While IL-2 can potently activate both NK and T cells, its short in vivo half-life, severe toxicity, and propensity to amplify Treg cells are major barriers that prevent IL-2 from being widely used ...for cancer therapy. In this study, we construct a recombinant IL-2 immunocytokine comprising a tumor-targeting antibody (Ab) and a super mutant IL-2 (sumIL-2) with decreased CD25 binding and increased CD122 binding. The Ab-sumIL2 significantly enhances antitumor activity through tumor targeting and specific binding to cytotoxic T lymphocytes (CTLs). We also observe that pre-existing CTLs within the tumor are sufficient and essential for sumIL-2 therapy. This next-generation IL-2 can also overcome targeted therapy-associated resistance. In addition, preoperative sumIL-2 treatment extends survival much longer than standard adjuvant therapy. Finally, Ab-sumIL2 overcomes resistance to immune checkpoint blockade through concurrent immunotherapies. Therefore, this next-generation IL-2 reduces toxicity while increasing TILs that potentiate combined cancer therapies.
With the rapid progression of additive manufacturing and the emergence of new 3D printing technologies, accuracy assessment is mostly being performed on isosymmetric test bodies. However, the ...accuracy of anatomic models can vary. The dimensional accuracy of root mean square values in terms of trueness and precision of 50 mandible replicas, printed with five common printing technologies, were evaluated. The highest trueness was found for the selective laser sintering printer (0.11 ± 0.016 mm), followed by a binder jetting printer (0.14 ± 0.02 mm), and a fused filament fabrication printer (0.16 ± 0.009 mm). However, highest precision was identified for the fused filament fabrication printer (0.05 ± 0.005 mm) whereas other printers had marginally lower values. Despite the statistically significance (
< 0.001), these differences can be considered clinically insignificant. These findings demonstrate that all 3D printing technologies create models with satisfactory dimensional accuracy for surgical use. Since satisfactory results in terms of accuracy can be reached with most technologies, the choice should be more strongly based on the printing materials, the intended use, and the overall budget. The simplest printing technology (fused filament fabrication) always scored high and thus is a reliable choice for most purposes.
Energy storage technology plays a significant role in the pursuit of the high-quality development of the electricity market. Many regions in China have issued policies and regulations of different ...intensities for promoting the popularization of the energy storage industry. Based on a variety of initial conditions of different regions, this paper explores the evolutionary process of electricity market players considering energy storage technology. The trilateral evolutionary game model is adopted to analyze the strategies of the power plant, the power grid, and the government. After assigning the model according to an actual situation, each equilibrium point corresponds to a real electricity market situation. The results indicate the following: (1) In the process of stabilizing, the role of “Advanced Imitators” leading the strategy of building energy storage changes between the power plant and the power grid. (2) In Eastern, Middle, and Southern China, the power plants and power grids on a greater-than-medium scale will choose to build energy storage without governmental regulations, due to the abundant net profit. (3) In the northeast of China, power plants with a medium-or-lower scale will choose not to build energy storage because of the relatively low on-grid price, and small power grids can make enough profits by operating energy storage facilities. (4) In Northern China, the large power plants and the medium power grids will choose to build energy storage due to the high electricity sale price and the resulting high profit. (5) In Western China, the small power plants and power grids cannot afford to build energy storage due to the low electricity price. The results lead to valuable policy suggestions for the local governments of China in promoting energy storage in the future. To meet the goal of energy storage popularization, regional electricity market plans need relevant policies based on its existing conditions, offering suitable external conditions for adding energy storage.
Large defects of jaw caused by tumor, trauma and so on in oral and maxillofacial region lead to facial deformity, language and chewing dysfunction, which severely damage the patient's life quality. ...Three-dimensional printing (3DP) is also named additive manufacturing (AM), which can print materials layer by layer to create three-dimensional objects. The complex shape of jaw defects can be accurately reconstructed using 3DP scaffold combined with image data, computer-aided-design and manufacture. It has specific advantages compared with traditional way of jaw reconstruction and has attracted much attention in the field of jaw tissue engineering recently. This article presented the progress of 3DP scaffold and its application in jaw reconstruction, providing a new idea for jaw reconstruction.
The most common three-dimensional (3D) printing method is material extrusion, where a pre-made filament is deposited layer-by-layer. In recent years, low-cost polycaprolactone (PCL) material has ...increasingly been used in 3D printing, exhibiting a sufficiently high quality for consideration in cranio-maxillofacial reconstructions. To increase osteoconductivity, prefabricated filaments for bone repair based on PCL can be supplemented with hydroxyapatite (HA). However, few reports on PCL/HA composite filaments for material extrusion applications have been documented. In this study, solvent-free fabrication for PCL/HA composite filaments (HA 0%, 5%, 10%, 15%, 20%, and 25% weight/weight PCL) was addressed, and parameters for scaffold fabrication in a desktop 3D printer were confirmed. Filaments and scaffold fabrication temperatures rose with increased HA content. The pore size and porosity of the six groups' scaffolds were similar to each other, and all had highly interconnected structures. Six groups' scaffolds were evaluated by measuring the compressive strength, elastic modulus, water contact angle, and morphology. A higher amount of HA increased surface roughness and hydrophilicity compared to PCL scaffolds. The increase in HA content improved the compressive strength and elastic modulus. The obtained data provide the basis for the biological evaluation and future clinical applications of PCL/HA material.
Computer-assisted surgery with three-dimensional (3D) printed surgical guides provides more accurate results than free-hand surgery. Steam sterilization could be one of the factors that affect the ...dimensions of surgical guide resin materials, leading to inaccuracies during surgeries. The purpose of this study was to evaluate the effects of steam sterilization on the dimensional accuracy of indication-specific hollow cube test bodies, manufactured in-house using Class IIa biocompatible resin materials (proprietary and third-party). To evaluate the pre- and post-sterilization dimensional accuracy, root mean square (RMS) values were calculated. The results indicate that, in all the groups, steam sterilization resulted in an overall linear expansion of the photopolymeric resin material, with an increase in outer dimensions and a decrease in inner dimensions. The effects on the dimensional accuracy of test bodies were not statistically significant in all the groups, except PolyJet Glossy (
> 0.05). The overall pre- and post-sterilization RMS values were below 100 and 200 µm, respectively. The highest accuracies were seen in proprietary resin materials, i.e., PolyJet Glossy and SLA-LT, in pre- and post-sterilization measurements, respectively. The dimensional accuracy of third-party resin materials, i.e., SLA-Luxa and SLA-NextDent, were within a comparable range as proprietary materials and can serve as an economical alternative.
The nucleoprotein (NP) is a major component of the viral ribonucleoprotein (vRNP) complex. During the replication of influenza virus, the vRNP complex undergoes nuclear-cytoplasmic shuttling, during ...which NP serves as one of the determinants. To date, many phosphorylation sites on NP have been identified, but the biological functions of many of these phosphorylation sites remain unknown. In the present study, the functions of the phosphorylation sites S9, Y10, and Y296 were characterized. These residues are highly conserved, and their phosphorylation was essential for virus growth in cell culture and in a mouse model by regulating the activity of the viral polymerase and the nuclear-cytoplasmic shuttling of NP. The phosphorylation and dephosphorylation of S9 and Y10 controlled nuclear import of NP by affecting the binding affinity between NP and different isoforms of importin-α. In addition, the phosphorylation of Y296 caused nuclear retention of NP by reducing the interaction between NP and CRM1. Furthermore, tyrosine phosphorylation of NP during the early stage of virus infection was ablated when Y296 was mutated to F. However, at later stages of infection, it was weakened by the Y10F mutation. Taken together, the present data indicate that the phosphorylation and dephosphorylation of NP control the shuttling of NP between the nucleus and the cytoplasm during virus replication.
It is well known that phosphorylation regulates the functions of viral proteins and the life cycle of influenza A virus. As NP is the most abundant protein in the vRNP complex of influenza A virus, several phosphorylation sites on this protein have been identified. However, the functions of these phosphorylation sites were unknown. The present study demonstrates that the phosphorylation status of these sites on NP can mediate its nuclear-cytoplasmic shuttling, which drives the trafficking of vRNP complexes in infected cells. The present data suggest that the phosphorylated residues of NP are multistep controllers of the virus life cycle and new targets for the design of anti-influenza drugs.
Additive manufacturing (AM) of patient-specific implants (PSIs) is gradually moving towards in-house or point-of-care (POC) manufacturing. Polyetheretherketone (PEEK) has been used in cranioplasty ...cases as a reliable alternative to other alloplastic materials. As only a few fused filament fabrication (FFF) printers are suitable for in-house manufacturing, the quality characteristics of the implants fabricated by FFF technology are still under investigated. This paper aimed to investigate PEEK PSIs fabricated in-house for craniofacial reconstruction, discussing the key challenges during the FFF printing process. Two exemplary cases of class III (Group 1) and class IV (Group 2) craniofacial defects were selected for the fabrication of PEEK PSIs. Taguchi’s L9 orthogonal array was selected for the following nonthermal printing process parameters, i.e., layer thickness, infill rate, number of shells, and infill pattern, and an assessment of the dimensional accuracy of the fabricated implants was made. The root mean square (RMS) values revealed higher deviations in Group 1 PSIs (0.790 mm) compared to Group 2 PSIs (0.241 mm). Horizontal lines, or the characteristic FFF stair-stepping effect, were more perceptible across the surface of Group 1 PSIs. Although Group 2 PSIs revealed no discoloration, Group 1 PSIs displayed different zones of crystallinity. These results suggest that the dimensional accuracy of PSIs were within the clinically acceptable range; however, attention must be paid towards a requirement of optimum thermal management during the printing process to fabricate implants of uniform crystallinity.
Porcine reproductive and respiratory syndrome virus (PRRSV) is a highly contagious virus that has led to enormous economic loss worldwide because of ineffective prevention and treatment. In view of ...their minimized size, high target specificity and affinity, nanobodies have been extensively investigated as diagnostic tools and treatments of many diseases. Previously, a PRRSV Nsp9-specific nanobody (Nb6) was identified as a PRRSV replication inhibitor. When it was fused with cell-penetrating peptide (CPP) TAT, Nb6-TAT could enter the cells for PRRSV suppression. However, delivery of molecules by CPP lack cell specificity and have a short duration of action. PRRSV has a tropism for monocyte/macrophage lineage, which expresses high levels of Fcγ receptors. Herein, we designed a nanobody containing porcine IgG Fc (Fcγ) to inhibit PRRSV replication in PRRSV permissive cells. Fcγ fused Nb6 chimeric antibody (Nb6-pFc) was assembled into a dimer with interchain disulfide bonds and expressed in a Pichia pastoris system. The results show that Nb6-pFc exhibits a well-binding ability to recombinant Nsp9 or PRRSV-encoded Nsp9 and that FcγR-mediated endocytosis of Nb6-pFc into porcine alveolar macrophages (PAM) was in a dose-dependent manner. Nb6-pFc can inhibit PRRSV infection efficiently not only by binding with Nsp9 but also by upregulating proinflammatory cytokine production in PAM. Together, this study proposes the design of a porcine IgG Fc-fused nanobody that can enter PRRSV susceptible PAM via FcγR-mediated endocytosis and inhibit PRRSV replication. This research reveals that nanobody-Fcγ chimeric antibodies might be effective for the control and prevention of monocyte/macrophage lineage susceptible pathogeneses.
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