Multi-omics study reveals different pathogenesis of the generation of skin lesions in SLE and IDLE patients.

Lupus erythematosus (LE) is a heterogeneous, antibody-mediated autoimmune disease. Isolate discoid LE (IDLE) and systematic LE (SLE) are traditionally regarded as the two ends of the spectrum, ranging from skin-limited damage to life-threatening multi-organ involvement. Both belong to LE, but IDLE and SLE differ in appearance of skin lesions, autoantibody panels, pathological changes, treatments, and immunopathogenesis. Is discoid lupus truly a form of LE or is it a completely separate entity? This question has not been fully elucidated. We compared the clinical data of IDLE and SLE from our center, applied multi-omics technology, such as immune repertoire sequencing, high-resolution HLA alleles sequencing and multi-spectrum pathological system to explore cellular and molecular phenotypes in skin and peripheral blood from LE patients. Based on the data from 136 LE patients from 8 hospitals in China, we observed higher damage scores and fewer LE specific autoantibodies in IDLE than SLE patients, more uCDR3 sharing between PBMCs and skin lesion from SLE than IDLE patients, elevated diversity of V-J recombination in IDLE skin lesion and SLE PBMCs, increased SHM frequency and class switch ratio in IDLE skin lesion, decreased SHM frequency but increased class switch ratio in SLE PBMCs, HLA-DRB1*03:01:01:01, HLA-B*58:01:01:01, HLA-C*03:02:02:01, and HLA-DQB1*02:01:01:01 positively associated with SLE patients, and expanded Tfh-like cells with ectopic germinal center structures in IDLE skin lesions. These findings suggest a significant difference in the immunopathogenesis of skin lesions between SLE and IDLE patients. SLE is a B cell-predominate systemic immune disorder, while IDLE appears limited to the skin. Our findings provide novel insights into the pathogenesis of IDLE and other types of LE, which may direct more accurate diagnosis and novel therapeutic strategies.

Soft Materials with Time-Programmed Changes in Physical Properties through Lyotropic Phase Transitions Induced by pH-Changing Reactions.

We present the development of time-programmable functional soft materials. The materials undergo reversible phase transitions between lyotropic phases with different topologies and symmetries, which in turn have very different physical properties: viscosity, diffusion, and optical transparency. Here, this behavior is achieved by combining pH-responsive lyotropic phases made from the lipid monoolein doped with 10% oleic acid, with chemical reactions that have well-defined controllable kinetics: autocatalytic urea-urease and methyl formate hydrolysis, which increase and decrease pH, respectively. In this case, we use small-angle X-ray scattering (SAXS) and optical imaging to show temporally controlled transitions between the cloudy hexagonal phase, which is a two-dimensional (2D) array of cylindrical inverse micelles, and the transparent, highly viscous three-dimensional (3D) bicontinuous cubic phases. By combining these into a single reaction mixture where the pH increases and then decreases again, we can induce a sequential transformation cycle from hexagonal to cubic and back to hexagonal over several hours. The sample therefore changes from cloudy to transparent and back again as a proof-of-concept demonstration for a wider range of soft materials with time-programmable changes in physical properties.

Intraepithelial mast cells drive gasdermin C-mediated type 2 immunity.

A specialized population of mast cells residing within epithelial layers, currently known as intraepithelial mast cells (IEMCs), was originally observed over a century ago, yet their physiological functions have remained enigmatic. In this study, we unveil an unexpected and crucial role of IEMCs in driving gasdermin C-mediated type 2 immunity. During helminth infection, αEß7 integrin-positive IEMCs engaged in extensive intercellular crosstalk with neighboring intestinal epithelial cells (IECs). Through the action of IEMC-derived proteases, gasdermin C proteins intrinsic to the epithelial cells underwent cleavage, leading to the release of a critical type 2 cytokine, interleukin-33 (IL-33). Notably, mast cell deficiency abolished the gasdermin C-mediated immune cascade initiated by epithelium. These findings shed light on the functions of IEMCs, uncover a previously unrecognized phase of type 2 immunity involving mast cell-epithelial cell crosstalk, and advance our understanding of the cellular mechanisms underlying gasdermin C activation.

Scenario analysis of COVID-19 dynamical variations by different social environmental factors: a case study in Xinjiang.

Background: With the rapid advancement of the One Health approach, the transmission of human infectious diseases is generally related to environmental and animal health. Coronavirus disease (COVID-19) has been largely impacted by environmental factors regionally and globally and has significantly disrupted human society, especially in low-income regions that border many countries. However, few research studies have explored the impact of environmental factors on disease transmission in these regions. Methods: We used the Xinjiang Uygur Autonomous Region as the study area to investigate the impact of environmental factors on COVID-19 variation using a dynamic disease model. Given the special control and prevention strategies against COVID-19 in Xinjiang, the focus was on social and environmental factors, including population mobility, quarantine rates, and return rates. The model performance was evaluated using the statistical metrics of correlation coefficient (CC), normalized absolute error (NAE), root mean square error (RMSE), and distance between the simulation and observation (DISO) indices. Scenario analyses of COVID-19 in Xinjiang encompassed three aspects: different population mobilities, quarantine rates, and return rates. Results: The results suggest that the established dynamic disease model can accurately simulate and predict COVID-19 variations with high accuracy. This model had a CC value of 0.96 and a DISO value of less than 0.35. According to the scenario analysis results, population mobilities have a large impact on COVID-19 variations, with quarantine rates having a stronger impact than return rates. Conclusion: These results provide scientific insight into the control and prevention of COVID-19 in Xinjiang, considering the influence of social and environmental factors on COVID-19 variation. The control and prevention strategies for COVID-19 examined in this study may also be useful for the control of other infectious diseases, especially in low-income regions that are bordered by many countries.

B cell-reactive triad of B cells, follicular helper and regulatory T cells at homeostasis.

Autoreactive B cells are silenced through receptor editing, clonal deletion and anergy induction. Additional autoreactive B cells are ignorant because of physical segregation from their cognate autoantigen. Unexpectedly, we find that follicular B cell-derived autoantigen, including cell surface molecules such as FcγRIIB, is a class of homeostatic autoantigen that can induce spontaneous germinal centers (GCs) and B cell-reactive autoantibodies in non-autoimmune animals with intact T and B cell repertoires. These B cell-reactive B cells form GCs in a manner dependent on spontaneous follicular helper T (TFH) cells, which preferentially recognize B cell-derived autoantigen, and in a manner constrained by spontaneous follicular regulatory T (TFR) cells, which also carry specificities for B cell-derived autoantigen. B cell-reactive GC cells are continuously generated and, following immunization or infection, become intermixed with foreign antigen-induced GCs. Production of plasma cells and antibodies derived from B cell-reactive GC cells are markedly enhanced by viral infection, potentially increasing the chance for autoimmunity. Consequently, immune homeostasis in healthy animals not only involves classical tolerance of silencing and ignoring autoreactive B cells but also entails a reactive equilibrium attained by a spontaneous B cell-reactive triad of B cells, TFH cells and TFR cells.

Ion channel TRPV2 is critical in enhancing B cell activation and function.

The function of transient receptor potential vanilloid (TRPV) cation channels governing B cell activation remains to be explored. We present evidence that TRPV2 is highly expressed in B cells and plays a crucial role in the formation of the B cell immunological synapse and B cell activation. Physiologically, TRPV2 expression level is positively correlated to influenza-specific antibody production and is low in newborns and seniors. Pathologically, a positive correlation is established between TRPV2 expression and the clinical manifestations of systemic lupus erythematosus (SLE) in adult and child SLE patients. Correspondingly, mice with deficient TRPV2 in B cells display impaired antibody responses following immunization. Mechanistically, the pore and N-terminal domains of TRPV2 are crucial for gating cation permeation and executing mechanosensation in B cells upon antigen stimulation. These processes synergistically contribute to membrane potential depolarization and cytoskeleton remodeling within the B cell immunological synapse, fostering efficient B cell activation. Thus, TRPV2 is critical in augmenting B cell activation and function.

Proinflammatory phenotype of B10 and B10pro cells elicited by TNF-α in rheumatoid arthritis.

OBJECTIVES: B10 and B10pro cells suppress immune responses via secreting interleukin (IL)-10. However, their regulators and underlying mechanisms, especially in human autoimmune diseases, are elusive. This study aimed to address these questions in rheumatoid arthritis (RA), one of the most common highly disabling autoimmune diseases. METHODS: The frequencies and functions of B10 and B10pro cells in healthy individuals and patients with RA were first analysed. The effects of proinflammatory cytokines, particularly tumour necrosis factor (TNF)-α on the quantity, stability and pathogenic phenotype of these cells, were then assessed in patients with RA before and after anti-TNF therapy. The underlying mechanisms were further investigated by scRNA-seq database reanalysis, transcriptome sequencing, TNF-α-/- and B cell-specific SHIP-1-/- mouse disease model studies. RESULTS: TNF-α was a key determinant for B10 cells. TNF-α elicited the proinflammatory feature of B10 and B10pro cells by downregulating IL-10, and upregulating interferon-γ and IL-17A. In patients with RA, B10 and B10pro cells were impaired with exacerbated proinflammatory phenotype, while anti-TNF therapy potently restored their frequencies and immunosuppressive functions, consistent with the increased B10 cells in TNF-α-/- mice. Mechanistically, TNF-α diminished B10 and B10pro cells by inhibiting their glycolysis and proliferation. TNF-α also regulated the phosphatidylinositol phosphate signalling of B10 and B10pro cells and dampened the expression of SHIP-1, a dominant phosphatidylinositol phosphatase regulator of these cells. CONCLUSIONS: TNF-α provoked the proinflammatory phenotype of B10 and B10pro cells by disturbing SHIP-1 in RA, contributing to the disease development. Reinstating the immunosuppressive property of B10 and B10pro cells might represent novel therapeutic approaches for RA.

Mechanical force determines chimeric antigen receptor microclustering and signaling.

Chimeric antigen receptor (CAR) T cells are activated to trigger the lytic machinery after antigen engagement, and this has been successfully applied clinically as therapy. The mechanism by which antigen binding leads to the initiation of CAR signaling remains poorly understood. Here, we used a set of short double-stranded DNA (dsDNA) tethers with mechanical forces ranging from ∼12 to ∼51 pN to manipulate the mechanical force of antigen tether and decouple the microclustering and signaling events. Our results revealed that antigen-binding-induced CAR microclustering and signaling are mechanical force dependent. Additionally, the mechanical force delivered to the antigen tether by the CAR for microclustering is generated by autonomous cell contractility. Mechanistically, the mechanical-force-induced strong adhesion and CAR diffusion confinement led to CAR microclustering. Moreover, cytotoxicity may have a lower mechanical force threshold than cytokine generation. Collectively, these results support a model of mechanical-force-induced CAR microclustering for signaling.

B cell activation and autoantibody production in autoimmune diseases.

B cells are central players in the immune system, responsible for producing antibodies and modulating immune responses. This review explores the intricate relationship between aberrant B cell activation and the development of autoimmune diseases, emphasizing the essential role of B cells in these conditions. We also summarize B cell receptor signaling and Toll-like receptor signaling in B cell activation, as well as their association with autoimmune diseases, shedding light on the molecular mechanisms behind these associations. Additionally, we explore the clinical observations involving B cell activation and their significance in autoimmune disease management. Various clinical studies related to B cell-targeted therapies are also discussed, offering insights into potential avenues for improving treatment strategies. Overall, this review serves as a resource for researchers and clinicians in the field of immunology and autoimmune diseases, providing a general view of B cell signaling and its role in autoimmunity.

Phylogenetic relationships and genetic differentiation of two Salamandrella species as revealed via COI gene from Northeastern China.

Due to traditional classification methods' limitations, some cryptic species remain undiscovered. To better explore the existence of the Schrenck salamander (Salamandrella tridactyla, a cryptic species of Siberian salamander S. keyserlingii) in China, we conducted a molecular phylogenetic analysis to confirm the taxonomic relationship among Salamandrella species and investigate genetic variation. We used complete sequences of the mitochondrial COI gene from 65 specimens collected across a wide range in Northeastern China. Thirty-five haplotypes were obtained from six populations. They showed medium-high haplotype diversity (Hd) and low nucleotide polymorphism (π). The phylogenetic tree and haplotype network analysis revealed that populations from Greater Khingan Ridge (Huma: HM) and Lesser Khingan Ridge (Tieli: TL) belong to S. keyserlingii, while populations from Changbai Mountain (Shangzhi-zhuziying: SZ, Shangzhi-cuijia: SC, Hailin: HL, and Baishan: BS) belong to S. tridactyla. This indicates the monophyly of Salamandrella and each of the two species. There was a substantial level of genetic differentiation between different species and within populations of the same species. This differentiation was significantly related to geographical distance. At last, the mismatch distribution and neutrality analyses indicated that the TL populations have undergone expansion of history. The study supplements the distributional range of Schrenck salamander. And it provides a theoretical basis for species conservation of Salamandrella species.

Risk Factors for Contrast Media Extravasation in Intravenous Contrast-Enhanced Computed Tomography: An Observational Cohort Study.

RATIONALE AND OBJECTIVES: To identify the risk factors for contrast media (CM) extravasation and provide effective guidance for reducing its incidence. MATERIALS AND METHODS: We observed adult inpatients (n = 38 281) who underwent intravenous contrast-enhanced computed tomography between January 1, 2018, and December 31, 2022. Risk factors for CM extravasation were evaluated using univariate and multivariate logistic regression. RESULTS: Among the 38 281 inpatients who underwent enhanced computed tomography angiography, 3885 received peripherally inserted central venous catheters (PICCs) and 34 396 received peripheral short catheters. In 3885 cases of PICCs, no CM extravasation occurred, but in five cases, ordinary PICCs that are unable to withstand high pressure were mistakenly used; three of those patients experienced catheter rupture, and eventually, all five patients underwent unplanned extubation. Among 34 396 cases of peripheral short catheters, 224 (0.65%) had CM extravasation. Female sex (odds ratio [OR]=1.541, 95% confidence interval [CI]: 1.111-2.137), diabetes (OR=2.265, 95% CI: 1.549-3.314), venous thrombosis (OR=2.157, 95% CI: 1.039-4.478), multi-site angiography (OR=9.757, CI: 6.803-13.994), and injection rate ≥ 3 mL/s (OR=6.073, 95% CI: 4.349-8.481) were independent risk factors for CM extravasation. Due to peripheral vascular protection measures in patients with malignant tumor, there was a low incidence of CM extravasation (OR=0.394, 95% CI: 0.272-0.570). CONCLUSION: Main risk factors for CM extravasation are female, diabetes, venous thrombosis, multi-site angiography, and injection rate ≥ 3 mL/s. However, patients with malignant tumor have a low incidence of CM extravasation. CLINICAL IMPACT: Analysis of these risk factors can help reduce the incidence of CM extravasation.

MCT1-governed pyruvate metabolism is essential for antibody class-switch recombination through H3K27 acetylation.

Monocarboxylate transporter 1 (MCT1) exhibits essential roles in cellular metabolism and energy supply. Although MCT1 is highly expressed in activated B cells, it is not clear how MCT1-governed monocarboxylates transportation is functionally coupled to antibody production during the glucose metabolism. Here, we report that B cell-lineage deficiency of MCT1 significantly influences the class-switch recombination (CSR), rendering impaired IgG antibody responses in Mct1f/fMb1Cre mice after immunization. Metabolic flux reveals that glucose metabolism is significantly reprogrammed from glycolysis to oxidative phosphorylation in Mct1-deficient B cells upon activation. Consistently, activation-induced cytidine deaminase (AID), is severely suppressed in Mct1-deficient B cells due to the decreased level of pyruvate metabolite. Mechanistically, MCT1 is required to maintain the optimal concentration of pyruvate to secure the sufficient acetylation of H3K27 for the elevated transcription of AID in activated B cells. Clinically, we found that MCT1 expression levels are significantly upregulated in systemic lupus erythematosus patients, and Mct1 deficiency can alleviate the symptoms of bm12-induced murine lupus model. Collectively, these results demonstrate that MCT1-mediated pyruvate metabolism is required for IgG antibody CSR through an epigenetic dependent AID transcription, revealing MCT1 as a potential target for vaccine development and SLE disease treatment.

Risk factors for peripherally inserted central catheter-related venous thrombosis in adult patients with cancer.

PURPOSE: The purpose of this study was to understand and analyze the risk factors of peripherally inserted central catheter (PICC)-related venous thrombosis in adult patients with cancer. METHODS: This observational cohort study included adult patients with cancer who underwent color Doppler ultrasound at the Xiangya Hospital of Central South University, Hunan Provincial Maternal and Child Healthcare Hospital, and Xiangya Changde Hospital, Hunan Province, from January 1, 2017 to December 31, 2021. Univariate and multivariate logistic regression analyses were performed to determine the risk factors of PICC-related venous thrombosis. RESULTS: After risk adjustment, multivariate logistic regression analysis revealed statistically significant associations between PICC-related venous thrombosis and age > 65 years old (OR: 1.791, CI: 1.343-2.389), male sex (OR: 1.398, CI: 1.057-1.849), white blood cell count > 9.5 × 109 /L (OR: 1.422, CI: 1.041-1.942), APTT < 25 s (OR: 2.006, CI: 1.431-2.811), gastrointestinal tumor (OR: 2.191, CI: 1.406-3.414), infection (OR:7.619, CI: 5.783-10.037), the use of cisplatin (OR: 2.374, CI: 1.714-3.214), vincristine (OR: 2.329, CI: 1.447-3.749), the use of polyurethane (OR: 2.449, CI: 1.863-3.219) and open-ended catheters (OR:1.660, CI: 1.131-2.439), keeping time of the catheter (days) (OR: 1.003, CI: 1.001-1.005) were associated with PICC-related venous thrombosis. CONCLUSION: We identified that the presence of age > 65 years old, male sex, white blood cell count > 9.5 × 109 /L, APTT < 25 s, gastrointestinal tumor, infection, the use of cisplatin and vincristine, the use of polyurethane, open-ended catheters and keeping time of the catheter (days), were associated with PICC-related venous thrombosis.

Atomic Zn-Doping Induced Sabatier Optimum in NiZn0.03 Catalyst for CO2 Electroreduction at Industrial-Level Current Densities.

The Sabatier principle defines the essential criteria for an ideal catalyst in heterogeneous catalysis, while reaching the Sabatier optimum is still challenging in catalyst design. Herein, an elegant strategy is described to reach the Sabatier optimum of Ni electrocatalyst in CO2 reduction reaction (CO2 RR) by atomically Zn doping. The incorporation of 3% Zn single atom into Ni lattice leads to the moderate degrade of d-band center via Ni-Zn electronic coupling, which balances the bonding strengths of *COOH and *CO, resulting in a relative low energy barrier for CO2 activation while not being substantially poisoned by CO. Consequently, NiZn0.03 /C exhibits unique catalytic activity (jCO >100 mA cm-2 at -0.6 V), wide potential range for selective CO production (FECO >90% from -0.65 to -1.15 V), and outstanding long-term stability (FECO >90% during 85 h electrolysis at -0.85 V). The results provide valuable insights for the rational fabrication of superior non-noble bimetallic electrocatalysts in CO2 electroreduction.

Development of Redox-Active Lyotropic Lipid Cubic Phases for Biosensing Platforms.

Enzyme-based electrochemical biosensors play an important role in point-of-care diagnostics for personalized medicine. For such devices, lipid cubic phases (LCP) represent an attractive method to immobilize enzymes onto conductive surfaces with no need for chemical linking. However, research has been held back by the lack of effective strategies to stably co-immobilize enzymes with a redox shuttle that enhances the electrical connection between the enzyme redox center and the electrode. In this study, we show that a monoolein (MO) LCP system doped with an amphiphilic redox mediator (ferrocenylmethyl)dodecyldimethylammonium bromide (Fc12) can be used for enzyme immobilization to generate an effective biosensing platform. Small-angle X-ray scattering (SAXS) showed that MO LCP can incorporate Fc12 while maintaining the Pn3m symmetry morphology. Cyclic voltammograms of Fc12/MO showed quasi-reversible behavior, which implied that Fc12 was able to freely diffuse in the lipid membrane of LCP with a diffusion coefficient of 1.9 ± 0.2 × 10-8 cm2 s-1 at room temperature. Glucose oxidase (GOx) was then chosen as a model enzyme and incorporated into 0.2%Fc12/MO to evaluate the activity of the platform. GOx hosted in 0.2%Fc12/MO followed Michaelis-Menten kinetics toward glucose with a KM and Imax of 8.9 ± 0.5 mM and 1.4 ± 0.2 µA, respectively, and a linearity range of 2-17 mM glucose. Our results therefore demonstrate that GOx immobilized onto 0.2% Fc12/MO is a suitable platform for the electrochemical detection of glucose.

Experimental Study and Numerical Analysis of the Seismic Performance of Glass-Fiber Reinforced Plastic Tube Ultra-High Performance Concrete Composite Columns.

To investigate the impact of the filament winding angle of glass-fiber reinforced plastic (GFRP) on the seismic behavior of GFRP tube ultra-high performance concrete (UHPC) composite columns, this study designs two types of GFRP tube UHPC composite columns. Quasi-static tests are conducted on the specimens subjected to horizontal reciprocating load and axial force, and the skeleton curve characteristics of the structure are analyzed. Furthermore, a finite element analysis model of the composite column is established to explore the effects of the diameter-thickness ratio, circumferential elastic modulus of confined tubes, and tensile strength of concrete on the seismic performance of the composite column. The analysis includes a review of the skeleton curve, energy dissipation capacity, and stiffness degradation of the structure under different designs. The results indicate that the use of GFRP tubes effectively enhances the seismic performance of UHPC columns. The failure mode, peak load, and peak displacement of the composite columns are improved. The finite element analysis results are in good agreement with the experimental results, validating the effectiveness of the analysis model. Extended analysis reveals that the bearing capacity of the specimen increases while the energy dissipation capacity decreases with a decrease in the diameter-thickness ratio and an increase in the circumferential elastic modulus. Although the tensile strength of concrete has some influence on the seismic performance of the specimen, its effect is relatively small. Through regression analysis, a formula for shear capacity suitable for GFRP tube UHPC composite columns is proposed. This formula provides a theoretical reference for the design and engineering practice of GFRP tube UHPC composite columns.

Correction: Farnesyl pyrophosphate is a new danger signal inducing acute cell death.

[This corrects the article DOI: 10.1371/journal.pbio.3001134.].