Small immune complexes cause type III hypersensitivity reactions that frequently result in tissue injury. The responsible mechanisms, however, remain unclear and differ depending on target organs. ...Here, we identify a kidney-specific anatomical and functional unit, formed by resident macrophages and peritubular capillary endothelial cells, which monitors the transport of proteins and particles ranging from 20 to 700 kDa or 10 to 200 nm into the kidney interstitium. Kidney-resident macrophages detect and scavenge circulating immune complexes “pumped” into the interstitium via trans-endothelial transport and trigger a FcγRIV-dependent inflammatory response and the recruitment of monocytes and neutrophils. In addition, FcγRIV and TLR pathways synergistically “super-activate” kidney macrophages when immune complexes contain a nucleic acid. These data identify a physiological function of tissue-resident kidney macrophages and a basic mechanism by which they initiate the inflammatory response to small immune complexes in the kidney.
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•Kidney macrophages (KM) are a resident population•KM are located at the abluminal side of peritubular capillaries•A unique function of KM is to monitor endothelial transport•Scavenging of immune complexes by KM triggers type III hypersensitivity
Kidney-resident macrophages and endothelial cells form an anatomical and functional unit that monitors the transport of proteins and particles according to their size and enables immediate detection of potential threats.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Innate lymphoid cells (ILCs) are generated early during ontogeny and persist predominantly as tissue-resident cells. Here, we examined how ILCs are maintained and renewed within tissues. We generated ...a single cell atlas of lung ILC2s and found that Il18r1+ ILCs comprise circulating and tissue-resident ILC progenitors (ILCP) and effector-cells with heterogeneous expression of the transcription factors Tcf7 and Zbtb16, and CD103. Our analyses revealed a continuous differentiation trajectory from Il18r1+ ST2− ILCPs to Il18r− ST2+ ILC2s, which was experimentally validated. Upon helminth infection, recruited and BM-derived cells generated the entire spectrum of ILC2s in parabiotic and shield chimeric mice, consistent with their potential role in the renewal of tissue ILC2s. Our findings identify local ILCPs and reveal ILCP in situ differentiation and tissue adaptation as a mechanism of ILC maintenance and phenotypic diversification. Local niches, rather than progenitor origin, or the developmental window during ontogeny, may dominantly imprint ILC phenotypes in adult tissues.
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•A single-cell atlas of BM ILCs and lung ILCs of healthy, infected, and parabiotic mice•Identification of tissue-associated ILC progenitors in neonatal and adult lung•Cells recruited from BM generate the entire spectrum of ILC2s in infected lungs•Local cues imprint the phenotypes of ILC2s differentiating in the adult lung
To investigate how innate lymphoid cells (ILCs) are locally maintained, Zeis et al. generated a single-cell atlas of lung ILCs and tracked Il18r1+ progenitor and effector ILC2s. Their work identifies tissue-resident and circulating ILC progenitors and highlights in situ differentiation and tissue adaptation as a mechanism of ILC renewal and phenotypic diversification.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
How embryonic progenitors coordinate cell fate specification and establish transcriptional and signaling competence is a fundamental question in developmental biology. Here, we show that ...transcription factor ΔNp63 profoundly changes the transcriptome and remodels thousands of open chromatin regions of Krt8+ progenitors during epidermal fate specification. ATAC-seq and single-cell RNA-seq reveal that ΔNp63-dependent programs govern epidermal lineage formation, and ΔNp63-independent programs, mediated by AP2 and AP1 transcription factors, promote epidermal differentiation and epithelial-to-mesenchymal transition. ΔNp63 promotes Wnt signaling by directly upregulating Wnt ligands, Frizzled receptors, and transcription factors. Deletion of β-catenin in Krt8+ progenitors delays their maturation into Krt5+ progenitors. The lack of epidermal Wnt production in the absence of ΔNp63 also incapacitates Wnt activation in the underlying dermal cells. These findings reveal the remarkable changes of the transcriptome, open chromatin, and signaling pathways at the onset of skin development and uncover the molecular cascade for epidermal lineage formation.
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•Transcriptome and open chromatin change profoundly during epidermal specification•ΔNp63 remodels epidermal open chromatin and activates Wnt signaling in the skin•Single-cell analyses reveal ΔNp63-dependent and -independent gene regulation programs•ΔNp63-dependent epidermal fate specification orchestrates dermal lineage formation
Employing single-cell RNA-seq and ATAC-seq, Fan et al. examine transcriptional and chromatin changes occurring during epidermal fate specification in mice. They characterize a developmental program, dependent on the transcription factor ΔNp63, generating epidermal progenitors, and ΔNp63-independent programs promoting epidermal differentiation and epithelial-to-mesenchymal transition.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Nanobodies show a great potential in biomedical and biotechnology applications. Bacterial expression is the most widely used expression system for nanobody production. However, the yield of ...nanobodies is relatively low compared to that of eukaryotic systems. In this study, the repetitive amino acid sequence motifs (GAGAGS) found in silk fibroin protein (SFP) were developed as a novel fusion tag (SF-tag) to enhance the expression of nanobodies in
Escherichia coli
. SF-tags of 1 to 5 hexapeptide units were fused to the C-terminus of 4G8, a nanobody against human epididymis protein 4 (HE4). The protein yield of 4G8 variants was increased by the extension of hexapeptide units and achieved a 2.5 ~ 7.1-fold increase compared with that of untagged 4G8 (protein yield of 4G8-5C = 0.307 mg/g vs that of untagged 4G8 = 0.043 mg/g). Moreover, the fusion of SF-tags not only had no significant effect on the affinity of 4G8, but also showed a slight increase in the thermal stability of SF-tag-fused 4G8 variants. The fusion of SF-tags increased the transcription of 4G8 by 2.3 ~ 7.0-fold, indicating SF-tags enhanced the protein expression at the transcriptional level. To verify the applicability of the SF-tags for other nanobody expression, we further investigated the protein expression of two other anti-HE4 nanobodies 1G8 and 3A3 upon fusion with the SF-tags. Results indicated that the SF-tags enhanced the protein expression up to 5.2-fold and 5.7-fold for 1G8 and 3A3, respectively. For the first time, this study reported a novel and versatile fusion tag system based on the SFP for improving nanobody expression in
Escherichia coli
, which may enhance its potential for wider applications.
Key points
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A silk fibroin protein–based fusion tag (SF-tag) was developed to enhance the expression of nanobodies in Escherichia coli.
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The SF-tag enhanced the nanobody expression at the transcriptional level.
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The fusion of SF-tag had no significant effect on the affinity of nanobodies and could slightly increase the thermal stability of nanobodies.
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CEKLJ, DOBA, EMUNI, FZAB, GEOZS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The welding of steel/aluminum has great significance for vehicle light weight. The quality of the welding joint largely depends on the selection of process parameters. In this paper, the random ...forest (RF) model was established to describe the nonlinear relationship between welding process parameters and optimization objectives. We used Bayesian optimization (BO) to adjust the hyperparameters of the RF model, and the BO-RF model as the objective function of the multi-objective jellyfish search algorithm to find the optimal welding process parameters and verify them through simulation and practical experiments. The results show that due to the appropriate selection of process parameters, the maximum tensile force of the welded joints was increased by 64 %, the maximum deformation was reduced by 32 %, and the welding cost was reduced by 12 %. What is more, the depth-to-width ratio of steel/aluminum welded joints was increased by 60.7 %, the thickness of brittle intermetallic compounds layer was reduced by about 47.2 % while the tensile fracture surface changed from cleavage fracture to quasi-cleavage fracture.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Efficient data dissemination in vehicular ad hoc networks (VANETs) is a challenging issue due to the dynamic nature of the network. To improve the performance of data dissemination, we study ...distributed data replication algorithms in VANETs for exchanging information and computing in an arbitrarily-connected network of vehicle nodes. To achieve low dissemination delay and improve the network performance, we control the number of message copies that can be disseminated in the network and then propose an efficient distributed data replication algorithm (EDDA). The key idea is to let the data carrier distribute the data dissemination tasks to multiple nodes to speed up the dissemination process. We calculate the number of communication stages for the network to enter into a balanced status and show that the proposed distributed algorithm can converge to a consensus in a small number of communication stages. Most of the theoretical results described in this paper are to study the complexity of network convergence. The lower bound and upper bound are also provided in the analysis of the algorithm. Simulation results show that the proposed EDDA can efficiently disseminate messages to vehicles in a specific area with low dissemination delay and system overhead.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
As one of the most widely used applications in domain adaption (DA), Cross-domain sentiment analysis (CDSA) aims to tackle the barrier of lacking in sentiment labeled data. Applying an adversarial ...network to DA to reduce the distribution discrepancy between source and target domains is a significant advance in CDSA. This adversarial DA paradigm utilizes a single global domain discriminator or a series of local domain discriminators to reduce marginal or conditional probability distribution discrepancies. In general, each discrepancy has a different effect on domain adaption. However, the existing CDSA algorithms ignore this point. Therefore, in this paper, we propose an effective, novel and unsupervised adversarial DA paradigm, Global-Local Dynamic Adversarial Learning (GLDAL). This paradigm is able to quantitively evaluate the weights of global distribution and every local distribution. We also study how to apply GLDAL to CDSA. As GLDAL can effectively reduce the distribution discrepancy between domains, it performs well in a series of CDSA experiments and achieves improvements in classification accuracy compared to similar methods. The effectiveness of each component is demonstrated through ablation experiments on different parts and a quantitative analysis of the dynamic factor. Overall, this approach achieves the desired DA effect with domain shifts.
The prefabricated cabin substation is a new type of intelligent substation integrating environmental protection, energy saving, high efficiency and economy. In view of the characteristics of the ...prefabricated cabin intelligent substation, its differences with conventional substations in terms of modularity and intelligent design are compared, the advantages of the prefabricated cabin substation are summarized, the key technology research of the cabin design is carried out, and its technical and economic indicators are analyzed. The research results show that, compared with conventional standardized substations, the use of prefabricated cabin substation mode can effectively improve the space utilization rate and the flexibility of station construction, the construction area can be reduced by 19%, the construction period is shortened by about 30%, and the cost is reduced by 5.35%, which has good economic and practical value.
Mutations in the TNF family of proteins have been associated with inherited forms of immune deficiency. Using an array-based sequencing assay, we identified an autosomal-dominant deficiency in ...TNF-like weak inducer of apoptosis (TWEAK; TNFSF12) in a kindred with recurrent infection and impaired antibody responses to protein and polysaccharide vaccines. This mutation occurs in the sixth exon of TWEAK and results in the amino acid substitution R145C within the conserved TNF-homology domain of the full-length protein. TWEAK mutant protein formed high molecular weight aggregates under nonreducing conditions, suggesting an increased propensity for intermolecular interactions. As a result, mutant TWEAK associated with B-cell–activating factor (BAFF) protein and down-regulated the BAFF-mediated activation of the noncanonical NF-κB pathway through inhibition of p100 processing to p52, resulting in inhibition of BAFF-dependent B-cell survival and proliferation. As BAFF mediates T-cell–independent isotype switching and B-cell survival, our data implicate TWEAK as a disease-susceptibility gene for a humoral immunodeficiency.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Compared with ordinary injection-molded parts, the slender, cantilevered, and thin-walled plastic parts are harsh on the injection molding process conditions. For complexity and particularity, it is ...difficult to form such parts. It is also more likely to cause excessive warpage deformation, affecting the molding quality and performance. The automobile audio shell is a typical slender, cantilevered, thin-walled plastic part. When the mold structure and material are determined, optimizing its injection molding process is the most economical and effective method to manufacture the products with the optimum properties. In order to minimize the warpage deformation, the adaptive network based fuzzy inference system (ANFIS) and genetic algorithm (GA) were adopted to optimize the injection molding process parameters. In particular, considering the high-dimensional nonlinear relationship between the process parameters and the warpage, the ANFIS is constructed as the prediction model of the warpage. Then, the GA is used to globally optimize the prediction model to determine the optimal process parameters. The results show that the optimization method based on ANFIS-GA has a good performance. The warpage is reduced to 0.0925 mm while reduced by 88.25 %. The optimal injection molding process parameters are used for simulation and manufacture, verifying the effectiveness and reliability of the optimization method.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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