NF-κB-Signaling-Targeted Immunomodulatory Nanoparticle with Photothermal and Quorum-Sensing Inhibition Effects for Efficient Healing of Biofilm-Infected Wounds.

The development of therapeutics with high antimicrobial activity and immunomodulatory effects is urgently needed for the treatment of infected wounds due to the increasing danger posed by recalcitrant-infected wounds. In this study, we developed light-controlled antibacterial, photothermal, and immunomodulatory biomimetic N/hPDA@M nanoparticles (NPs). This nanoplatform was developed by loading flavonoid naringenin onto hollow mesoporous polydopamine NPs in a π-π-stacked configuration and encasing them with macrophage membranes. First, our N/hPDA@M NPs efficiently neutralized inflammatory factors present within the wound microenvironment by the integration of macrophage membranes. Afterward, the N/hPDA@M NPs effectively dismantled bacterial biofilms through a combination of the photothermal properties of PDA and the quorum sensing inhibitory effects of naringenin. It is worth noting that N/hPDA@M NPs near-infrared-enhanced release of naringenin exhibited specificity toward the NF-κB-signaling pathway, effectively mitigating the inflammatory response. This innovative design not only conferred remarkable antibacterial properties upon the N/hPDA@M NPs but also endowed them with the capacity to modulate inflammatory responses, curbing excessive inflammation and steering macrophage polarization toward the M2 phenotype. As a result, this multifaceted approach significantly contributes to expediting the healing process of infected skin wounds.

Western US intraplate deformation controlled by the complex lithospheric structure.

The western United States is one of Earth's most tectonically active regions, characterized by extensive crustal deformation through intraplate earthquakes and geodetic motion. Such intracontinental deformation is usually ascribed to plate boundary forces, lithospheric body forces, and/or viscous drag from mantle flow. However, their relative importance in driving crustal deformation remains controversial due to inconsistent assumptions on crustal and mantle structures in prior estimations. Here, we utilize a fully dynamic three-dimensional modeling framework with data assimilation to simultaneously compute lithospheric and convective mantle dynamics within the western United States. This approach allows for quantitative estimations of crustal deformation while accounting for the realistic three-dimensional lithospheric structure. Our results show the critical role of the complex lithospheric structure in governing intraplate deformation. Particularly, the interaction between the asthenospheric flow and lithospheric thickness step along the eastern boundary of the Basin and Range represents a key driving mechanism for localized crustal deformation and seismicity.

Hepatitis B Virus Status and Clinical Outcomes in IgA Nephropathy.

Introduction: Immunoglobulin A nephropathy (IgAN) has been reported to coexist with hepatitis B virus (HBV) infection. Despite the clinical significance of this association, there is a lack of comprehensive research investigating the impact of various common conditions following HBV infection and the potential influence of anti-HBV therapy on the progression of IgAN. Methods: We investigated 3 distinct states of HBV infection, including chronic HBV infection, resolved HBV infection, and the deposition of hepatitis B antigens in renal tissue, in a follow-up database of 1961 patients with IgAN. IgAN progression was defined as a loss of estimated glomerular filtration rate (eGFR) >40%. Multivariable cause-specific hazards models to analyze the relationship between HBV states and IgAN progression. Results: Chronic HBV infection was identified as an independent risk factor for IgAN progression, supported by both prematching analysis (hazard ratio [HR], 1.61; 95% confidence interval [CI], 1.06-2.44; P = 0.024) and propensity-score matching analysis (HR, 1.74; 95% CI 1.28-2.37; P < 0.001). Conversely, resolved HBV infection showed no significant association with IgAN progression (HR, 1.01; 95% CI 0.67-1.52; P = 0.969). Moreover, the presence of HBV deposition in the kidneys and the utilization of anti-HBV therapy did not appear to be significant risk factors for renal outcomes (P > 0.05). Conclusion: Chronic HBV infection is an independent risk factor for IgAN progression, whereas resolved HBV infection is not. In patients with IgAN, management of concurrent chronic HBV infection should be enhanced. The presence of HBV deposition in the kidneys and the use of anti-HBV medications do not impact the kidney disease progression in patients with IgAN with concurrent HBV infection.

Effect of Telitacicept on Circulating Gd-IgA1 and IgA-Containing Immune Complexes in IgA Nephropathy.

Introduction: Telitacicept, a transmembrane activator and cyclophilin ligand interactor (TACI) fusion protein targeting B cell activating factor and a proliferation-inducing ligand (APRIL), has proven efficacy in treating Immunoglobulin A (IgA) nephropathy (IgAN). However, serum biomarkers that could predict the clinical response during the treatment remain unclear. Methods: Plasma samples from 24 participants in the phase 2 clinical trial were collected at baseline and after 4, 12, and 24 weeks; with 8 participants in the placebo group, 9 in the 160 mg group, and 7 in the 240 mg group. We measured the levels of galactose-deficient-IgA1 (Gd-IgA1), IgA-containing immune complexes, C3a, C5a, and sC5b-9. The association between the changes in these markers and proteinuria reduction was analyzed. Results: After 24 weeks of treatment, Gd-IgA1 decreased by 43.9% (95% confidence interval: 29.8%, 55.1%), IgG-IgA immune complex by 31.7% (14.4%, 45.5%), and poly-IgA immune complex by 41.3% (6.5%, 63.1%) in the 160 mg group; Gd-IgA1 decreased by 50.4% (38.6%, 59.9%), IgG-IgA immune complex decreased by 42.7% (29.5%, 53.4%), and poly-IgA immune complex decreased by 67.2% (48.5%,79.1%) in the 240 mg group. There were no significant changes in the circulatory C3a, C5a, or sC5b-9 levels during telitacicept treatment. Decreases in both plasma Gd-IgA1 and IgG-IgA or poly-IgA immune complexes were associated with proteinuria reduction. In turn, IgG-IgA or poly-IgA immune complexes showed a dose-dependent effect, consistent with proteinuria reduction during telitacicept treatment. Conclusion: Telitacicept lowered both circulating Gd-IgA1 and IgA-containing immune complexes, whereas IgA immune complex levels were more consistent with decreased proteinuria.

Corrigendum: Distinct characteristics and prognosis of IgA nephropathy patients with nephrotic syndrome: a propensity score-matched cohort study.

[This corrects the article DOI: 10.3389/fmed.2024.1344219.].

Multi-scale Lesion Feature Fusion and Location-Aware for Chest Multi-disease Detection.

Accurately identifying and locating lesions in chest X-rays has the potential to significantly enhance diagnostic efficiency, quality, and interpretability. However, current methods primarily focus on detecting of specific diseases in chest X-rays, disregarding the presence of multiple diseases in a single chest X-ray scan. Moreover, the diversity in lesion locations and attributes introduces complexity in accurately discerning specific traits for each lesion, leading to diminished accuracy when detecting multiple diseases. To address these issues, we propose a novel detection framework that enhances multi-scale lesion feature extraction and fusion, improving lesion position perception and subsequently boosting chest multi-disease detection performance. Initially, we construct a multi-scale lesion feature extraction network to tackle the uniqueness of various lesion features and locations, strengthening the global semantic correlation between lesion features and their positions. Following this, we introduce an instance-aware semantic enhancement network that dynamically amalgamates instance-specific features with high-level semantic representations across various scales. This adaptive integration effectively mitigates the loss of detailed information within lesion regions. Additionally, we perform lesion region feature mapping using candidate boxes to preserve crucial positional information, enhancing the accuracy of chest disease detection across multiple scales. Experimental results on the VinDr-CXR dataset reveal a 6% increment in mean average precision (mAP) and an 8.4% improvement in mean recall (mR) when compared to state-of-the-art baselines. This demonstrates the effectiveness of the model in accurately detecting multiple chest diseases by capturing specific features and location information.

Unveiling the transition of tumbling and tank-treading dynamics of star-shaped polyelectrolytes in shear flow by modulating the solution's dielectric properties.

The effects of the solution's dielectric properties on the conformation and dynamics of star-shaped polyelectrolytes in shear flow are investigated using a hybrid simulation method coupling multi-particle collision dynamics and molecular dynamics. The simulation results showed that by modulating the dielectric properties of the solution, star-shaped polyelectrolytes showed a three-step dynamic behavior transition from tumbling to tank-treading to tumbling dynamics under shear flow. The analysis indicated that this distinct transition in dynamics could be attributed to the uneven distribution of counterions induced by shear on the chain, resulting in a change in the polyelectrolyte conformation and degree of segmental alignment in arms. These findings contribute to a comprehensive understanding of the non-equilibrium dynamics of star-shaped polyelectrolytes in shear flow and offer a viable approach for controlling the dynamic behavior of star-shaped polyelectrolytes by adjusting the dielectric properties of the solution.

Heterozygous mutations in factor H aggravate pathological damage in a stable IgA deposition model induced by Lactobacillus casei cell wall extract.

Introduction: Activation of complement through the alternative pathway (AP) has a key role in the pathogenesis of IgA nephropathy (IgAN). We previously showed, by intraperitoneal injection of Lactobacillus casei cell wall extract (LCWE), C57BL/6 mice develop mild kidney damage in association with glomerular IgA deposition. To further address complement activity in causing glomerular histological alterations as suggested in the pathogenesis of IgAN, here we used mice with factor H mutation (FHW/R) to render AP overactivation in conjunction with LCWE injection to stimulate intestinal production of IgA. Methods: Dose response to LCWE were examined between two groups of FHW/R mice. Wild type (FHW/W) mice stimulated with LCWE were used as model control. Results: The FHW/R mice primed with high dose LCWE showed elevated IgA and IgA-IgG complex levels in serum. In addition to 100% positive rate of IgA and C3, they display elevated biomarkers of kidney dysfunction, coincided with severe pathological lesions, resembling those of IgAN. As compared to wild type controls stimulated by the same high dose LCWE, these FHW/R mice exhibited stronger complement activation in the kidney and in circulation. Discussion: The new mouse model shares many disease features with IgAN. The severity of glomerular lesions and the decline of kidney functions are further aggravated through complement overactivation. The model may be a useful tool for preclinical evaluation of treatment response to complement-inhibitors.

Research Progress in Structure Synthesis, Properties, and Applications of Small-Molecule Silicone Surfactants.

Silicone surfactants have garnered significant research attention owing to their superior properties, such as wettability, ductility, and permeability. Small-molecular silicone surfactants with simple molecular structures outperform polymeric silicone surfactants in terms of surface activity, emulsification, wetting, foaming, and other areas. Moreover, silicone surfactants with small molecules exhibit a diverse and rich molecular structure. This review discusses various synthetic routes for the synthesis of different classes of surfactants, including single-chain, "umbrella" structure, double chain, bolaform, Gemini, and stimulus-responsive surfactants. The fundamental surface/interface properties of the synthesized surfactants are also highlighted. Additionally, these surfactants have demonstrated enormous potential in agricultural synergism, drug delivery, mineral flotation, enhanced oil recovery, separation, and extraction, and foam fire-fighting.

Genome-wide identification of ZmMYC2 binding sites and target genes in maize.

BACKGROUND: Jasmonate (JA) is the important phytohormone to regulate plant growth and adaption to stress signals. MYC2, an bHLH transcription factor, is the master regulator of JA signaling. Although MYC2 in maize has been identified, its function remains to be clarified. RESULTS: To understand the function and regulatory mechanism of MYC2 in maize, the joint analysis of DAP-seq and RNA-seq is conducted to identify the binding sites and target genes of ZmMYC2. A total of 3183 genes are detected both in DAP-seq and RNA-seq data, potentially as the directly regulating genes of ZmMYC2. These genes are involved in various biological processes including plant growth and stress response. Besides the classic cis-elements like the G-box and E-box that are bound by MYC2, some new motifs are also revealed to be recognized by ZmMYC2, such as nGCATGCAnn, AAAAAAAA, CACGTGCGTGCG. The binding sites of many ZmMYC2 regulating genes are identified by IGV-sRNA. CONCLUSIONS: All together, abundant target genes of ZmMYC2 are characterized with their binding sites, providing the basis to construct the regulatory network of ZmMYC2 and better understanding for JA signaling in maize.

KIF15 promotes the development and progression of chordoma via activating PI3K-AKT signalling pathway.

Aims: Despite its implication in various human cancers, the expression and functional significance of Kinesin family member 15 (KIF15) in chordomas remain unexplored. Main methods: The evaluation of KIF15 protein levels was conducted through immunohistochemistry (IHC) staining and Western blot analysis. Cell proliferation was quantified using MTT and CCK8 assays, whereas cell migration was examined using wound healing and Transwell assays. Furthermore, flow cytometric analysis was utilized to assess cell apoptosis and the cell cycle. Additionally, in vivo experiments were performed using a mouse xenograft model. Key findings: Our study revealed significantly higher expression of KIF15 in stage III chordoma tissues compared to stage II tissues. Knockdown of KIF15 led to notable inhibition of cell proliferation and migration, along with enhanced apoptosis and cell cycle arrest. In vivo studies further confirmed the inhibitory effects of KIF15 knockdown on chordoma tumour growth. In terms of mechanism, we identified the involvement of the PI3K-AKT signalling pathway mediated by KIF15 in chordomas. Notably, the anti-tumour effects of KIF15 deficiency on chordomas were partially reversed by the addition of an AKT activator. Significance: KIF15 promotes chordoma development and progression through the activation of the PI3K-AKT signalling pathway. Thus, targeting KIF15 might be a promising therapeutic strategy for treating chordomas.

Unintentional persistent organic pollutants in cremation process: Emissions, characteristics, and inventory.

Pollutants produced by cremation furnaces have gradually caused concern because of the increasing rate of cremation around the world. In this study, the levels, patterns, and emission factors of unintentional persistent organic pollutants (UPOPs) from cremation were investigated. The toxic equivalent (TEQ) concentrations (11 % O2 normalized) of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) in flue gas ranged from 0.036 to 22 ng TEQ/Nm3, while the levels of polychlorinated biphenyls (PCBs) and polychlorinated naphthalenes (PCNs) in flue gas samples ranged from 0.0023 to 1.2 ng TEQ/Nm3 and 0.17-44 pg TEQ/Nm3, respectively. The average concentrations of UPOPs in flue gas from car-type furnaces were higher than those from flat-panel furnaces. Secondary chambers and air pollution control devices were effective for controlling UPOPs emissions. However, heat exchangers were not as effective for reducing UPOPs emissions. It was observed that the UPOPs profiles exhibited dissimilarities between fly ash and flue gas samples. HxCDF, OCDD, and PeCDF were the dominant homologs of PCDD/Fs in flue gas, while HxCDF, PeCDF, and HpCDF were the dominant homologs in fly ash. The fractions of MoCBs and MoCNs in fly ash were higher than those in flue gas. Finally, we conducted an assessment of the global emissions of UPOPs from cremation in the years of 2019 and 2021. The total emission of UPOPs in 47 countries was estimated at 239 g TEQ in 2021, which was during the peak period of the COVID-19 pandemic worldwide. The emissions in 2021 increased by approximately 24 % compared to 2019, with the impact of COVID-19 being a significant factor that cannot be disregarded.

Circulating Proteins and IgA Nephropathy.

BACKGROUND: The therapeutic options for IgA nephropathy are rapidly evolving, but early diagnosis and targeted treatment remain challenging. We aimed to identify circulating plasma proteins associated with IgA nephropathy by proteome-wide mendelian randomization studies across multiple ancestry populations. METHODS: In this study, we applied Mendelian randomization and colocalization analyses to estimate the putative causal effects of 2615 proteins on IgA nephropathy in Europeans and 235 proteins in East Asians. Following two-stage network Mendelian randomization, multi-trait colocalization analysis and protein-altering variant annotation were performed to strengthen the reliability of the results. A protein-protein interaction network was constructed to investigate the interactions between the identified proteins and the targets of existing medications. RESULTS: Putative causal effects of 184 and 13 protein-disease pairs in European and East Asian ancestries were identified, respectively. Two protein-disease pairs showed shared causal effects across them (CFHR1 and FCRL2). Supported by the evidence from colocalization analysis, potential therapeutic targets were prioritized and four drug-repurposing opportunities were suggested. The protein-protein interaction network further provided strong evidence for existing medications and pathways that are known to be therapeutically important. CONCLUSIONS: Our study identified a number of circulating proteins associated with IgA nephropathy and prioritized several potential drug targets that require further investigation.

Rare Cases of Pseudomonas aeruginosa Meningitis in Children: 10-Year Experience in a Single Center.

OBJECTIVE: The primary objective was to elucidate the epidemiologic characteristics, risk determinants, and clinical outcomes associated with Pseudomonas aeruginosa-induced meningitis. METHODS: All cases of meningitis caused by Pseudomonas aeruginosa that were treated at the hospital between 2012 and 2022 were retrospectively analyzed and detailed. RESULTS: During a 10-year period, only 10 patients satisfied the inclusion criteria. Three patients had previously undergone neurosurgical procedures and 4 patients had leukemia. CONCLUSIONS: Although Pseudomonas aeruginosa meningitis possesses a low incidence rate, the rate of mortality is high. Patients with leukemia or those who have undergone neurosurgery are the most susceptible to diagnosis. Cases of severe neutropenia present only mild or no cerebrospinal fluid pleocytosis. In patients with sensitive Pseudomonas aeruginosa meningitis, the timely use of anti-Pseudomonas carbapenems for intravenous treatment is highly effective. For drug-resistant Pseudomonas aeruginosa meningitis, intrathecal polymyxins administration can be an effective treatment option.

Adipose tissue reconstruction facilitated with low immunogenicity decellularized adipose tissue scaffolds.

There is currently an urgent need to develop engineered scaffolds to support new adipose tissue formation and facilitate long-term maintenance of function and defect repair to further generate prospective bioactive filler materials capable of fulfilling surgical needs. Herein, adipose regeneration methods were optimized and decellularized adipose tissue (DAT) scaffolds with good biocompatibility were fabricated. Adipose-like tissues were reconstructed using the DAT and 3T3-L1 preadipocytes, which have certain differentiation potential, and the regenerative effects of the engineered adipose tissuesin vitroandin vivowere explored. The method improved the efficiency of adipose removal from tissues, and significantly shortened the time for degreasing. Thus, the DAT not only provided a suitable space for cell growth but also promoted the proliferation, migration, and differentiation of preadipocytes within it. Following implantation of the constructed adipose tissuesin vivo, the DAT showed gradual degradation and integration with surrounding tissues, accompanied by the generation of new adipose tissue analogs. Overall, the combination of adipose-derived extracellular matrix and preadipocytes for adipose tissue reconstruction will be of benefit in the artificial construction of biomimetic implant structures for adipose tissue reconstruction, providing a practical guideline for the initial integration of adipose tissue engineering into clinical medicine.

A cluster of type I interferon-regulated genes associates with disease activity and prognosis in patients with IgA nephropathy.

The exact pathogenesis of IgA nephropathy (IgAN) is complex and so far, not well defined. Since it has been shown that microbial infections could induce high levels of type I interferon (IFN-I) and there is an evident link between mucosal infection and gross hematuria in IgAN, we hypothesized that IFN-I may play a role in the pathogenic process. In this study, we investigated the type I interferon status in IgAN based on the expression of 17 IFN-regulated genes (IRGs) in whole blood from 59 IgAN patients in a cross-sectional study, of which 34 patients followed longitudinally. Analysis of the IFN-score showed that there was a significant elevated IFN-score in the IgAN patients compared with healthy controls (n = 28, p = 9.80 × 10-3), and we observed an elevated IFN-score in the group with less tubular atrophy/interstitial fibrosis (p = 1.07 × 10-2) and with a lower proportion of mesangial hypercellularity (p = 1.23 × 10-2). In the longitudinal analysis, Cox regression analysis revealed that a higher IFN level was associated with a better renal outcome in IgAN after adjustments for gender and age (hazard ratio, 0.90; 95 % confidence interval, 0.81 to 0.97; p = 4.20 × 10-2). In conclusion, our finding suggested that IFN score may represent a novel type of biomarker in IgAN, which requires further exploration on its mechanism and therapeutic targeting.

Distinct characteristics and prognosis of IgA nephropathy patients with nephrotic syndrome: a propensity score-matched cohort study.

Introduction: IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis globally. While nephrotic syndrome (NS) is uncommon in IgAN, its significance remains unclear. Methods: We conducted a retrospective analysis of 170 IgAN patients, classifying them into NS (n = 85) and non-NS (n = 5) groups. Our study aims to compare their clinical characteristics, treatment responses, and prognoses. Patients were selected based on renal biopsy from 2003 to 2020. Propensity score matching ensured comparability. Clinical, pathological, and immunological data were analyzed. Composite endpoints were defined as end-stage kidney disease (ESKD) or a 30% decline in estimated glomerular filtration rate (eGFR). Results: NS patients showed higher eGFR (74.3 ± 36.8 vs. 61.5 ± 33.6 mL/min.1.73 m2, p = 0.02), severe hematuria (35.0 (4.7,147.5) vs. 4.0 (1.8,45,0) cells/µl, p < 0.001), severe foot process effacement (p = 0.01), and lower C3 levels (1.0 ± 0.3 vs. 1.1 ± 0.2 g/L, p = 0.03). In contrast, the non-NS group had higher BMI (24.3 ± 4.0 vs. 26.8 ± 3.7 kg/m2, p < 0.001) and elevated serum uric acid levels (376 (316,417) vs. 400 (362, 501) mmol/L, p = 0.001), suggesting metabolic factors might contribute to their condition. Both groups exhibited similar MESTC scores. NS patients had higher complete remission rates (26.2% vs. 14.1%, p = 0.04). Cox regression revealed NS independently associated with a higher risk of composite endpoints (HR = 1.97, 95% CI 1.05-3.72, p = 0.04). Linear mixed models did not show significant eGFR trajectory differences. Discussion: This study has established that IgAN patients with NS exhibit distinct characteristics, including active disease and increased complement activation. NS is independently associated with a poorer prognosis, emphasizing the need for targeted interventions in this subgroup.

Distinct cellular microenvironment with cytotypic effects regulates orderly regeneration of vascular tissues.

Regeneration of the architecturally complex blood vascular system requires precise temporal and spatial control of cell behaviours. Additional components must be integrated into the structure to achieve clinical success for in situ tissue engineering. Consequently, this study proposed a universal method for including any substrate type in vascular cell extracellular matrices (VCEM) via regulating selective adhesion to promote vascular tissue regeneration. The results uncovered that the VCEM worked as cell adhesion substrates, exhibited cell type specificity, and functioned as an address signal for recognition by vascular cells, which resulted in matching with the determined cells. The qPCR and immunofluorescence results revealed that a cell type-specific VCEM could be designed to promote or inhibit cell adhesion, consistenting with the expression patterns of eyes absent 3 (Eya3). In addition, a 3D vascular graft combined with VCEM which could recapitulate the vascular cell-like microenvironment was fabricated. The vascular graft revealed a prospective role for cellular microenvironment in the establishment of vascular cell distribution and tissue architecture, and potentiated the orderly regeneration and functional recovery of vascular tissues in vivo. The findings demonstrate that differential adhesion between cell types due to the cellular microenvironment is sufficient to drive the complex assembly of engineered blood vessel functional units, and underlies hierarchical organization during vascular regeneration.