Reciprocal regulation of T follicular helper cells and dendritic cells drives colitis development.

The immunological mechanisms underlying chronic colitis are poorly understood. T follicular helper (TFH) cells are critical in helping B cells during germinal center reactions. In a T cell transfer colitis model, a lymphoid structure composed of mature dendritic cells (DCs) and TFH cells was found within T cell zones of colonic lymphoid follicles. TFH cells were required for mature DC accumulation, the formation of DC-T cell clusters and colitis development. Moreover, DCs promoted TFH cell differentiation, contributing to colitis development. A lineage-tracing analysis showed that, following migration to the lamina propria, TFH cells transdifferentiated into long-lived pathogenic TH1 cells, promoting colitis development. Our findings have therefore demonstrated the reciprocal regulation of TFH cells and DCs in colonic lymphoid follicles, which is critical in chronic colitis pathogenesis.

25-Hydroxycholesterol regulates lysosome AMP kinase activation and metabolic reprogramming to educate immunosuppressive macrophages.

Macrophages are critical to turn noninflamed "cold tumors" into inflamed "hot tumors". Emerging evidence indicates abnormal cholesterol metabolites in the tumor microenvironment (TME) with unclear function. Here, we uncovered the inducible expression of cholesterol-25-hydroxylase (Ch25h) by interleukin-4 (IL-4) and interleukin-13 (IL-13) via the transcription factor STAT6, causing 25-hydroxycholesterol (25HC) accumulation. scRNA-seq analysis confirmed that CH25Hhi subsets were enriched in immunosuppressive macrophage subsets and correlated to lower survival rates in pan-cancers. Targeting CH25H abrogated macrophage immunosuppressive function to enhance infiltrating T cell numbers and activation, which synergized with anti-PD-1 to improve anti-tumor efficacy. Mechanically, lysosome-accumulated 25HC competed with cholesterol for GPR155 binding to inhibit the kinase mTORC1, leading to AMPKα activation and metabolic reprogramming. AMPKα also phosphorylated STAT6 Ser564 to enhance STAT6 activation and ARG1 production. Together, we propose CH25H as an immunometabolic checkpoint, which manipulates macrophage fate to reshape CD8+ T cell surveillance and anti-tumor response.

Zinc-finger protein ZFP488 regulates the timing of oligodendrocyte myelination and remyelination.

Oligodendrocyte myelination and remyelination after injury are intricately regulated by various intrinsic and extrinsic factors, including transcriptional regulators. Among these, the zinc-finger protein ZFP488 is an oligodendrocyte-enriched transcriptional regulator that promotes oligodendrocyte differentiation in the developing neural tube and in oligodendroglial cell lines. However, the specific in vivo genetic requirements for ZFP488 during oligodendrocyte development and remyelination have not been defined. To address this gap, we generated a lineage-traceable ZFP488 knock-out mouse line, wherein a H2b-GFP reporter replaces the ZFP488-coding region. Using these mice of either sex, we examined the dynamics of ZFP488 expression from the endogenous promoter in the developing central nervous system (CNS). We observed a unique expression pattern in the oligodendrocyte lineage, with ZFP488 expression particularly enriched in differentiated oligodendrocytes. ZFP488 loss resulted in delayed myelination in the developing CNS and impaired remyelination after demyelinating injury in the brain. Integrated transcriptomic and genomic profiling further revealed that ZFP488 loss decreased expression of myelination-associated genes but not oligodendrocyte progenitor-associated genes, suggesting that ZFP488 serves as a positive regulator of myelination by regulating maturation programs. Thus, our genetic loss-of-function study revealed that ZFP488 regulates a stage-dependent differentiation program that controls the timing of CNS myelination and remyelination.Significance statement Precise timing of myelination is essential for efficient neural communication and is linked to the development of cognitive and motor skills as well as myelin repair after injury. ZFP488 is a transcriptional regulator enriched in oligodendrocytes, however its in vivo functions remain unclear. By generating ZFP488 loss-of-function mice, we demonstrated that ZFP488 is critical for the timing of myelination and remyelination and that its loss impaired the initial differentiation of oligodendrocytes but not their precursor formation and proliferation. Transcriptomic profiling showed that ZFP488 functions as a positive regulator of myelination by modulating oligodendrocyte maturation programs. Thus, our findings underscore the important role of ZFP488 in myelination and the potential of ZFP488 augmentation as an avenue to enhance oligodendrocyte regeneration.

PPARα phosphorylation regulates colorectal tumor immune escape.

A high level of PD-L1 in cancer cells promotes tumor immune escape and inhibits tumor immunotherapy. Although PD-L1 gene expression is upregulated by multiple pathways, its gene transcriptional repression is still unclear. Here we found that loss of PPARα, one of the peroxisome-proliferator-activated receptors (PPARs) family members, promoted colorectal tumor immune escape. Mechanistically, PPARα directly bound to the PD-L1 promoter resulting in its gene transcriptional repression, which in turn increased T cell activity, and PPARα agonist enhanced this event. However, ERK induced PPARα-S12 phosphorylation leading to blockade of PPARα-mediated PD-L1 transcriptional repression, and the combination of ERK inhibitor with PPARα agonist significantly inhibited tumor immune escape. These findings suggest that the ERK-PPARα pathway inhibited PD-L1 gene transcriptional repression and promoted colorectal tumor immune escape.

Outer Sphere Electron Transfer Enabling High-Voltage Aqueous Electrolytes.

Aqueous electrolytes with a low voltage window (1.23 V) and prone side reactions, such as hydrogen evolution reaction and cathode dissolution, compromise the advantages of high safety and low cost of aqueous metal-ion batteries. Herein, introducing catechol (CAT) into the aqueous electrolyte, an outer sphere electron transfer mechanism is initiated to inhibit the water reactivity, achieving an electrochemical window of 3.24 V. In a typical Zn-ion battery, the outer sphere electrons jump from CAT to Zn2+-H2O at a geometrically favorable situation and between the solvation molecules without breaking or forming chemical bonds as that of the inner sphere electron transfers. The excited state π-π stacking further leads to the outer sphere electron transfer occurring at the electrolyte/electrode interface. This high-voltage electrolyte allows achieving an operating voltage two times higher than that of the usual aqueous electrolytes and provides almost the highest energy density and power density for the V2O5-based aqueous Zn-ion full batteries. The Zn//Zn symmetric battery delivers a 4000 h lifespan, and the Zn//V2O5 full battery achieves a ∼380 W h kg-1 energy density and a 92% capacity retention after 3000 cycles at 1 A g-1 and a 2.4 V output voltage. This outer sphere electron transfer strategy paves the way for designing high-voltage aqueous electrolytes.

Deformable Smart DNA Nanomachine for Synergistic Intracellular Cancer-Related miRNAs Imaging and Chemo-Gene Therapy of Drug-Resistant Tumors.

Diagnosis and treatment of tumor especially drug-resistant tumor remains a huge challenge, which requires intelligent nanomedicines with low toxic side effects and high efficacy. Herein, deformable smart DNA nanomachines are developed for synergistic intracellular cancer-related miRNAs imaging and chemo-gene therapy of drug-resistant tumors. The tetrahedral DNA framework (MA-TDNA) with fluorescence quenched component and five antennas is self-assembled first, and then DOX molecules are loaded on the MA-TDNAs followed by linking MUC1-aptamer and Mcl-1 siRNA to the antennas of MA-TDNA, so that the apt-MA-TDNA@DOX-siRNA (DNA nanomachines) is constructed. The DNA nanomachine can respond to two tumor-related miRNAs in vitro and in vivo, which can undergo intelligent miRNA-triggered opening of the framework, resulting in the "turn on" of the fluorescence for sensitively and specifically sensing intracellular miRNAs. Meanwhile, both miRNA-responded rapid release and pH-responded release of DOX are achieved for chemotherapy of tumor. In addition, the gene therapy of the DNA nanomachines is achieved due to the miRNA-specific capture and the RNase H triggered release of Mcl-1 siRNA. The DNA nanomachines intergrading both tumor imaging and chemo-gene therapy in single nanostructures realized efficient tumor-targeted, image-guided, and microenvironment-responsive tumor diagnosis and treatment, which provides a synergetic antitumor effect on drug-resistant tumor.

A Contrast-Enhanced Tri-Modal MRI Technique for High-Performance Hypoxia Imaging of Breast Cancer.

Personalized radiotherapy strategies enabled by the construction of hypoxia-guided biological target volumes (BTVs) can overcome hypoxia-induced radioresistance by delivering high-dose radiotherapy to targeted hypoxic areas of the tumor. However, the construction of hypoxia-guided BTVs is difficult owing to lack of precise visualization of hypoxic areas. This study synthesizes a hypoxia-responsive T1, T2, T2 mapping tri-modal MRI molecular nanoprobe (SPION@ND) and provides precise imaging of hypoxic tumor areas by utilizing the advantageous features of tri-modal magnetic resonance imaging (MRI). SPION@ND exhibits hypoxia-triggered dispersion-aggregation structural transformation. Dispersed SPION@ND can be used for routine clinical BTV construction using T1-contrast MRI. Conversely, aggregated SPION@ND can be used for tumor hypoxia imaging assessment using T2-contrast MRI. Moreover, by introducing T2 mapping, this work designs a novel method (adjustable threshold-based hypoxia assessment) for the precise assessment of tumor hypoxia confidence area and hypoxia level. Eventually this work successfully obtains hypoxia tumor target and accurates hypoxia tumor target, and achieves a one-stop hypoxia-guided BTV construction. Compared to the positron emission tomography-based hypoxia assessment, SPION@ND provides a new method that allows safe and convenient imaging of hypoxic tumor areas in clinical settings.

The Hybridization of Polymers with Metal Oxide Clusters for the Design of Non-Fluorinated Proton Exchange Membranes.

As the key component of various energy storage and conversion devices, proton exchange membranes (PEMs) have been attracting significant interest. However, their further development is limited by the high cost of perfluorosulfonic acid polymers and the poor stability of acid-dopped non-fluorinated polymers. Recently, a new group of PEMs has been developed by hybridizing polyoxometalates (POMs), a group of super acidic sub-nanoscale metal oxide clusters, with polymers. POMs can serve simultaneously as both proton sponges and stabilizing agents, and their complexation with polymers can further improve polymers' mechanical performance and processability. Enormous efforts have been focused on studying supramolecular complexation or covalent grafting of POMs with various polymers to optimize PEMs in terms of cost, mechanical properties and stabilities. This concept summarizes recent advances in this emerging field and outlines the design strategies and application perspectives employed for using POM-polymer hybrid materials as PEMs.

Maximizing Electrostatic Interaction in Ultramicroporous Metal-Organic Frameworks for the One-Step Purification of Acetylene from Ternary Mixture.

Developing efficient adsorbents for acetylene purification from multicomponent mixtures is of critical significance in the chemical industry, but the trade-off between regenerability and selectivity significantly restricts practical industrial applications. Here, we report ultramicroporous metal-organic frameworks with acetylene-affinity channels to enhance electrostatic interaction between C2H2 and frameworks for the efficient one-step purification of C2H2 from C2H2/CO2/C2H4 mixtures, in which the electrostatic interaction led to high regenerability. The obtained SNNU-277 exhibits significantly higher adsorption capacity for C2H2 than that for both C2H4 and CO2 at 298 K and 0.1 bar, while an ultrahigh selectivity of C2H2/C2H4 (100.6 at 298 K) and C2H2/CO2 (32.8 at 298 K) were achieved at 1 bar. Breakthrough experiments validated that SNNU-277 can efficiently separate C2H2 from C2H2/C2H4/CO2 mixtures. CO2 and C2H4 broke through the adsorption column at 4 and 14.8 min g-1, whereas C2H2 was detected until 177.6 min g-1 at 298 K. Theoretical calculations suggest that the framework is electrostatically compatible with C2H2 and electrostatically repels C2H4 and CO2 in the mixed components. This work highlights the importance of rational pore engineering for maximizing the electrostatic effect with the preferentially absorbed guest molecule for efficient multicomponent separation.

Association between plasma maresin 1 and the risk of atherosclerotic cardiovascular disease in Chinese adults: A community-based cohort study.

BACKGROUND AND AIMS: It has been reported that maresin 1 (MaR1) is able to protect against the development of atherogenesis in cellular and animal models. This study was performed to investigate whether plasma MaR1 is associated with the risk of atherosclerotic cardiovascular disease (ASCVD) at the population level. METHODS AND RESULTS: The study included 2822 non-ASCVD participants from a community-based cohort who were followed for about 8 years. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for ASCVD events according to baseline MaR1 quartiles were calculated using the Cox proportional hazards model. During follow-up, a total of 290 new ASCVD cases were identified. The restricted cubic spline analysis indicated a linear dose-response association between plasma MaR1 and incident ASCVD. In addition, the adjusted-HR (95% CI) for ASCVD events associated with one standard deviation increase in MaR1 was 0.79 (0.68-0.91). Moreover, the adjusted-HRs (95% CIs) for ASCVD events associated with the second, third and fourth quartiles versus the first quartile of plasma MaR1 were 1.00, 1.04 (0.76, 1.42), 0.88 (0.64, 1.22) and 0.58 (0.41, 0.84), respectively. Mediation analyses showed that the association between MaR1 and incident ASCVD was partially mediated by small dense low-density lipoprotein cholesterol, with a mediation proportion of 9.23%. Further, the net reclassification improvement and integrated discrimination improvement of ASCVD risk were significantly improved when MaR1 was added to basic model established by conventional risk factors (all p < 0.01). CONCLUSIONS: Elevated plasma MaR1 concentrations are associated with a lower risk of ASCVD development.

PriTKT: A Blockchain-Enhanced Privacy-Preserving Electronic Ticket System for IoT Devices.

Electronic tickets (e-tickets) are gradually being adopted as a substitute for paper-based tickets to bring convenience to customers, corporations, and governments. However, their adoption faces a number of practical challenges, such as flexibility, privacy, secure storage, and inability to deploy on IoT devices such as smartphones. These concerns motivate the current research on e-ticket systems, which seeks to ensure the unforgeability and authenticity of e-tickets while simultaneously protecting user privacy. Many existing schemes cannot fully satisfy all these requirements. To improve on the current state-of-the-art solutions, this paper constructs a blockchain-enhanced privacy-preserving e-ticket system for IoT devices, dubbed PriTKT, which is based on blockchain, structure-preserving signatures (SPS), unlinkable redactable signatures (URS), and zero-knowledge proofs (ZKP). It supports flexible policy-based ticket purchasing and ensures user unlinkability. According to the data minimization and revealing principle of GDPR, PriTKT empowers users to selectively disclose subsets of (necessary) attributes to sellers as long as the disclosed attributes satisfy ticket purchasing policies. In addition, benefiting from the decentralization and immutability of blockchain, effective detection and efficient tracing of double spending of e-tickets are supported in PriTKT. Considering the impracticality of existing e-tickets schemes with burdensome ZKPs, we replace them with URS/SPS or efficient ZKP to significantly improve the efficiency of ticket issuing and make it suitable for use on smartphones.

Alkylide derivatives of diphyllin: synthesis and preliminary anticancer evaluation.

Fourteen diphyllin 4-C-substituted alkylide derivatives were designed and synthesized using a Heck coupling and subsequent hydrogenation reaction. Olefins 3g and 3i exhibited the highest cytotoxicity on breast cancer cell lines MCF-7 with IC50 values of 0.08 and 0.07 µM, and they showed weaker V-ATPase inhibitory potency compared to diphyllin.

Monocular Vision Loss After Ear Filler Injection.

Ophthalmic artery occlusion caused by facial hyaluronic acid filler injection has always been a rare but devastating complication. With the pursuit of beauty, people have become more interested in ears and hyaluronic acid fillers. Herein, we report the case of a more serious rare complication of ophthalmic artery occlusion caused by ear filler injection. A 45-year-old woman developed vision loss on the left side immediately after receiving cosmetic hyaluronic acid injection in the ear, with only the visual field at the inferior temporal side remaining. She was diagnosed with central retinal artery occlusion in the left eye. After treatment with hyaluronidase injection, dexamethasone, hyperbaric oxygen, and oral alprostadil, blood flow was partially restored in the left ophthalmic artery, and her vision improved. Vascular complications after ear injections are rare. However, as the demand for ear filler injections increases, the probability of serious vascular complications is predicted to increase. The potential mechanism by which occlusion occurred involved the filler reaching the superficial temporal artery system through the superior auricular artery, thus occluding the ophthalmic artery. Having an understanding of anatomy is an important measure to avoid complications.Level of Evidence IV This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based medicine ratings, please refer to the Table of contents or the online Instructions to Authors www.springer.com/00266 .

Fluorination of a conserved tyrosine in POR offers new clues for proton transfer.

Reduction of the 17,18-double bond in the D-ring during chlorophyll biosynthesis is catalyzed by the rare, naturally occurring photoenzyme protochlorophyllide oxidoreductase (POR). A conserved tyrosine residue has been suggested to donate a proton to C18 of the substrate in the past decades. Taylor and colleagues scrutinized the model with a powerful tool that utilized a modified genetic code to introduce fluorinated tyrosine analogues into POR. The presented results show that the suggested catalytically critical tyrosine is unlikely to participate in the reaction chemistry but is required for substrate binding, and instead, a cysteine residue preceding the lid helix is proposed to have the role of proton donor.

Culture and effectiveness of distance restriction policies: evidence from the COVID-19 pandemic.

Natural disasters bring indelible negative impacts to human beings, and people usually adopt some post hoc strategies to alleviate such impacts. However, the same strategies may have different effects in different countries (or regions), which is rarely paid attention by the academic community. In the context of COVID-19, we examine the effect of distance restriction policies (DRP) on reducing human mobility and thus inhibiting the spread of the virus. By establishing a multi-period difference-in-differences model to analyse the unique panel dataset constructed by 44 countries, we show that DRP does significantly reduce mobility, but the effectiveness varies from country to country. We built a moderating effect model to explain the differences from the cultural perspective and found that DRP can be more effective in reducing human mobility in countries with a lower indulgence index. The results remain robust when different sensitivity analyses are performed. Our conclusions call for governments to adapt their policies to the impact of disasters rather than copy each other.

Multiscale modeling of solid starch-based foods digestion in the intestinal tract for dietary property-based glycemic prediction.

The digestion of starch-based foods in the intestinal tract is important for human health. Modeling the details enhances fundamental understanding and glycemic prediction accuracy. It is, however, a challenge to take granular properties into account. A multiscale digestion model has been proposed to characterize mass transfer and hydrolysis reaction at both the intestine and particle scales, seamlessly integrating inter-scale mass exchange. A specific grid scheme was formulated for the shrinkage and transport of the particle computational domain. By incorporating additional glycemic-related processes, e.g., intestinal absorption, a dietary property-based glycemic prediction system has been developed. Its effectiveness was validated based on a human tolerance experiment of cooked rice particles. The model-based investigation comprehensively reveals the impact of initial size on digestion behavior, specifically in terms of enzyme distribution and particle evolution. This work also demonstrates the significance of modeling both particle-scale diffusion and intestine-scale transport, a combination not previously explored. The results indicate that ignoring the former mechanism leads to an overestimation of the glycemic peak by at least 50.8%, while ignoring the latter results in an underestimation of 16.3%.

Development and validation of a nomogram for predicting fatigue in patients with primary Sjögren's syndrome.

OBJECTIVE: To develop and validate a nomogram to predict fatigue in patients with primary Sjögren's syndrome (pSS). METHODS: In this cross-sectional study, 251 patients with SS from the Affiliated Hospital of Nantong University were recruited. The patients were randomly divided into two groups: training group (n = 167) and validation group (n = 84). In the training group, univariate analysis and multivariate Cox regression analysis were performed on sociodemographic factors, disease activity, anxiety/depression, clinical indicators, and so on. According to the risk factors of fatigue in SS patients, a nomograph was established. In the training group and validation group, the performance of the nomogram was verified by three forms: receiver operating characteristic curve, calibration curve, and decision curve analysis (DCA). RESULT: The incidence of fatigue was 40.6%. EULAR Sjögren's Syndrome Disease Activity Index, EULAR SS patient reported index, and depression were independent risk factors of fatigue in SS patients. The C-index of nomogram was 0.8532 in training set and 0.7381 in verification set, respectively. As to the Hosmer-Lemeshow test, the P value of modeling patients is 0.996 in verification (P > 0.05). DCA further validated the clinical utility of this nomogram. CONCLUSION: The nomogram constructed in this study can effectively predict the occurrence of fatigue in SS patients, which is helpful for clinical decision-making and subsequent intervention implementation. Key Points • Fatigue was widespread in patients with primary Sjögren's syndrome, and the incidence of fatigue was 40.6%. • Disease activity and depression were independent risk factors of fatigue in patients with Sjögren's syndrome. • This was the first comprehensive nomogram to predict fatigue for Sjögren's syndrome patients.

Comparative study on Al-SBA-15 prepared by spray drying and traditional methods for bulky hydrocarbon cracking: Properties, performance and influencing factors.

Mesoporous aluminosilicates Al-SBA-15 with large pore sizes and suitable acid properties are promising substitutes to zeolites for catalytic cracking of bulky hydrocarbons without molecular diffusion limitation. The conventional processes to synthesize Al-SBA-15 are time-consuming and often suffer from low "framework" Al contents. Herein, Al-SBA-15 microspheres are synthesized using the rapid and scalable microfluidic jet spray drying technique. They possess uniform particle sizes (45-60 µm), variable surface morphologies, high surface areas (264-340 m2/g), uniform mesopores (3.8-4.9 nm) and rich acid sites (126-812 µmol/g) and high acid strength. Their physicochemical properties are compared with the counterparts synthesized using traditional hydrothermal and evaporation-induced self-assembly methods. The spray drying technique results in a higher incorporation of aluminum (Al) atoms into the silica "framework" compared to the other two methods. The catalytic cracking efficiencies of 1,3,5-triisopropylbenzene (TIPB) on the Al-SBA-15 materials synthesized using the three different methods and nanosized ZSM-5 are compared. The optimal spray-dried Al-SBA-15 exhibits the best performance with 100 % TIPB conversion, excellent selectivity (about 75 %) towards the formation of deeply cracked products (benzene and propylene) and high stability. The catalytic performances of the spray-dried Al-SBA-15 with varying Si/Al ratios are also compared. The reasons for the different performances of the different materials are discussed, where the mesopores, high acid density and strength are observed to play the most critical role. This work might provide a basis for the synthesis of mesoporous rich metal-substituted silica materials for different catalytic applications.

BCL6 is required for the thymic development of TCRαß+CD8αα+ intraepithelial lymphocyte lineage.

TCRαß+CD8αα+ intraepithelial lymphocytes (CD8αα+ αß IELs) are a specialized subset of T cells in the gut epithelium that develop from thymic agonist selected IEL precursors (IELps). The molecular mechanisms underlying the selection and differentiation of this T cell type in the thymus are largely unknown. Here, we found that Bcl6 deficiency in αß T cells resulted in the near absence of CD8αα+ αß IELs. BCL6 was expressed by approximately 50% of CD8αα+ αß IELs and by the majority of thymic PD1+ IELps after agonist selection. Bcl6 deficiency blocked early IELp generation in the thymus, and its expression in IELps was induced by thymic TCR signaling in an ERK-dependent manner. As a result of Bcl6 deficiency, the precursors of IELps among CD4+CD8+ double-positive thymocytes exhibited increased apoptosis during agonist selection and impaired IELp differentiation and maturation. Together, our results elucidate BCL6 as a crucial transcription factor during the thymic development of CD8αα+ αß IELs.

NMR Precision Metabolomics: Dynamic Peak Sum Thresholding and Navigators for Highly Standardized and Reproducible Metabolite Profiling of Clinical Urine Samples.

Metabolomics, especially urine-based studies, offers incredible promise for the discovery and development of clinically impactful biomarkers. However, due to the unique challenges of urine, a highly precise and reproducible workflow for NMR-based urine metabolomics is lacking. Using 1D and 2D non-uniform sampled (NUS) 1H-13C NMR spectroscopy, we systematically explored how changes in hydration or specific gravity (SG) and pH can impact biomarker discovery. Further, we examined additional sources of error in metabolomics studies and identified Navigator molecules that could monitor for those biases. Adjustment of SG to 1.002-1.02 coupled with a dynamic sum-based peak thresholding eliminates false positives associated with urine hydration and reduces variation in chemical shift. We identified Navigator molecules that can effectively monitor for inconsistencies in sample processing, SG, protein contamination, and pH. The workflow described provides quality assurance and quality control tools to generate high-quality urine metabolomics data, which is the first step in biomarker discovery.