Search

SummaryRevealing differential tumor immune microenvironment (TIME) characteristics between true versus de novo hepatocellular carcinoma (HCC) recurrence could help optimal development and use of immunotherapies. Here, we studied the TIME of recurrent HBV-related HCCs by 5’and VDJ single-cell and bulk RNA-sequencing, flow cytometry, and multiplexed immunofluorescence. Analyses of mutational profiles, evolutionary trajectories, and clonal architecture using whole-exome sequencing identified de novo versus true recurrences, some of which occurred before clinical diagnosis. The TIME of truly recurrent HCCs was characterized by an increased abundance in KLRB1+CD8+ T cells with memory phenotype and low cytotoxicity. In contrast, we found an enrichment in cytotoxic and exhausted CD8+ T cells in the TIME of de novo recurrent HCCs. Transcriptomic and interaction analyses showed an upregulated GDF15 expression level on HCC cells in proximity to dendritic cells, which may have dampened antigen presentation and inhibited anti-tumor immunity in the TIME of truly recurrent lesions. In contrast, we found that myeloid cells’ crosstalk with T cells mediated T cell exhaustion and immunosuppression in the TIME of de novo recurrent HCC. In conclusion, our results support genomic diagnosis and immune profiling for guiding immunotherapy implementation based on the type of HCC recurrence and TIME.HighlightsTruly recurrent lesions are seeded before primary tumor diagnosis, and that de novo cancer can occur earlier than the clinically used 2-year limit.ScRNA-seq unravels distinct immune ecosystems in true versus de novo HCC recurrences, highlighting the need for different immunotherapy strategies for two types of HCC recurrence.CD8+ T cells in de novo recurrence displayed cytotoxic and exhausted phenotypes while those in truly recurrent lesions showed a memory phenotype with weak cytotoxicity.HCC cells expressing the inhibitory molecule GDF15 were in the proximity of DCs only in truly recurrent lesions.High GDF15 expression level was associated with truly recurrent HCC and worse prognosis.Graphical abstract

Ionic skin with a high performance has been extensively explored due to its ability to convert external stimuli into obvious electrical signals for wearable electronics and intelligent detection. H...

Scavenger receptors are pattern recognition receptors that recognize both foreign and self-ligands, and initiate different mechanisms of cellular activation, often as co-receptors. The function of scavenger receptor CD36 in the immune system has mostly been studied in macrophages but it is also highly expressed by innate type B cells where its function is less explored. Here we report that CD36 is involved in macro-autophagy/autophagy in B cells, and in its absence, the humoral immune response is impaired. We found that CD36-deficient B cells exhibit a significantly reduced plasma cell formation, proliferation, mitochondrial mobilization and oxidative phosphorylation. These changes were accompanied by impaired initiation of autophagy, and we found that CD36 regulated autophagy and colocalized with autophagosome membrane protein MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3). When we investigated T-cell-dependent immune responses, we found that mice with CD36 deficiency, specifically in B cells, exhibited attenuated germinal center responses, class switching, and antibody production as well as autophagosome formation. These findings establish a critical role for CD36 in B cell responses and may also contribute to our understanding of CD36-mediated autophagy in other cells as well as in B cell lymphomas that have been shown to express the receptor. Abbreviations: AICDA/AID: activation-induced cytidine deaminase; ATG5: autophagy related 5; ATP: adenosine triphosphate; BCR: B-cell receptor; CPG: unmethylated cytosine-guanosine; CQ: chloroquine; DC: dendritic cells; FOB: follicular B cells; GC: germinal center; Ig: immunoglobulin; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MFI: mean fluorescence intensity; MZB: marginal zone B cells; NP-CGG: 4-hydroxy-3-nitrophenylacetyl-chicken gamma globulin; OCR: oxygen consumption rate; oxLDL: oxidized low-density lipoprotein; PC: plasma cells; Rapa: rapamycin; SQSTM1/p62: sequestosome 1; SRBC: sheep red blood cells; Tfh: follicular helper T cells; TLR: toll-like receptor.

Conductive elastomers (CEs) with strong mechanical properties have been fabricated and used in flexible electronics. However, the development of CEs with both super-high mechanical strength and extreme stretchability remains challenging. This paper reports on the development of a series of mechanically strong and tough CEs based on photopolymerizable deep eutectic solvents (PDESs) with dense hydrogen bonding interactions. One of these CEs exhibits the highest reported mechanical performance for elastomers, with tensile strength, strain at break and toughness up to 31.21 MPa, 3645% and 615 MJ m−3, respectively. Notably, this CE tolerates puncture and can lift a 10.5 kg weight (9500 times its own weight) without any failure. In addition, the series of CEs also shows excellent transparency (>94% in the visible range), favorable conductivity (0.007–0.04 S m−1), tunable stretchability (strain from 22% to 6164%) and good self-healing capability (electrical healing efficiency of 99% within 0.26 s). In view of the comprehensive properties of the CEs, we demonstrate the practical suitability of CEs by including them in a strain sensor to detect human motion. Based on their extremely facile preparation process and practical functionalities, we believe that CEs will not only contribute new methods for the development of mechanically strong conductors, but also open up novel avenues for flexible electronics.

Simultaneously achieving transparency, high mechanical strength and self-healing capability in conductive elastomers with simple and green features is a challenge. Here we develop a novel strategy for a tough yet self-healing supramolecular network by introducing Al(III)-carboxyl complexes into photo-polymerizable deep eutectic solvent (PDES). The resulting polymer simultaneously exhibits high transparency, ionic conductivity, and high stretchability. Notably, due to synergetic interactions of the H-bonds and coordination bonds in the polymer matrix, the supramolecular network shows a high stress at break while achieving good self-healing capability. In view of the outstandingly comprehensive properties, we continue to verify the practicability of our prepared materials as strain sensors to monitor external stimuli such as human motions. Our methodology is simple, green and time-saving, and the fundamental design concept derived from the multifunctional PDES will contribute to the development of tough, self-healing transparent materials and flexible electronics.

BACKGROUND: B-cell affinity maturation in germinal center relies on regulated actin dynamics for cell migration and cell-to-cell communication. Activating mutations in the cytoskeletal regulator Wiskott-Aldrich syndrome protein (WASp) cause X-linked neutropenia (XLN) with reduced serum level of IgA. OBJECTIVE: We investigated the role of B cells in XLN pathogenesis. METHODS: We examined B cells from 6 XLN patients, 2 of whom had novel R268W and S271F mutations in WASp. By using immunized XLN mouse models that carry the corresponding patient mutations, WASp L272P or WASp I296T, we examined the B-cell response. RESULTS: XLN patients had normal naive B cells and plasmablasts, but reduced IgA+ B cells and memory B cells, and poor B-cell proliferation. On immunization, XLN mice had a 2-fold reduction in germinal center B cells in spleen, but with increased generation of plasmablasts and plasma cells. In vitro, XLN B cells showed reduced immunoglobulin class switching and aberrant cell division as well as increased production of immunoglobulin-switched plasma cells. CONCLUSIONS: Overactive WASp predisposes B cells for premature differentiation into plasma cells at the expense of cell proliferation and immunoglobulin class switching. ispartof: JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY vol:149 issue:3 pages:1069-1084 ispartof: location:United States status: published

Ionic conductors are normally prepared from water-based materials in the solid form and feature a combination of intrinsic transparency and stretchability. The sensitivity toward humidity inevitably leads to dehydration or deliquescence issues, which will limit the long-term use of ionic conductors. Here, a novel ionic conductor based on natural bacterial cellulose (BC) and polymerizable deep eutectic solvents (PDESs) is developed for addressing the abovementioned drawbacks. The superstrong three-dimensional nanofiber network and strong interfacial interaction endow the BC-PDES ionic conductor with significantly enhanced mechanical properties (tensile strength of 8 × 105 Pa and compressive strength of 6.68 × 106 Pa). Furthermore, compared to deliquescent PDESs, BC-PDES composites showed obvious mechanical stability, which maintain good mechanical properties even when exposed to high humidity for 120 days. These materials were demonstrated to possess multiple sensitivity to external stimulus, such as strain, pressure, bend, and temperature. Thus, they can easily serve as supersensitive sensors to recognize physical activity of humans such as limb movements, throat vibrations, and handwriting. Moreover, the BC-PDES ionic conductors can be used in flexible, patterned electroluminescent devices. This work provides an efficient strategy for making cellulose-based sustainable and functional ionic conductors which have broad application in artificial flexible electronics and other products.

In this paper, nanochitin was used as an alternative natural nanomaterial to combine with cellulose fibers for fabricating high-strength paper. Two typical chitin nanowhiskers having contrasting sign of surface charge were compared to evaluate the enhancement performance on paper in details. The results show that nanochitin with positive charges on the surface has a significant effect on the strength properties of the prepared paper, especially on wet strength. When the dosage of chitin nanowhiskers was 2%, the wet strength index was increased to 2.48 N·m/g, which is important for paper-based analytical devices with the common use in liquid analysis. Typical colorimetric glucose assays were successfully performed, suggesting the improved analytical performance on these prepared paper.

It is a challenge to synthesize all-in-one molecular networks that are autonomously self-healable over a wide temperature range (from subzero to high), transparent, stretchable, and conductive. Her...

A new type of supramolecular elastomer, photopolymerized from two rationally designed polymerizable deep eutectic solvent (PDES) monomers, was reported. The resultant network was highly transparent, intrinsically conductive, stretchable, and self-healable. In particular, the healing process can even take place in various organic solvents, simultaneously with enhanced adaptability.

Three-dimensional covalent organic frameworks (3D COFs) have gained increasing attention for their attractive features. However, the development of 3D COFs is strongly restricted, mainly due to their synthetic difficulty and complicated structure determination. Post-synthetic modification, which can avoid these problems by incorporating functional moieties into a predetermined framework, provides an alternative way to construct 3D COFs with specific functions. Herein, we report the designed synthesis and characterization of a series of highly crystalline 3D COFs with different loadings of ethynyl groups. Notably, these alkyne-tagged 3D COFs provide a platform for targeted anchoring various specific groups onto the pore walls via click reactions. Moreover, the pore surface engineering can accordingly change their properties, for example, the obtained click products exhibited higher CO2 /N2 selectivity. We describe a simple but powerful strategy to build functional 3D COFs, which will certainly advance them for a ranging of interesting applications in the future.

With the gradual construction of the land and space planning system and the acceleration of the urban-rural integrated development process, China’s rural land planning and preparation have ushered in substantial innovations, and at the same time, they are also facing huge challenges. Among them, the low utilization rate of rural land and cultural desertification are the crux of the lagging rural development. This paper takes Guifengshan Village in Macheng City, Hubei Province as an example. Through the analysis of the current advantages of the village, the analysis of challenges, and the evaluation of the suitability of land use, this paper proposes to promote the mutual benefit of agriculture, culture and tourism, and promote the revitalization of Guifengshan Village, forming a “agricultural industry + characteristic cultural creation + red ecology”. “Tourism” jointly develops rural planning strategies. It aims to link rural agriculture, tourism and cultural industries closely on the basis of people-oriented and ecological protection, with income generation as the goal of rural revitalization, to achieve the establishment and extension of the industrial chain, and to promote rural revitalization.

Both lncRNAs and the N6-methyladenosine (m6A) modification are key regulators of tumorigenesis and innate immunity. However, little is known about the m6A modification of lncRNAs and their clinical and immune relevance in bladder cancer. In this study, we identified m6A-related lncRNAs using Pearson correlation analysis in The Cancer Genome Atlas (TCGA) and the IMvigor210 datasets. Next, univariate Cox regression was performed using the TCGA dataset to filter prognostic m6A-related lncRNAs, which were further subjected to the least absolute shrinkage and selection operator (LASSO) Cox regression to establish a 12 m6A-related lncRNA prognostic score (m6A-LRS). The m6A-LRS was validated in the IMvigor210 dataset. In addition, high m6A-LRS tumors, characterized by decreased tumor mutation load and neoantigen load, showed poorer response to immunotherapy than those with low m6A-LRS in the IMvigor210 dataset. Further, we constructed an m6A-LRS-based nomogram that demonstrated a strong ability to predict overall survival in patients with bladder cancer. Moreover, enrichment analysis revealed that tumor-associated biological processes, oncogenic signaling, and tumor hallmarks were commonly associated with a high m6A-LRS. Gene set variation analysis also indicated that high m6A-LRS was associated with activation of canonical oncogenic signatures, such as the epithelial-to-mesenchymal transition, cell cycle regulators, and DNA replication, as well as activation of immunosuppressive signatures, such as the T-cell exhaustion and pan-fibroblast-TGF-β response signatures. Furthermore, we observed distinct tumor microenvironment cell infiltration characteristics between high- and low-risk tumors. High m6A-LRS tumors showed reduced infiltration of CD8+ T-cells and enhanced infiltration of macrophages and fibroblasts. Additionally, we established a competing endogenous RNA network based on the12 m6A-related lncRNAs. Finally, three lncRNAs (SNHG16, SBF2-AS1, and BDNF-AS) were selected for further validation. The qualitative PCR assay on 10 pairs of bladder cancer and adjacent normal control samples validated the differential expression, and methylated RNA immunoprecipitation (MeRIP) analysis demonstrated a robust m6A enrichment in T24 bladder cancer cells compared with normal uroepithelial cells (SVHUC-1). In conclusion, this study introduced an m6A-related lncRNA signature that identified a subgroup of patients with poor prognoses and suboptimal immune responses, thus providing novel approaches for treatment response prediction and patient stratification in bladder cancer.

Stretchable and antifreezing conductive hydrogels, especially prepared from natural polymers, are beneficial for important and rapidly growing stretchable electronic devices. Unfortunately, the pot...

Garnet electrolyte is a promising candidate for the development of all-solid-state Li-metal batteries, because of its safety and stability against Li metal. However, its practical application is limited by the difficulty in production of its high-density thin sheet. In this work, we have fabricated garnet thin sheet electrolytes (Li6.4La3Zr1.4Ta0.6O12, LLZTO) by tape-casting technique. By using Li2O as a liquid-phase sintering additive, a high relative density up to 99% was achieved. Electrochemical results show the LLZTO sheets have an ionic conductivity of 5.2 × 10−4 S cm−1 at 30 °C and good cycling stability against Li metal. Based on the sheets, all-solid-state Li/LLZTO/LiFePO4 batteries exhibit excellent reversible cycles at 60 °C and 0.1C with an initial discharge specific capacity of 125.8 mA h g−1 and a retention of 92.3% after 50 cycles. These results indicate that the tape-casting process demonstrated here provides an effective method of producing high-density garnet thin sheet electrolytes for high-performance all-solid-state Li-metal batteries.

Garnets are promising solid electrolytes for developing solid state Li batteries, owing to their features of relatively high conductivity and stability against lithium metal. However, they show shortcoming of Li penetration through garnets during Li plating and stripping, which limits their practice application. Herein, we present a strategy to solve such problem by coating SnO2 films on the surfaces of the Li6·4La3Zr1·4Ta0·6O12 pellets. Through conversion reaction of SnO2 with Li at 200 °C, the nanocomposite layers consisting of crosslinked LixSn and Li2O are formed between the Li and the Li6·4La3Zr1·4Ta0·6O12 electrolytes. This leads to transition from lithiophobicity to lithiophilicity, thus greatly reducing interfacial resistance from 1100 Ω cm2 to 25 Ω cm2. Furthermore, taking advantage of suppressing volume change of LixSn alloy which is about 260%, the intermediate layers maintain integrity under the current densities of 0.2 mA cm−2 for 650 h cycles. In addition, the critical current density of Li/SnO2-Li6.4La3Zr1·4Ta0·6O12-SnO2/Li can be as high as 1.15 mA cm−2. As a proof-of-concept, this effective interface modification based on conversion reaction method contributes to a useful way of solving the Li/garnet interface problem and promoting the solid state Li batteries development.

Recently, flutter-driven triboelectric nanogenerator (TENG) has shown huge potential in wind energy harvesting from ambient environments. However, almost all the reported devices are based on parallel structure which suffers from a critical problem of insufficient contact between triboelectric surfaces. In this work, we propose an angle-shaped TENG (AS-TENG) with the above issue resolved. The device is based on two Al layers stacked to form an angle shape and a FEP film positioned in between by sharing a common side. Thanks to this design, the FEP film can contact fully and intimately with the Al layers to facilitate the effect of contact electrification and electrostatic induction. Compared with the existing parallel-structured TENG, the AS-TENG shows an overwhelming output performance because of the enhanced contact area. Furthermore, the AS-TENG is introduced a wedge-shaped wind guide channel which can provide a driving force for the flutter and hence lower the start-up wind speed largely. To further enhance the electric output, the AS-TENGs can be facilely integrated into a 360° radial array, showing an enlarged windward area and a high level of integration. The AS-TENG array can be applied to harvest outdoor weak wind and act as a direct power source to charge a capacitor or drive electronic devices. This work provides a design strategy for natural weak wind scavenging which may push forward the practical applications of TENG for wind power.

An accurate quantification method with a wide linearity range is paramount for the development of low-cost, portable and point-of-care sensors. This work reports a new approach to analyze the colorimetric assays on paper-based sensors using the quantification from a light transmission method. Compared to the commonly-developed color intensity measurement on scanned digital images, a portable transmission densitometer is capable of directly quantifying the optical density of colorimetric results. The detection of heavy metals in an aqueous system, including Fe(ii), Cu(ii), and Ni(ii), was carried out to demonstrate the good performance and reliability of this method. Our measurements show that the linear quantification range spans from 0.5-500 mg L-1 for the assays of Cu(ii) and Fe(ii) and from 2-500 mg L-1 for Ni(ii) based on the reading of transmitted light through the assay spot. As a comparison, the linear range is restricted to 0.5-50 mg L-1 for the same assays when analysed by the common reflection method, suggesting a significant improvement in the accuracy and sensitivity of high analyte concentrations from the light transmission method. By expanding the linearity range, this method further streamlines the sampling procedure during analysis and will greatly advance the future development of paper-based analytical sensors.

The development of porous MOFs exhibiting highly selective C2H2/CH4 and CO2/CH4 separations is quite important to meet the requirement of high-purity C2H2 and CH4 in various industries. By employing a ligand heterobifunctionalization strategy, we designed and synthesized an aminopyridine-functionalized diisophthalate ligand, and successfully targeted its corresponding copper-based NbO-type MOF ZJNU-98. Gas adsorption studies revealed that ZJNU-98 exhibited significantly enhanced adsorption of C2H2 and CO2 over CH4 compared to its parent MOF, NOTT-101. At 298 K and 1 atm, C2H2 and CO2 uptakes of ZJNU-98 are 10.0% and 16.7% higher than the corresponding values of NOTT-101, while 14.2% and 18.8% increases in C2H2/CH4 and CO2/CH4 adsorption selectivities were observed for the equimolar gas mixtures in ZJNU-98 compared to NOTT-101. Furthermore, the contribution of the functional group effect on gas adsorption has been assessed, demonstrating that the amine group plays a more important role than the pyridinic-N atom despite its lower Lewis basicity. This work provided an effective way and significant experimental evidence for the design of new porous MOFs with highly enhanced gas adsorption performance.

The design and construction of porous materials for high-efficient adsorption-based separation of CH4 from C2H2 and CO2 is a fundamental goal in the chemical industry. In this work, a lactam-functionalized bent diisophthalate linker, 5,5'-(1-methylpyridin-2(1H)-one-3,5-diyl) diisophthalic acid, was judiciously designed and utilized to construct a dicopper paddlewheel-based MOF under solvothermal conditions. Single-crystal X-ray diffraction revealed that the resulting solid is a three-dimensional mfj-type network incorporating Lewis-acidic copper sites and accessible lactam groups as two different kinds of functional sites. Furthermore, gas adsorption studies indicated that the material exhibited great promise for C2H2/CH4 and CO2/CH4 separations. In particular, compared to the unmodified parent compound, the resultant MOF exhibits 9.4% and 12.9% higher C2H2 and CO2 uptake capacities and 48.0% and 28.3% higher C2H2/CH4 and CO2/CH4 adsorption selectivities for the equimolar gas mixtures at 298 K and 1 atm, despite the lower specific surface area and pore volume. This work reported the first lactam-functionalized MOF displaying significantly enhanced adsorption of CO2 and C2H2 over CH4.

The structure–property relationship investigation is of prime importance to development of porous MOFs exhibiting better performance. In this work, two regioisomeric diisophthalate ligands, with the only difference being the position of methyl and amino groups with respect to isophthalate moieties, were rationally designed and synthesized, and their corresponding dicopper paddlewheel-based MOFs were successfully fabricated under suitable solvothermal conditions. Single-crystal X-ray diffraction studies showed that they displayed the same network topology of ssa type, thus providing a platform to investigate the impact of the substituent's arrangement on gas adsorption properties. As revealed by gas adsorption studies, the pore textural properties and gas uptake capacities with respect to C2H2, CO2, and CH4 of ZJNU-11 are significantly higher than those of its isomer ZJNU-12 despite their same structures, indicating that the arrangement of functional groups makes a difference to the framework stabilities against desolvation and thus to the gas adsorption properties. In addition, ZJNU-11 is also capable of selectively adsorptive separation of C2H2 and CO2 from CH4, with high C2H2/CH4 (v/v, 1/1) and CO2/CH4 (v/v, 1/1) adsorption selectivities of 36.2 and 5.9 at 298 K and 1 atm. This work not only reported a porous MOF material for highly selective C2H2/CH4 and CO2/CH4 separations, but also demonstrated that the rational arrangement of substituent groups will be favorable to improve the MOF's stabilities and thus gas adsorption properties, which needs to be taken into account upon design and construction of porous MOFs.

Combining a linear diisophthalate ligand, 5,5′-(2,3-dimethylbenzene-1,4-diyl)diisophthalic acid, with CuCl2·2H2O under different solvothermal conditions afforded two distinct copper-based metal–organic frameworks (ZJNU-96 and ZJNU-97), which were structurally characterized by various techniques. Single-crystal X-ray diffraction analyses reveal that they contain the same inorganic and organic building units but exhibit different topological structures, thus belonging to supramolecular isomers. Furthermore, gas adsorption studies show that ZJNU-96 not only exhibits better stability against desolvation than ZJNU-97 but also displays promising potential for selective adsorptive separation of C2H2 and CO2 from CH4, with C2H2 (CO2) uptake of 183.6 (88.7) cm3 (STP) g−1 and C2H2 (CO2)/CH4 (v/v, 50/50) IAST adsorption selectivity of 26.6 (5.2) at 298 K and 1 atm.

Tailoring the structures and properties of metal–organic frameworks (MOFs) is very important for developing porous MOFs for targeted applications. Bent diisophthalate ligands offer a rich opportunity to construct MOFs with variable topologies because of their conformation flexibility and diversity. In this work, by employing a substituent-induced ligand conformation regulation strategy, we designed and synthesized three bent diisophthalate ligands bearing different substituents, and successfully constructed their corresponding dicopper paddlewheel-based MOFs under suitable solvothermal conditions. As revealed by single-crystal structural analyses, they feature distinct topological structures, depending on the attached substituents. Interestingly, the methoxy-functionalized MOF exhibits a novel topology, thus enriching the structural diversity of copper-bent diisophthalate frameworks. Furthermore, their gas adsorption properties with respect to C2H2, CO2, and CH4 were systematically investigated, revealing their promising potential for industrially important C2H2/CH4 and CO2/CH4 separations. More significantly, their separation performance can be greatly tailored by changing the substituents. Under ambient conditions, C2H2 and CO2 uptake capacities vary from 157.7 to 184.5 cm3 (STP) g−1, and 90.8 to 101.3 cm3 (STP) g−1, respectively, while C2H2/CH4 (50/50, v/v) and CO2/CH4 (50/50, v/v) adsorption selectivities range from 30.0 to 36.2, and 5.27 to 6.01, respectively. The amino-functionalized MOF performed better than the other two counterparts, which might be due to the synergistic effect arising from Lewis basic amino groups, higher density of open copper sites, and more suitable pore size. This work not only reported three MOFs for preferable adsorption of C2H2 and CO2 over CH4, but also demonstrated that the substituent-driven ligand conformation regulation is a facile way to modulate the structures and thus gas adsorption properties of MOFs.

The development of porous MOFs with novel structures and functional properties is a key research topic in the MOF chemistry and materials field. In this article, by employing a ligand conformation preorganization strategy, we designed a nonplanar methyl-substituted triisophthalate ligand, which was used to successfully construct a copper–hexacarboxylate framework with a novel topological structure. More importantly, the obtained MOF not only exhibits good hydrolytic stability but also shows utility as an adsorbent for efficient separation and purification of C2H2 and natural gas under ambient conditions. At ambient temperature and atmospheric pressure, the C2H2 and CO2 uptake capacities reach up to 149.1 and 83.1 cm3 (STP) g−1, while the IAST-predicted C2H2/CH4 (50/50, v/v), C2H2/CO2 (50/50, v/v), and CO2/CH4 (50/50, v/v) adsorption selectivities are as high as 22.2, 3.81, and 5.13.

The cumulative exposure to metals affects cardiac conduction, and the effect of polymetallic exposure on heart rate in children is unknown. To evaluate the relationship between cumulative exposure to metal mixtures and heart rate among Chinese preschoolers, the determination of urinary 24 metals was processed by high-resolution inductively coupled plasma-mass spectrometry. Heart rate was recorded when measuring blood pressure after resting 5 min or longer. As a method to compute the Environmental risk score (ERS) according to heart rate under heavy metal mixtures, adaptive elastic net (AENET) with 299 predictors which were formed by the combination of main effects, squared terms, and pairwise interactions of heavy metals with a total number of 23, 23, 253 respectively. To further assess the associations between ERS and heart rate, regression analyses were performed with complex survey designs. The construction of ERS under heart rate-related metal mixtures was returned by AENET in according to 11 main effects (tin, arsenic, zinc, iron, titanium, vanadium, nickel, manganese, cobalt, copper and chromium) and 2 squared terms (tungsten and rubidium). A high correlation was monitored between the alteration of ERS in the study population and heart rate (β = 1.030, 95% CI: 0.730 - 1.330 in 1239; β = 1.085, 95% CI: 0.777 - 1.393 in 1061). Significant associations of ERS with higher heart rates were also pointed out (Ps 0.05). Our study elucidates the association of the cumulative exposure of heavy metals as mixtures and heart rate among Chinese preschoolers. Further research is obliged to corroborate these findings in longitudinal studies.

Purpose: Targeted therapy and immunotherapy are transforming the treatment approach for intrahepatic cholangiocarcinoma (ICC). However, little is known about the intertumor heterogeneity (ITH) of multifocal ICC and its impacts on patient response to these treatments. We aimed to characterize the immunogenomic and epigenomic heterogeneity of multifocal ICC to guide treatment decision making. Experimental Design: We obtained 66 tumor samples from 16 patients with multifocal ICC and characterized the tumor and immune heterogeneity using whole-exome sequencing, bulk and single-cell RNA sequencing, methylation microarray, and multiplex immunostaining. Patients were divided into high- or low-ITH groups according to the median ITH index. Two independent cohorts were used to validate findings. Responses to anti-PD-1 therapy were assessed. Results: Multifocal ICC presented considerable intertumor genomic, transcriptional, and epigenomic heterogeneity within a patient in high ITH group. The immune profile among multiple tumors within a patient was relatively less heterogeneous in high- or low-ITH group, and consistent responses of multiple tumors to anti-PD-1 immunotherapy were observed. Unsupervised clustering of immune markers identified one low and one high immune subtype, with higher immune cell infiltration, closer tumor–immune cell interactions, and upregulated IFN-signature expression in high-immune subtype. Determining expression levels of CD8B and ICOS facilitated this immune classification and prediction of patient prognosis. Finally, promoter DNA methylation contributed to different immune profiles of two subtypes by regulating immune-gene expression. Conclusions: There is comprehensive heterogeneity in the genome, transcriptome, and epigenome of multifocal ICC. On the basis of the less heterogeneous immune profile of ICC, we suggest an immune classification that stratifies patients' prognosis and may support personalized immunotherapy.

X-linked neutropenia (XLN) is caused by gain-of-function mutations in the actin regulator Wiskott-Aldrich Syndrome protein (WASp). XLN patients have reduced numbers of cytotoxic cells in peripheral blood; however, their capacity to kill tumor cells remains to be determined. Here, we examined NK and T cells from 2 patients with XLN harboring the activating WASpL270P mutation. XLN patient NK and T cells had increased granzyme B content and elevated degranulation and IFN-γ production when compared with healthy control cells. Murine WASpL272P NK and T cells formed stable synapses with YAC-1 tumor cells and anti-CD3/CD28-coated beads, respectively. WASpL272P mouse T cells had normal degranulation and cytokine response whereas WASpL272P NK cells showed an enhanced response. Imaging experiments revealed that while WASpL272P CD8+ T cells had increased accumulation of actin upon TCR activation, WASpL272P NK cells had normal actin accumulation at lytic synapses triggered through NKp46 signaling but had impaired response to lymphocyte function associated antigen-1 engagement. When compared with WT mice, WASpL272P mice showed reduced growth of B16 melanoma and increased capacity to reject MHC class I-deficient cells. Together, our data suggest that cytotoxic cells with constitutively active WASp have an increased capacity to respond to and kill tumor cells. ispartof: JCI INSIGHT vol:6 issue:6 ispartof: location:United States status: published

Fiber and textile electronics provide a focus for a new generation of wearable electronics due to their unique lightness and flexibility. However, fabricating knittable fibers from conductive materials with high tensile and transparent properties remains a challenge, especially for applicability in harsh environments. Here, we report a simple photopolymerization approach for the rapid preparation of a new type of a transparent conductive polymer fiber, poly(polymerizable deep eutectic solvent (PDES)) fiber, which exhibits excellent stability at high/low temperature, in organic solvents, especially in dry environments, and overcomes the volatility and freezability of traditional gel materials. A poly(PDES) fiber possesses outstanding mechanical and sensing properties, including negligible hysteresis and creep, fast resilience after a long stretch (10 min), and signal stability during high-frequency cyclic stretching (1 Hz, 10 000 cycles). In addition, the poly(PDES) fibers are knitted into a plain-structured sensor on textile with breathability and high tolerance to damage, enabling stable and accurate monitoring of human stretching, bending, and rotation motions. Furthermore, its dry-cleaning resistance guarantees the feasibility of long-term monitoring, with the electrical signal remaining stable after five dry-cleaning cycles. These promising features of poly(PDES) fibers will promote potential applications in the fields of human movement monitoring, intelligent fibers, and soft robotics.

To expand the structural diversity and optimize the material performance, it is essential but challenging to regulate MOF structures in a predictable and controllable manner. In this work, by manipulating the substituents to engineer the ligand conformations, we designed and synthesized two asymmetric tricarboxylate ligands, and used them to successfully target two copper-tricarboxylate frameworks with diversified topologies depending on the ligand conformations. Besides, the ligand asymmetry induced the formation of two uncommon kinds of copper-carboxylate clusters, thus greatly expanding the library of copper-carboxylate secondary building units. Furthermore, the two compounds also displayed tunable gas adsorption properties pertinent to C2H2 separation and purification. At 298 K and 1 atm, the uptake capacity of C2H2 varies from 79.5 to 104.6 cm3 (STP) g-1, while the adsorption selectivities of C2H2 with respect to CO2 and CH4 are in the range of 2.3-3.8 and 15.3-21.6 for the equimolar components, respectively. Compared to the nitro counterpart, the methoxy MOF features higher C2H2 uptake capacity, larger C2H2/CO2 and C2H2/CH4 adsorption selectivities, and lower regeneration energy. This work demonstrates that simple ligand modification can be used to engineer the structures and tune gas adsorption properties of the resulting MOFs.

To obtain a large number of infrared images of insulators, we designed and carried out infrared imaging tests on 35kV line insulators facing environmental interference. Based on these tests, an improved adaptive median filter method is proposed to eliminate the noise in the grayscale. For image enhancement and segmentation, double-threshold Ostu with histogram equalization are combined. A genetic algorithm is introduced to optimize the calculations, and a BPNN recognition model for a zero-value insulator was designed and tested. Overall, we conclude that the algorithm and the BPNN model proposed in this paper are effective.

This research aims to analyze transient processes during loop closing and opening operations in distribution grids with DGs. The realization of load transfer without blackouts can improve the reliability of a power supply, reducing economic loss. Hence, we summarize the problems appearing during loop closing and opening processes. Based on this analysis, a loop closing operation was executed at one 110 kV substation, and the voltage and current waveform were recorded. A theoretical analysis of field experiments results yielded the spectral characteristics of the system. A loop closing operation was simulated using EMTP-ATP software. The simulation and the field experiment results matched closely, thus validating the simulation model. We conclude that closing and opening operation are influenced by voltage difference, including the amplitude and phase angle difference. The system capacitance and inductance have impact not only on the transient over- voltage, but also on the frequency characteristics of the system.

We report a rapid fabrication strategy of highly transparent piezoresistive balls with excellent pressure-sensitivity and toughness by photopolymerization of polymerizable deep eutectic solvents. By careful design and integration, a number of optoelectronic devices have been constructed with the piezoresistive balls as building blocks.

β-Catenin recruits BRD4 and other coregulators to protect pluripotency gene transcription against network perturbation., Mouse embryonic stem cells cultured with MEK (mitogen-activated protein kinase kinase) and GSK3 (glycogen synthase kinase 3) inhibitors (2i) more closely resemble the inner cell mass of preimplantation blastocysts than those cultured with SL [serum/leukemia inhibitory factor (LIF)]. The transcriptional mechanisms governing this pluripotent ground state are unresolved. Release of promoter-proximal paused RNA polymerase II (Pol2) is a multistep process necessary for pluripotency and cell cycle gene transcription in SL. We show that β-catenin, stabilized by GSK3 inhibition in medium with 2i, supplies transcriptional coregulators at pluripotency loci. This selectively strengthens pluripotency loci and renders them addicted to transcription initiation for productive gene body elongation in detriment to Pol2 pause release. By contrast, cell cycle genes are not bound by β-catenin, and proliferation/self-renewal remains tightly controlled by Pol2 pause release under 2i conditions. Our findings explain how pluripotency is reinforced in the ground state and also provide a general model for transcriptional resilience/adaptation upon network perturbation in other contexts.

Recently, ambient energy harvesting has attracted a great deal of attention to develop clean and renewable energy technologies. In this work, a flexible photo-thermoelectric nanogenerator (PTENG) based on MoS2/PU photothermal film and Te/PEDOT thermoelectric layer has been demonstrated for harvesting environmental infrared (IR) light. The MoS2/PU photothermal film is carefully designed to exhibit excellent flexibility, transferability, and photothermal property. By integrating the photothermal layer with a Te/PEDOT thermoelectric device, the PTENG can produce electrical output without a spatial temperature gradient which is necessary for conventional thermoelectric device. Under IR light illumination, a high temperature difference can be generated across the device, and hence a potential difference established between two electrodes based on a coupling of photothermal effect and Seebeck effect. This type of PTENG exhibits numerous advantages, such as flexible, shape-adaptive, light-weight, and simple-fabrication, which may have a great potential of application in photo-thermoelectric energy harvesting for wearable electronics and implantable electronics.

Investigation of the impact of ligand-originated MOF (metal–organic framework) isomerism and ligand functionalization on gas adsorption is of vital importance because a study in this aspect provides valuable guidance for future fabrication of new MOFs exhibiting better performance. For the abovementioned purpose, two NbO-type ligand-originated MOF isomers based on methoxy-functionalized diisophthalate ligands were solvothermally constructed in this work. Their gas adsorption properties toward acetylene, carbon dioxide, and methane were systematically investigated, revealing their promising potential for the adsorptive separation of both acetylene/methane and carbon dioxide/methane gas mixtures, which are involved in the industrial processes of acetylene production and natural gas sweetening. In particular, compared to its isomer ZJNU-58, ZJNU-59 displays larger acetylene and carbon dioxide uptake capacities as well as higher acetylene/methane and carbon dioxide/methane adsorption selectivities despite its lower pore volume and surface area, demonstrating a very crucial role that the effect of pore size plays in acetylene and carbon dioxide adsorption. In addition, the impact of ligand modification with a methoxy group on gas adsorption was also evaluated. ZJNU-58 exhibits slightly lower acetylene and carbon dioxide uptake capacities but higher acetylene/methane and carbon dioxide/methane adsorption selectivities as compared to its parent compound NOTT-103. By contrast, enhanced adsorption selectivities and uptake capacities were observed for ZJNU-59 as compared to its parent compound ZJNU-73. The results demonstrated that the impact of ligand functionalization with a methoxy group on gas adsorption might vary from MOF to MOF, depending on the chosen parent compound. The results might shed some light on understanding the impact of both ligand-originated MOF isomerism and methoxy group functionalization on gas adsorption.

Natural hydrogels have attracted extensive research interest and shown great potential for many biomedical applications. In this study, a series of biocompatible hydrogels was reported based on the self-assembly of positively charged partially deacetylated α-chitin nanofibers (α-DECHN) and negatively charged 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)-oxidized cellulose nanofibers (TOCNF) for anticancer drug delivery. The formation mechanisms of the α-DECHN/TOCNF hydrogels with different mixing proportions were studied, and their morphological, mechanical, and swelling properties were comprehensively investigated. Additionally, the drug delivery performance of the hydrogels was compared via sustained release test of an anticancer drug (5-fluorouracil). The results showed that the hydrogel with higher physical cross-linking degree exhibited a higher drug loading efficiency and drug release percentage.

NbO-type MOFs constructed from dicopper paddlewheel secondary building units and diisophthalate ligands not only exhibit great promise for the separation of environment and energy-related gas pairs but also more importantly provide an excellent platform for the fundamental investigation of structure–property relationships. In this work, two NbO-type MOFs (ZJNU-91 and ZJNU-92) derived from linear and zigzag-shaped thieno[3,2-b]thiophene-functionalized diisophthalate ligands were solvothermally prepared and structurally characterized. Their gas adsorption properties with respect to C2H2, CO2, and CH4 were systematically investigated, revealing that they exhibit promising potential for selective adsorptive separation of C2H2–CH4 and CO2–CH4 binary gas mixtures which are associated with acetylene production and natural gas upgrading. In particular, compared to its isomer ZJNU-92, ZJNU-91 displays larger C2H2 and CO2 uptake capacities as well as higher C2H2/CH4 and CO2/CH4 adsorption selectivities under ambient conditions, despite its lower surface area and pore volume. On the basis of structural analyses, the better performance of ZJNU-91 compared to its isomer ZJNU-92 can be ascribed to its more optimized pore size.

Evaluating the effect of the substituents on structural stabilities and gas adsorption properties of MOFs is fundamentally important for rational design and synthesis of new MOFs with better performance. For this purpose, three isoreticular copper-based MOFs (ZJNU-87, ZJNU-88 and ZJNU-89) with ssa-type topology were successfully constructed from bent diisophthalate ligands bearing different substituents. Permanent porosity studies reveal that the substituent has a significant effect on framework stabilities against desolvation. Utilizing nonpolar n-hexane as an activation solvent can give more optimized permanent porosity for nonpolar or less-polar substituent-modified ZJNU-88 and ZJNU-89. Furthermore, their gas adsorption properties with respect to C2H2, CO2 and CH4 were systematically investigated, revealing their promising potential for selective C2H2/CH4 and CO2/CH4 separations. In particular, methoxy-modified ZJNU-89 performs better than the methyl-modified ZJNU-88 in terms of uptake capacity and adsorption selectivity, which might be attributed to more suitable pore space of ZJNU-89.

For acetylene production and natural gas purification, the development of porous materials exhibiting highly selective C2H2/CH4 and CO2/CH4 separations is very important but remains a major challenge. In this work, we employed three unsymmetrical diisophthalate ligands to construct an isoreticular series of copper-based MOFs exhibiting highly selective adsorption of C2H2 and CO2 from CH4 under ambient conditions. The gravimetric uptake capacities at 298 K and 1 atm vary from 171.7 to 200.4 cm3 (STP) per g for C2H2, and from 104.1 to 115.6 cm3 (STP) per g for CO2. The IAST adsorption selectivity is in the range of 27.6–34.5 for an equimolar C2H2/CH4 mixture, and 5.73–7.14 for an equimolar CO2/CH4 mixture at 298 K and 1 atm. These values are among the highest reported for MOFs constructed from bent diisophthalate ligands under the same conditions. The effect of alkoxy group functionalization on gas adsorption was also explored, revealing that compared to the parent compound, the alkoxy group functionalized MOFs exhibit a reduced uptake capacity but an improved adsorption selectivity. This work demonstrates that the three MOFs are promising materials for C2H2/CH4 and CO2/CH4 separations, and provides a fundamental understanding of alkoxy group functionalization on gas adsorption properties.

Understanding the structure–property relationship is conducive to the rational design and synthesis of porous MOFs with better performance. In this work, we constructed three isoreticular MOFs derived from quinoline-functionalized bent diisophthalate ligands as a platform to investigate the positional effect of nitrogen functional sites on the structural stabilities and gas adsorption properties of the resulting MOFs. N2 adsorption experiments performed at 77 K revealed that the three MOF compounds exhibited different stabilities against the framework desolvation, which we think is attributed to different accessibility degrees of nitrogen functional sites leading to different interactions between the frameworks and activated solvent molecules. In addition, as a consequence of the incorporation of nitrogen functional sites into the framework, the most stable MOF ZJNU-84 outperformed its parent compound ZJNU-71 in terms of C2H2 and CO2 uptake capacities and C2H2/CH4 and CO2/CH4 adsorption selectivities, indicating its promising potential for the selective separation of C2H2 and CO2 from CH4. However, the enhancement is not as remarkable as expected due to a low degree of accessibility of nitrogen functional sites in the framework.

Manipulation of bubbles in water is of great importance in the mineral industry, oil production and separation, wastewater treatments, boiling processes, biological cell incubations, microfluidics and miniature reactor technologies. Generally, bubbles in an aqueous environment are inclined to stick to the channel walls, resulting in blockage and energy-consuming treatments. Herein, we report the fabrication of low-adhesion graphene-oxide (GO)/gold-nanoparticle (GNP) hybrid films with a good underwater superaerophobicity, which have the ability to arbitrarily manipulate bubbles in water. Owing to the hydrophilic nature of GO nanosheets and hierarchical structures of aggregated GNPs, the GO/GNP hybrid films showed low adhesion towards bubbles in water. Thus, bubbles could be freely manipulated using home-made tools coated with these low-adhesion, underwater superaerophobic GO/GNP hybrid films. The controlled 1D and 2D movements of one bubble and merging/reaction of two bubbles can be achieved. This study provides a new avenue to design new strategies for bubble manipulations, and further extends the application of superwettable 2D materials in interface fields involving gas phases.

Three copper-based ligand-originated MOF isomers (ZJNU-81, ZJNU-82 and ZJNU-83) derived from methyl-functionalized V-shaped diisophthalate ligands were solvothermally synthesized and structurally characterized. Single-crystal X-ray diffraction studies revealed that the position of the methyl group in the central phenyl spacer of diisophthalate ligands exerted a significant effect on determining the final structures of the resulting MOFs, which was rationalized to result from the steric effect imposed by the methyl group controlling the conformational structures of the ligands during the self-assembly process. Furthermore, their gas adsorption properties with respect to C2H2, CO2, and CH4 were systematically investigated and comparatively analyzed. Gratifyingly, the three MOFs exhibited respectable C2H2 and CO2 uptake capacities as well as impressive C2H2/CH4 and CO2/CH4 adsorption selectivities. Although the disparity is small, the different gas uptake capacities and adsorption selectivities exhibited by the three MOFs demonstrate that the position of the methyl group has a certain impact on gas adsorption properties. This work not only reported three MOFs with promising potential for C2H2/CH4 and CO2/CH4 separations, but also more importantly afforded a fundamental understanding of the positional effect of functional groups on the structures and gas adsorption properties of the resulting MOFs, which provides valuable guidance for future design and synthesis of porous MOFs displaying better performance.

The combination of an angular diisophthalate ligand, 5,5′-(naphthyl-2,7-yl)diisophthalate (H4L), and copper ions under different solvothermal conditions afforded two polymorphous metal–organic frameworks (ZJNU-77 and ZJNU-78) with the same framework composition of [Cu2(L)(H2O)2], providing a platform to investigate the relationship between MOF polymorphism and gas adsorption properties. As determined by single-crystal X-ray diffraction, ZJNU-77 and ZJNU-78 exhibited three-dimensional networks crystallizing in different space groups. Their structural differences were mainly manifested by the ligand's conformation, the level of framework interpenetration and the network's topology. Interestingly, gas adsorption studies showed that the two compounds after desolvation displayed comparable gas adsorption properties with respect to C2H2, CO2 and CH4, despite their different surface areas and pore volumes. The C2H2, CO2, and CH4 uptake capacities at 298 K and 1 atm are 120.2, 78.1, and 18.4 cm3 (STP) g−1 for ZJNU-77, and 122.0, 82.0, and 18.9 cm3 (STP) g−1 for ZJNU-78, respectively. The IAST adsorption selectivities for the equimolar C2H2/CH4 and CO2/CH4 mixtures are 28.6 and 5.7 for ZJNU-77, and 28.4 and 5.9 for ZJNU-78 at 298 K and 1 atm. These results indicate that besides the surface area, the pore size also plays a crucial role in gas adsorption. This work not only represents an intriguing example of MOF polymorphism achieved by controlling solvothermal conditions, but also provides an insight into the correlation between MOF polymorphism and gas adsorption properties.

We report a green fabrication of conductive paper based on in situ polymerization of polymerizable deep eutectic solvents (PDESs) through a screen printing process. By pre-designed circuit paths and careful integration, on-demand input/output 3D circuits can be achieved, showing its flexibility to origami electronics.

The ligand truncation strategy provides facile access to a wide variety of linkers for the construction of MOFs bearing diverse structures and intriguing properties. In this work, we employed this strategy to design and prepare a novel bent diisophthalate ligand, and used it to successfully construct a copper-based MOF ZJNU-51 with the formula of [Cu2L(H2O)2]·5DMF (H4L = 5,5'-(triphenylamine-4,4'-diyl) diisophthalic acid), which was thoroughly characterized by various techniques including FTIR, TGA, PXRD and single-crystal X-ray diffraction. ZJNU-51 is a two-fold interpenetrated network in which the single network consists of dicopper paddlewheel units connected by the organic ligands and contains open channels as well as six distinct types of metal-organic cages. Furthermore, gas adsorption properties with respect to C2H2, CO2, and CH4 were systematically investigated, demonstrating that ZJNU-51 is a highly promising material for C2H2/CH4 and CO2/CH4 separations. Specifically, the IAST adsorption selectivity at 298 K and 1 atm reaches 35.6 and 5.4 for the equimolar C2H2/CH4 and CO2/CH4 gas mixtures, respectively. More significantly, as revealed by PXRD and N2 adsorption measurements, ZJNU-51 exhibits excellent chemical stability, which lays a good foundation for its practical application.

Solvothermal reactions of cyclotriphosphazene-functionalized hexacarboxylate derivatives bearing different substituents (methoxy, chloro, bromo and methyl) with Ho(NO3)3·6H2O gave rise to four new three-dimensional lanthanide metal–organic frameworks (Ln-MOFs). Single-crystal X-ray diffraction analyses reveal that they all feature rod-shaped Ho-carboxylate chains as inorganic secondary building units but display substituent-driven structural diversities instead of the isoreticular structures. N2 adsorption and desorption studies show that among these Ln-MOFs, only the methoxy-modified Ln-MOF ZJNU-63 after activation exhibits permanent porosity. Furthermore, the gas adsorption properties of ZJNU-63 with respect to C2H2, C2H4, C2H6, CO2, and CH4 were systematically investigated, revealing its possible potential for natural gas purification. Although the separation performance is not very impressive compared to the other reported MOFs, ZJNU-63 presents a rare example of permanently porous Ln-MOFs constructed from flexible organic ligands displaying selective gas adsorption. Besides, ZJNU-63 can adsorb a large amount of C4 hydrocarbons with uptake capacities ranging from 58.8 to 75.7 cm3 (STP) g−1 at 298 K and 1 atm.

Solid-state batteries (SSBs) have already attracted significant attention due to their potential to offer high energy density and excellent safety as compared to the currently used lithium-ion batteries with liquid electrolytes. The use of a lithium anode in SSBs is extremely important to realize these advantages. Starting from the synthesis of a highly conductive cubic garnet solid electrolyte (Li6.375La3Zr1.375Nb0.625O12, LLZNO) using Nb as a structure stabilizer, in this study, we demonstrated the resolution of interfacial problems between the garnet electrolyte and lithium anode and the integration of the lithium anode into garnet-based SSBs by modifying the as-synthesized LLZNO with a Sn thin film. Due to the Sn modification, the interfacial resistances between the garnet electrolyte and the lithium anode decreased approximately 20 times to only 46.6 Ω cm2. The fast and reversible lithium plating/stripping under high current densities and the excellent battery performance of Li/Sn-LLZNO/LiFePO4 full cells were achieved. This improvement is ascribed to the formation of a Li–Sn alloy interlayer, which severs as a self-limited stable and conductive interface, bridging the garnet electrolyte and the lithium anode and enabling fast and stable lithium transport. As a proof-of-concept, this effective surface modification method will offer inspirations to researchers for overcoming the interfacial problems and promoting the development of high-performance SSBs.