Rack1 regulates B-cell development and function by binding to and stabilizing the transcription factor Pax5.

The transcription factor Pax5 activates genes essential for B-cell development and function. However, the regulation of Pax5 expression remains elusive. The adaptor Rack1 can interact with multiple transcription factors and modulate their activation and/or stability. However, its role in the transcriptional control of B-cell fates is largely unknown. Here, we show that CD19-driven Rack1 deficiency leads to pro-B accumulation and a simultaneous reduction in B cells at later developmental stages. The generation of bone marrow chimeras indicates a cell-intrinsic role of Rack1 in B-cell homeostasis. Moreover, Rack1 augments BCR and TLR signaling in mature B cells. On the basis of the aberrant expression of Pax5-regulated genes, including CD19, upon Rack1 deficiency, further exploration revealed that Rack1 maintains the protein level of Pax5 through direct interaction and consequently prevents Pax5 ubiquitination. Accordingly, Mb1-driven Rack1 deficiency almost completely blocks B-cell development at the pro-B-cell stage. Ectopic expression of Pax5 in Rack1-deficient pro-B cells partially rescues B-cell development. Thus, Rack1 regulates B-cell development and function through, at least partially, binding to and stabilizing Pax5.

An IGHG1 variant exhibits polarized prevalence and confers enhanced IgG1 antibody responses against life-threatening organisms.

Evolutionary pressures sculpt population genetics, whereas immune adaptation fortifies humans against life-threatening organisms. How the evolution of selective genetic variation in adaptive immune receptors orchestrates the adaptation of human populations to contextual perturbations remains elusive. Here, we show that the G396R coding variant within the human immunoglobulin G1 (IgG1) heavy chain presents a concentrated prevalence in Southeast Asian populations. We uncovered a 190-kb genomic linkage disequilibrium block peaked in close proximity to this variant, suggestive of potential Darwinian selection. This variant confers heightened immune resilience against various pathogens and viper toxins in mice. Mechanistic studies involving severe acute respiratory syndrome coronavirus 2 infection and vaccinated individuals reveal that this variant enhances pathogen-specific IgG1+ memory B cell activation and antibody production. This G396R variant may have arisen on a Neanderthal haplotype background. These findings underscore the importance of an IGHG1 variant in reinforcing IgG1 antibody responses against life-threatening organisms, unraveling the intricate interplay between human evolution and immune adaptation.

Role and functional mechanisms of IL­17/IL­17R signaling in pancreatic cancer (Review).

Interleukin­17 (IL­17), an inflammatory cytokine primarily secreted by T helper 17 cells, serves a crucial role in numerous inflammatory diseases and malignancies via its receptor, IL­17R. In addition to stimulating inflammatory responses, IL­17 exhibits dual functions in tumors, exerting both pro­ and antitumor effects. Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic malignancy and accounts for >90% of pancreatic cancer cases. PDAC is characterized by a prominent stromal microenvironment with significant heterogeneity, which contributes to treatment resistance. IL­17/IL­17R signaling has a notable effect on tumorigenesis, the tumor microenvironment and treatment efficacy in various cancer types, including PDAC. However, the specific mechanisms of IL­17/IL­17R signaling in pancreatic cancer remain uncertain. This review presents a brief overview of the current knowledge and recent advances in the role and functional mechanisms of IL­17/IL­17R signaling in pancreatic cancer. Furthermore, the potential of IL­17­targeted therapeutic strategies for PDAC treatment is also discussed.

Discovery of a Covalent Inhibitor of Pro-Caspase-1 Zymogen Blocking NLRP3 Inflammasome Activation and Pyroptosis.

Caspase-1 plays a central role in innate immunity, as its activation by inflammasomes induces the production of proinflammatory cytokines and pyroptosis. However, specific inhibition of the enzymatic activity of this protease is not effective in suppressing inflammation, owing to its enzyme-independent function. Herein, we identified a cyclohexenyl isothiocyanate compound (CIB-1476) that potently inhibited caspase-1 activity and suppressed the assembly and activation of the NLRP3 inflammasome and gasdermin-D-mediated pyroptosis. Mechanistically, CIB-1476 directly targeted pro-caspase-1 as an irreversible covalent inhibitor by binding to Cys285 and Cys397, resulting in more durable anti-inflammatory effects in the suppression of enzyme-dependent IL-1ß production and enzyme-independent nuclear factor κB activation. Chemoproteomic profiling demonstrated the engagement of CIB-1476 with caspase-1. CIB-1476 showed potent therapeutic effects by suppressing inflammasome activation in mice, which was abolished in Casp1-/- mice. These results warrant further development of CIB-1476 along with its analogues as a novel strategy for caspase-1 inhibitors.

An end-to-end deep learning method for mass spectrometry data analysis to reveal disease-specific metabolic profiles.

Untargeted metabolomic analysis using mass spectrometry provides comprehensive metabolic profiling, but its medical application faces challenges of complex data processing, high inter-batch variability, and unidentified metabolites. Here, we present DeepMSProfiler, an explainable deep-learning-based method, enabling end-to-end analysis on raw metabolic signals with output of high accuracy and reliability. Using cross-hospital 859 human serum samples from lung adenocarcinoma, benign lung nodules, and healthy individuals, DeepMSProfiler successfully differentiates the metabolomic profiles of different groups (AUC 0.99) and detects early-stage lung adenocarcinoma (accuracy 0.961). Model flow and ablation experiments demonstrate that DeepMSProfiler overcomes inter-hospital variability and effects of unknown metabolites signals. Our ensemble strategy removes background-category phenomena in multi-classification deep-learning models, and the novel interpretability enables direct access to disease-related metabolite-protein networks. Further applying to lipid metabolomic data unveils correlations of important metabolites and proteins. Overall, DeepMSProfiler offers a straightforward and reliable method for disease diagnosis and mechanism discovery, enhancing its broad applicability.

Well-Dispersed CsPbBr3@TiO2 Heterostructure Nanocrystals from Asymmetric to Symmetric.

Metal halide perovskites (MHPs) have undergone rapid development in the fields of solar cells, light diodes, lasing, photodetectors, etc. However, the MHPs still face significant challenges, such as poor stability and heterocompositing with other functional materials at the single nanoparticle level. Herein, the successful synthesis of well-dispersed CsPbBr3@TiO2 heterostructure nanocrystals (NCs) is reported, in which each heterostructure NC has only one CsPbBr3 with a precise anatase TiO2 coating ranging from asymmetric to symmetric. Due to the protection of anatase TiO2, CsPbBr3 shows dramatically improved chemical stability and photostability. More significantly, the synthesized CsPbBr3@TiO2 heterostructure NCs form a type II heterojunction, which strongly promoted efficient photogenerated carrier separation between anatase TiO2 and CsPbBr3, hence leading to improved optoelectronic activity. This study provides a robust avenue for synthesizing stable and highly efficient MHPs@metal oxide heterostructure NCs, paving the way for the practical application of all inorganic perovskites.

An adapted white-coat and warm-heart intervention on nurses' knowledge, general stigmatizing attitudes, and work avoidance behaviors towards HIV: a quasi-experimental study.

OBJECTIVES: To determine the effect of an adapted white-coat and warm-heart intervention (AWWI) among nurses. BACKGROUND: HIV discrimination among medical staff hinders progress in HIV prevention. METHODS: A total of 779 nurses were randomized into intervention and control groups. The intervention group was provided with AWWI training. The control group did not receive AWWI training. HIV-related knowledge, attitudes, and behaviors of participants were assessed. RESULTS: Participants in the intervention group had better HIV-related knowledge and less stigmatizing attitudes and work avoidance behavior levels than participants in the control group after the 1-, 3-, and 6-month interventions (P < .05). The main effects of group and time factors were highly significant in the intervention group. There were significant interaction effects in group and time factors. CONCLUSIONS: AWWI effectively improved the level of HIV-related knowledge and reduced general stigmatizing attitudes and work avoidance behaviors among nurses based on self-reported data in a tertiary hospital in China during a 6-month period.

Emodin alleviates intestinal ischemia-reperfusion injury through antioxidant stress, anti-inflammatory responses and anti-apoptosis effects via Akt-mediated HO-1 upregulation.

BACKGROUND: Intestinal ischemia-reperfusion (I/R) injury is a severe vascular emergency. Previous research indicated the protective effects of Emodin on I/R injury. Our study aims to explore the effect of Emodin on intestinal I/R (II/R) injury and elucidate the underlying mechanisms. METHODS: C57BL/6 mice and Caco-2 cells were used for in vivo and in vitro studies. We established an animal model of II/R injury by temporarily occluding superior mesenteric artery. We constructed an oxygen-glucose deprivation/reoxygenation (OGD/R) cell model using a hypoxia-reoxygenation incubator. Different doses of Emodin were explored to determine the optimal therapeutic dose. Additionally, inhibitors targeting the protein kinase B (Akt) or Heme oxygenase-1 (HO-1) were administered to investigate their potential protective mechanisms. RESULTS: Our results demonstrated that in animal experiments, Emodin mitigated barrier disruption, minimized inflammation, reduced oxidative stress, and inhibited apoptosis. When Akt or HO-1 was inhibited, the protective effect of Emodin was eliminated. Inhibiting Akt also reduced the level of HO-1. In cell experiments, Emodin reduced inflammation and apoptosis in the OGD/R cell model. Additionally, when Akt or HO-1 was inhibited, the protective effect of Emodin was weakened. CONCLUSIONS: Our findings suggest that Emodin may protect the intestine against II/R injury through the Akt/HO-1 signaling pathway.

Soft-Template-Based Manufacturing of Gold Nanostructures for Energy and Sensing Applications.

Implantable and wearable bioelectronic systems can enable tailored therapies for the effective management of long-term diseases, thus minimising the risk of associated complications. In this context, glucose fuel cells hold great promise as in- or on-body energy harvesters for ultra-low-power bioelectronics and as self-powered glucose sensors. We report here the generation of gold nanostructures through a gold electrodeposition method in a soft template for the abiotic electrocatalysis of glucose in glucose fuel cells. Two different types of soft template were used: a lipid cubic phase-based soft template composed of Phytantriol and Brij®-56, and an emulsion-based soft template composed of hexane and sodium dodecyl sulphate (SDS). The resulting gold structures were first characterised by SAXS, SEM and TEM to elucidate their structure, and then their electrocatalytic activity towards glucose was compared in both a three-electrode set-up and in a fuel cell set-up. The Phytantriol/Brij®-56 template led to a nanofeather-like Au structure, while the hexane/SDS template led to a nanocoral-like Au structure. These templated electrodes exhibited similar electrochemical active surface areas (0.446 cm2 with a roughness factor (RF) of 14.2 for Phytantriol/Brij®-56 templated nanostructures and 0.421 cm2 with an RF of 13.4 for hexane/SDS templated nanostructures), and a sensitivity towards glucose of over 7 µA mM-1 cm-2. When tested as the anode of an abiotic glucose fuel cell (in a phosphate-buffered solution with a glucose concentration of 6 mM), a maximum power density of 7 µW cm-2 was reached; however the current density in the case of the fuel cell with the Phytantriol/Brij®-56 templated anode was approximately two times higher, reaching the value of 70 µA cm-2. Overall, this study demonstrates two simple, cost-effective and efficient strategies to manipulate the morphology of gold nanostructures, and thus their catalytic property, paving the way for the successful manufacturing of functional abiotic glucose fuel cells.

Identification of novel biomarker hsa_circ_0003914 for rheumatoid arthritis from plasma exosomes.

Rheumatoid arthritis (RA) is a complex autoimmune disease featuring invasive and infiltrative fibroblast-like synoviocytes (FLS) that lead to joint damage. While current RA pathological mechanisms remain incompletely defined, exosomes have been implicated as having the potential to drive disease progression due to their ability to deliver different types of biomolecules to tissues effected by RA. One potentially disease exacerbating molecule type found in exosomes are Circular RNAs (circRNAs), which are highly stable and have been previously implicated in RA pathogenesis. Here, we examine hsa_circ_0003914, a circRNA found in exosomes located in blood plasma, for a role in RA. Plasma exosomes were isolated and injected into collagen-induced arthritis (CIA) mice, followed by functional experiments to analyze the influence of exosomes on FLS formation. Sequencing revealed the presence of hsa_circ_0003914 in exosomes, so we examined its association with clinical markers in RA. Finally, the role for hsa_circ_0003914 in RA was directly confirmed through in vivo and in vitro experiments. We found that plasma exosomes isolated from RA patients could aggravate the disease of CIA mice, compared to exosomes isolated from healthy control patients. Hsa_circ_0003914 was highly enriched in the exosomes of RA patients. Mechanistically, Hsa_circ_0003914 promoted abnormal cell proliferation, migration, invasion and stimulated the secretion of inflammatory cytokines in FLSs through targeting NF-κB/p65 signaling pathway. Interestingly, knockdown of hsa_circ_0003914 rescued disease phenotypes in CIA mice. Taken together, these data implicate hsa_circ_0003914 as a potential therapeutic target for the prevention and management of RA.

An antioxidant hydrogel dressing with wound pH indication function prepared based on silanized bacterial nanocellulose crosslinked with beet red pigment extract.

Maintaining wound moisture and monitoring of infection are crucial aspects of chronic wound treatment. The development of a pH-sensitive functional hydrogel dressing is an effective approach to monitor, protect, and facilitate wound healing. In this study, beet red pigment extract (BRPE) served as a native and efficient pH indicator by being grafted into silane-modified bacterial nanocellulose (BNC) to prepare a pH-sensitive wound hydrogel dressing (S-g-BNC/BRPE). FTIR confirmed the successful grafting of BRPE into the BNC matrix. The S-g-BNC/BRPE showed superior mechanical properties (0.25 MPa), swelling rate (1251 % on average), and hydrophilic properties (contact angle 21.83°). The composite exhibited a notable color change as the pH changed between 4.0 and 9.0. It appeared purple-red when the pH ranged from 4.0 to 6.0, and appeared light pink at pH 7.0 and 7.4, and appeared ginger-yellow at pH 8.0 and 9.0. Subsequently, the antioxidant activity and cytotoxicity of the composite was evaluated, its DPPH·, ABTS+, ·OH scavenging rates were 32.33 %, 19.31 %, and 30.06 %, respectively, and the cytotoxicity test clearly demonstrated the safety of the dressing. The antioxidant hydrogel dressing, fabricated with a cost-effective and easy method, not only showed excellent biocompatibility and dressing performance but could also indicated the wound state based on pH changes.

Emodin alleviates intestinal ischemia/reperfusion-induced lung injury by upregulating HO-1 expression via PI3K/AkT pathway.

BACKGROUND: Emodin, a natural anthraquinone derivative found in various Chinese medicinal herbs, has been proved to be an effective therapeutic agent in the treatment of many diseases. However, its effect on lung injury after intestinal ischemia/reperfusion injury remains unknown. This research was designed to investigate whether emodin protects against intestinal ischemia/reperfusion-induced lung injury and to elucidate the underlying molecular mechanisms in vivo and in vitro. METHODS: Intestinal ischemia/reperfusion injury was induced by occluding the superior mesenteric artery in mice, and mouse lung epithelial-12 cells were subjected to oxygen-glucose deprivation and reoxygenation to establish an in vitro model. RESULTS: Our data indicated that emodin treatment reduced intestinal ischemia/reperfusion-induced oxidative stress, inflammation and apoptosis in lung tissues and alleviated lung injury. However, the protective effects of emodin on intestinal ischemia/reperfusion-induced lung injury were reversed by the protein kinase B inhibitor triciribine or the heme oxygenase-1 inhibitor tin protoporphyrin IX. The protein kinase inhibitor triciribine also downregulated the expression of heme oxygenase-1. CONCLUSION: In conclusion, our data suggest that emodin treatment protects against intestinal ischemia/reperfusion-induced lung injury by enhancing heme oxygenase-1 expression via activation of the PI3K/protein kinase pathway. Emodin may act as a potential therapeutic agent for the prevention and treatment of lung injury induced by intestinal ischemia/reperfusion.

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.

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.

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.

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 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.

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.