoelectron spectroscopy (XPS), temperature-programmed reduction (TPR) and NH3-temperature-programmed desorption (NH3-TPD), were used to characterize physicochemical properties. Among the different catalysts, the MnCe/ZrO2catalyst with the lowest specific surface area (39.7 m2/g) shows the best catalytic activity. In terms of toluene conversion, the activity order is as follows: MnCe/ZrO2 > MnCe/TiO2 ≈ MnCe/SiO2 > MnCe/Al2O3. The better performance of MnCe/ZrO2should be attributed to the low-temperature reducibility, and abundant surface species (Mn4+and lattice oxygen). And XPS and TPR results reveal that more surface abundant Mn and Ce elements generate good interaction in MnCe/ZrO2. The weak interaction between metal oxide and support also boosts the dispersion and complete reduction of MnCe oxides at low temperature. In addition, the in-situDRIFTS results clarify that the carbonate species are main intermediates in MnCe/ZrO2sample during surface reaction process.

• We reduce a 3K-dimension SIR mean field model to an equivalent low dimension model by the reducing-dimension technique. • We provide the exact expression of the final size and the epidemic duration based on the mean-field model. • We formulate two isolation measures of high-degree nodes and analyze the effects of the measures on the final size and the epidemic duration. • We find the crucial isolation time for the final size and the epidemic duration. It has been a challenge to formulate network-based control measures on infectious diseases, especially on emerging diseases, due to the complexity of the network topology. Generally, isolating high-degree nodes is one of the intuitive intervention measures. The final size and the epidemic duration are two vital evaluation indices of infectious diseases severity, but the last one has not been explicitly calculated so far in network-based models. Therefore, in this paper, we studied the effects of two measures of isolating high-degree nodes at different time—complete isolation and incomplete isolation, on these two indices. We applied the reducing-dimension method to convert the mean-field model in networks into an equivalent and simpler low-dimension model, and then calculated the exact expression of the final size and the epidemic duration. We found that, in complete isolation the final size always reduces but there exists an isolation time threshold of the epidemic duration in some cases, before that such a strategy lengthens the epidemic duration, and otherwise shortens that period. In contrast, in incomplete isolation the epidemic duration always increases but there exists an isolation time threshold of the final size, before which, the incomplete isolation reduces the final size, and otherwise increases the final size. This result provides a new insight into controlling infectious diseases in network. [ABSTRACT FROM AUTHOR]

Background:MicroRNAs (miR) are non-coding RNAs that play a role in regulation multiple functions in different cell types. Previous studies have shown that miR-204 is downregulated in T-ALL. We previously reported that matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) gene polymorphisms may be associated with the risk of T-cell acute lymphoblastic leukemia (T-ALL). The present study aims to decipher the role of miR-204 and MMP-2/MMP-9 in T-ALL occurrence to guide the diagnosis and treatment of T-ALL in the clinics.

Objectives:Mesenchymal stem cells (MSCs) and killer cell immunoglobulin-like receptor (KIR) ligand-mismatch, which can trigger the alloreactivity of natural killer (NK) cells, have been shown to be protective for severe acute and chronic graft-versus-host disease (aGVHD, cGVHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, there are no prospective or retrospective studies exploring their relationship. Here, we investigated the potential influence of KIR matching, MSCs and their coaction on GVHD prophylaxis, overall survival (OS) and relapse rate (RR) of allo-HSCT.

Low levels or lack of antibodies to the hepatitis B surface antigen (anti-HBsAg, respectively) have been associated with an increased risk of developing an hepatitis B virus (HBV) response in patients with resolved HBV infection after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Levels of HB core antibodies (anti-HBc) is a new marker associated with the natural history and treatment response of chronic HBV infection.

There is currently no unified standard protocol for the prevention of hepatitis B virus (HBV) infection in patients with hematopoietic stem cell transplantation. The incidence of HBV infection is high in China, particularly in the Fujian Province of China. Nevertheless, there are also many transplanted patients who are not infected with HBV as indicated by serology markers (negative for HBsAg, anti-HBsAb, HBeAg, anti-HBeAb, anti-HBcAb, HBV-DNA). Therefore, there is a need to develop a protocol to prevent hepatitis virus infection in these non-infected patients.

Objective:Several microRNAs have been revealed to be involved in the pathophysiological process of GVHD. This study aimed to characterize the functional relevance of epidermal growth factor (EGF)-stimulated microRNA-21 (miR-21) in the bone marrow-derived mesenchymal stem cells (BMSCs) in a mouse model of aGVHD.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

Induction of antigen-specific immune tolerance is desirable in autoimmune diseases, transplantation, gene therapy, and some protein therapies in order to prevent or reverse adverse immune responses. Our previous studies have demonstrated that targeting FVIII or FIX expression to platelets under control of the platelet-specific aIIb promoter can restore hemostasis and induce immune tolerance in hemophilia mice. Here we explored if this approach can be applied to prevent graft rejection and induce immune tolerance to a non-coagulant protein even with pre-existing immunity. We used ovalbumin (OVA) as a non-coagulant protein and constructed a lentiviral vector in which OVA is driven by the aIIb promoter (2bOVA). We designed another vector, 2bVpOVA, which includes the VWF propeptide (Vp) cassette to secure OVA storage in platelet granules. The third construct, 2bGFP, in which the GFP cassette is driven by the same promoter, was used as a control vector.

Abstract Zika virus epidemic poses a major threat to public health globally. Initially, this disease was limited to Africa but now it is spreading throughout the World. It is well known that zika virus is transmitted to human by the bites of Aedes mosquitoes. Recently, there are reported cases of sexual transmission and transmission due to blood transfusion in many countries e.g., Argentina, France, New Zealand, USA etc. In this paper a mathematical model of Zika virus on complex network is formulated and analyzed keeping in mind both mosquito-borne and sexual transmission of this disease. The existence and global stability of disease-free equilibrium are discussed in detail. The basic reproduction number R 0 of the model is computed and it is found that for R 0 < 1 , the disease-free equilibrium of the model is globally asymptotically stable under some condition. In addition to this the final size relation of the proposed model is also computed. The key parameters of the model are computed using curve fitting to the real data by least-square method. Sensitivity analysis and numerical simulation are also performed for our proposed model. Finally, this model is extended to optimal control problem, to find the suitable cost-effective and time-dependent control strategies to reduce the number of infectives in a desired interval of time. [ABSTRACT FROM AUTHOR]

Baumgartner: Novo Nordisk: Research Funding. Shi:BloodCenter of Wisconsin: Patents & Royalties: METHOD OF INDUCING IMMUNE TOLERANCE THROUGH TARGETTED GENE EXPRESSION..

Montgomery: Baxter: Consultancy; Bayer: Consultancy; CSL: Consultancy; Biogen: Consultancy; Octapharma: Consultancy; Grifols: Consultancy. Shi:BloodCenter of Wisconsin: Patents & Royalties: METHOD OF INDUCING IMMUNE TOLERANCE THROUGH TARGETTED GENE EXPRESSION..

Our previous studies using hemophilia A and B mouse models have demonstrated that targeting FVIII or FIX expression to platelets under control of the aIIb promoter through lentivirus-mediated delivery to hematopoietic stem cells (HSCs) results in transgene protein expression and storage in platelet a-granules and that platelet-derived FVIII or FIX not only restores hemostasis but also induces immune tolerance in transduced recipients. In the current studies, we explored how immune tolerance is induced after platelet-specific gene therapy and whether this approach can be applied to induce immune tolerance to a non-coagulant protein. We used ovalbumin (OVA) as a non-coagulant protein and constructed a lentiviral vector in which OVA is driven by the aIIb promoter (2bOVA). Since VWF propeptide (Vp) can reroute secreting proteins to a storage pathway, we designed another vector, 2bVpOVA, which contains Vp to secure OVA storage in platelet granules. We first confirmed that 2bOVA or 2bVpOVA lentiviral gene delivery to HSCs can induce anti-OVA immune tolerance in wild-type (WT) C57BL6 mice. 2bOVA or 2bVpOVA-transduced HSCs (CD45.2/B6) were transplanted into CD45.1/B6 recipients pre-conditioned with 6.6Gy total body irradiation (TBI). We found that 95% and 98% of OVA protein in whole blood was stored in platelets with an OVA protein level of 24.22±8.72 ng/108platelets (n=10) and 1.41±0.73 ng/108platelets (n=10) in 2bOVA and 2bVpOVA transduced recipients, respectively. Electronic microscope analysis demonstrated that the OVA transgene protein using both vectors was stored in transduced platelet a-granules. When the transduced recipients were immunized with OVA, anti-OVA antibody titers in both the 2bOVA group (560±68, n=10) and the 2bVpOVA group (320±34, n=10) were significantly lower than in untransduced controls (10424±2837, n=24), demonstrating that platelet-specific OVA gene delivery to HSCs can suppress the anti-OVA immune response. Of note, the titer of anti-OVA total IgG titer in 2bF8 (an unrelated control vector) transduced FVIIInull/B6 recipients without OVA immunization was 413±61 (n=12), which was not significantly different compared to the 2bOVA or 2bVpOVA group even after OVA immunization. In another unrelated control group, 2bGFP, anti-OVA titer was 84±17 (n=9), which was significantly higher than the data obtained from untransduced WT animals without immunization (33±7, n=24). Why there were various levels of anti-OVA antibody titers in unrelated vectors transduced recipients is still unclear and needed further investigation.

Immune response to factor VIII (FVIII) is not only a severe complication in protein replacement therapy, but also a major concern in gene therapy of hemophilia A. Our previous studies have demonstrated that platelet-targeted FVIII (2bF8) gene therapy together with in vivodrug-selection of transduced cells can not only rescue the bleeding diathesis but also induce anti-FVIII specific immune tolerance in FVIIInullmice. In the current study, we investigated 1) whether our non-selectable lentiviral vector (LV) for the induction of platelet-FVIII expression is sufficient to induce immune tolerance and 2) which cell compartment is tolerized after platelet gene therapy. Platelet-specific FVIII expression was introduced by 2bF8LV-transduction of hematopoietic stem cells followed by syngeneic transplantation into FVIIInullmice preconditioned with 660 cGy total body irradiation (TBI) or Busulfan (Bu) plus ATG (anti-thymocyte globulin). After bone marrow transplantation and reconstitution, animals were analyzed by PCR, qPCR, FVIII:C assay, and tail clipping test to confirm the success of 2bF8 gene therapy. Sixteen weeks after transplantation, animals were challenged with recombinant human FVIII (rhF8) via retro-orbital venous administration at a dose of 50 U/kg weekly for 4 weeks. The titers of anti-FVIII inhibitory antibodies (inhibitors) were determined by Bethesda assay. The CFSE-labeled CD4 T cell proliferation assay and ELISPOT-based memory B cell maturation assay were used to determine which cell compartment is tolerized to FVIII after 2bF8 gene therapy. The level of platelet-FVIII expression was 1.44 ± 0.39 mU/108platelets (n = 6) in the 660 cGy group, which is not significantly different from the level obtained from the Bu+ATG group [3.04 ± 1.19 mU/108platelets (n = 6)]. Even after rhF8 challenge, no antibodies were detected in 2bF8LV-transduced recipients in either group. In contrast, all animals in the control group that did not undergo gene therapy developed various levels of inhibitors (204±97 BU/ml, n=7). The frequency of regulatory T cells in both 660 cGy TBI (11.01±0.52%) and Bu+ATG (11.02±0.68%) groups were significantly higher than the control group (8.05±0.57%). T cell proliferation assay demonstrated that CD4+T cells from 2bF8 LV-transduced recipients that had been challenged with rhF8 did not proliferate when restimulated with rhF8 in vitro.The daughter CD4+T cells in the group with 10 U/ml of rhF8 were 5.84 ± 2.49% (n = 6), which was not significantly different from the control group without no rhF8 stimulation (0 U/ml) (5.33 ± 1.72%). CD4+T cells from primed FVIIInullmice did proliferate after rhF8 restimulation. The proliferated daughter cell was 13.12 ± 6.76% (n = 7) in the group with rhF8 (10 U/ml) re-stimulation, which is significantly higher than the group without rhF8 co-culture (4.99 ± 1.16%). Since FVIII-specific memory B cell maturation is CD4+T cell dependent, we isolated CD4+T and memory B cells from 2bF8LV-transduced or FVIIInullmice after rhF8 immunization and co-cultured with rhF8 followed by ELISPOT assay to examine the antibody secreting cells. No spots were detected when memory B cells from rhF8-primed FVIIInullmice were co-cultured with CD4+T cells from 2bF8LV-transduced recipients. In contrast, when memory B cells from either rhF8 immunized 2bF8LV-transduced or untreated FVIIInullmice were cultured with CD4+T cells from rhF8-primed FVIIInullmice, there were 142 and 205 anti-FVIII antibody secreting cells, respectively, detected per 106cells seeded. These results indicate that CD4+T cells from 2bF8LV-transduced mice are tolerized to rhF8 stimulation. In conclusion, 2bF8 lentiviral gene transfer without in vivoselection of genetically manipulated cells can introduce FVIII-specific immune tolerance in hemophilia A mice and this immune tolerance is CD4+T cell-mediated.

No relevant conflicts of interest to declare.

Donor lymphocyte transfusion (DLI) may induce the graft-versus-leukemia (GVL) effect, but may also increase the risk of graft-versus-host disease (GVHD). Thus, the escalating-dose DLI and/or co-administration with short-term immunosuppressive agents are one of the clinical strategies to keep the balance between GVHD / GVL nowadays.

The hematopoietic potential from induced pluripotent stem cells (iPS) has been explored for some years. However, the direct reprogramming from the blood cells to hematopoietic progenitors bypass the pluripotency is even more attractive for the clinical practice.The lentiviral vector encoding human reprogramming factors (Oct-4, Sox2, c-Myc, Klf4FOSCK) were transfected along with packaging plasmid pCMV-dR8.91 and envelope plasmid pCMV-VSV-G in 293T package cells to produce lentiviral particles. The construction was then confirmed by RT-PCR and restriction enzyme digestion anaysis, and the lentivirus titer was determined using GFP/DAPI based on cell count by Image J software. Primary mouse embryo fibroblast (PMEF) feeder cells were isolated and prepared from CF-1 inbred mouse strain to help maintain pluripotency and to provide a cellular matrix for stem cells growing. Lastly, the lentivirus carrying OSCK factors was used totransduce HL-60 cells in three consecutive rounds of spin-infection on the prepared feeder layers with an interval of 12 hours, while the lentivirus carrying GFP served as a negative control. The cell clusters were picked based on morphology and alkaline phosphatase(AP) staining. The stem cell properties were tested by the expression of cell surface antigens using Flow cytometry. and the mRNA expression of OCT4, SOX2, C-MYC,KLF4,etc. by QT-PCR.The lentiviral particles were successful packaged and used to infect HL-60 cells. We occasionally observed some Human embryonic stem cells (hES) cell-like colonies in between the cells around 14 days after infection. These cell colonies also showed similarity to hES cells in feeder dependency. Detection of cell surface CD34 by FCM showed that HL-60 cells were switched to be a hematopoietic fate, expression of CD34 from 1.77% to 98.42%. Simultaneously, expressions of the myeloid antigen CD13, CD117 decreased. The gene expressions of OCT4, SOX2 indicated that the exogenous gene were down-regulation or silence while the endogenous gene were up-regulation. However, the cell colonies can survive only for a short time which might due to the absence of the survival factors they require or the first hematopoietic microenvironment, like the yolk sac.After being reprogrammed, the HL-60 cell derived colonies showed the similarity to hES cells in morphology, feeder dependency and the expression of stem cell antigens. However, they may need an appropriate microenvironment at different time points to be programmed into primitive hematopoietic stem cells.No relevant conflicts of interest to declare.

It is well documented that the co-medication with the triazole antifungal agents is associated with a flattening of the CSA blood concentration profile via the cytochrome P450 3A4 dependent metabolic pathway in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Then it raises the question if the therapeutic monitoring of CsA trough levels is sufficient enough to reflect the drug exposure and to assess the transplant-related complications such as transplant rejection and drug toxicity.To evaluate the tolerability, toxicity and clinical outcome of the co-administration of CSA and triazole antifungal agents in allo-HSCT recipients.A retrospective review of the medical records of 104 consecutive patients undergoing allo-HSCT for hematologic malignancies at our transplant center over past 5 years was conducted. The causality of administration of CSA in combination with triazole in 12 cases with life-threatening complications experiencing supratherapeutic trough levels of CSA were identified and analyzed.In all these 12 patients, the CSA trough levels remained highly than therapeutic range even after gradual tapering of CSA dosage. Shortly after the engraftment, 6 patients (50 %) developed acute graft-versus-host disease (aGVHD) and non-infectious pulmonary complication, and 2 patient (16.66 %) acute graft rejection. Which indicates the trough plasma concentration might be inadequately reflect CSA absorption profile. Whereas, 4 (33.33 %) patients were evaluated with neurological complications, 1 (8.33%) patient cardiovascular complication accompanied by acute renal failure and liver dysfunction, that might be ascribed to CSA-related adverse effects. 10 (83.33 %) out of the 12 patients eventually died, 2 (16.66 %) patient are still alive after graft rejecting. The major causes of death were GVHD related pulmonary injury with fungi infectionAlthough preemptive CSA dosage reduction and the close monitoring of its whole blood trough levels may minimize the drug-toxicity when co-administration with triazole antifungal agents, the different clinical spectrum and different disease evolution post transplant in this group warn that in the set of hematopoietic cell transplantation with CSA as immunosuppression agent the individual variables influence the drug-exposure and drug-toxicity. Thereof, as clinicians we should not be mislead by trough plasma concentrations as a routine therapeutic drug monitoring in terms of CSA exposure related efficacy or toxicity, especially when CSA in combination with triazole.No relevant conflicts of interest to declare.

The spatial pattern of epidemic is one key metric describing epidemiological spread features, beneficial to formulation of the intervention measures. Networked reaction–diffusion (RD) systems have become popular to mathematically portray such patterns due to discrete distribution of human habitat. However, most of the current research focused on diffusion along pairwise interactions. Effect of diffusion along higher-order interactions is still understood poorly. To this end, in the paper, based on one classic SIR epidemic RD model, we study its Turing instability in simplicial complexes and analyze the impact of the simplex strength on Turing patterns. It is found by theoretical analysis and simulation that the distribution of infections in patterns tends to become homogeneity with the increase of the simplex strength, i.e., infection density of most nodes concentrates near the steady state. Obviously, for a newly emerging epidemic, such homogeneous scenario is unfavorable to epidemic control. Because it may lead to the decentralized allocation of limited resources, which is not enough to contain epidemic. In contrast, heterogeneous scenario that nodes with low and high infection density prominently distribute in two sides of steady state allows to put all limited resources into the targeted treatment of nodes with high infection density. Our findings link epidemic control with higher-order interactions and may provide a new insight into intervening epidemic from higher-order networks. • Increasing the simplex strength may homogenize the infection density of nodes. • The increase in average higher–order degree centralizes the infection density. • Heterogeneous infection densities help allocate limited medical resources. [ABSTRACT FROM AUTHOR]