Deficiency of Transcription Factor Sp1 Contributes to Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most prevalent monogenic heart disorder. However, the pathogenesis of HCM, especially its nongenetic mechanisms, remains largely unclear. Transcription factors are known to be involved in various biological processes including cell growth. We hypothesized that SP1 (specificity protein 1), the first purified TF in mammals, plays a role in the cardiomyocyte growth and cardiac hypertrophy of HCM. METHODS: Cardiac-specific conditional knockout of Sp1 mice were constructed to investigate the role of SP1 in the heart. The echocardiography, histochemical experiment, and transmission electron microscope were performed to analyze the cardiac phenotypes of cardiac-specific conditional knockout of Sp1 mice. RNA sequencing, chromatin immunoprecipitation sequencing, and adeno-associated virus experiments in vivo were performed to explore the downstream molecules of SP1. To examine the therapeutic effect of SP1 on HCM, an SP1 overexpression vector was constructed and injected into the mutant allele of Myh6 R404Q/+ (Myh6 c. 1211C>T) HCM mice. The human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from a patient with HCM were used to detect the potential therapeutic effects of SP1 in human HCM. RESULTS: The cardiac-specific conditional knockout of Sp1 mice developed a typical HCM phenotype, displaying overt myocardial hypertrophy, interstitial fibrosis, and disordered myofilament. In addition, Sp1 knockdown dramatically increased the cell area of hiPSC-CMs and caused intracellular myofibrillar disorganization, which was similar to the hypertrophic cardiomyocytes of HCM. Mechanistically, Tuft1 was identified as the key target gene of SP1. The hypertrophic phenotypes induced by Sp1 knockdown in both hiPSC-CMs and mice could be rescued by TUFT1 (tuftelin 1) overexpression. Furthermore, SP1 overexpression suppressed the development of HCM in the mutant allele of Myh6 R404Q/+ mice and also reversed the hypertrophic phenotype of HCM hiPSC-CMs. CONCLUSIONS: Our study demonstrates that SP1 deficiency leads to HCM. SP1 overexpression exhibits significant therapeutic effects on both HCM mice and HCM hiPSC-CMs, suggesting that SP1 could be a potential intervention target for HCM.

Novel CAR-T cells targeting TRKB for the treatment of solid cancer.

Chimeric antigen receptor (CAR) T-cell therapy is highly effective for treating blood cancers such as B-cell malignancies, however, its effectiveness as an approach to treat solid tumors remains to be further explored. Here, we focused on the development of CAR-T cell therapies targeting tropomyosin-related kinase receptor B (TRKB), a highly expressed protein that is significantly associated with tumor progression, malignancy, and drug resistance in multiple forms of aggressive solid tumors. To achieve this, we screened brain-derived neurotrophic factor (BDNF) and neurotrophin 4 (NTF4) ligand-based CAR-T cells for their efficiency in targeting the TRKB receptor in the context of solid tumors, particularly hepatocellular carcinoma and pancreatic cancer. We demonstrated that TRKB is overexpressed not only in hepatocellular carcinoma and pancreatic carcinoma cell lines but also in cancer stem-like cells (CSCs). Notably, BDNF-CAR T and NTF4-CAR T cells could not only effectively target and kill TRKB-expressing pan-cancer cell lines in a dose-dependent manner but also effectively kill CSCs. We also performed in vivo studies to show that NTF4-CAR T cells have a better potential to inhibit the tumor growth of hepatocellular carcinoma xenografts in mice, compared with BDNF-CAR T cells. Taken together, our findings suggest that CAR-T targeting TRKB may be a promising approach for developing novel therapies to treat solid cancers.

Boosting Efficient Alkaline Hydrogen Evolution Reaction of CoFe-Layered Double Hydroxides Nanosheets via Co-Coordination Mechanism of W-Doping and Oxygen Defect Engineering.

While surface defects and heteroatom doping exhibit promising potential in augmenting the electrocatalytic hydrogen evolution reaction (HER), their performance remains unable to rival that of the costly Pt-based catalysts. Yet, the concurrent modification of catalysts by integrating both approaches stands as a promising strategy to effectively address the aforementioned limitation. In this work, tungsten dopants are introduced into self-supported CoFe-layered double hydroxides (LDH) on nickel foam using a hydrothermal method, and oxygen vacancies (Ov) are further introduced through calcination. The analysis results demonstrated that tungsten doping reduces the Ov formation energy of CoFeW-LDH. The Ov acted as oxophilic sites, facilitating water adsorption and dissociation, and reducing the barrier for cleaving HO─H bonds from 0.64 to 0.14 eV. Additionally, Ov regulated the electronic structure of CoFeW-LDH to endow optimized hydrogen binding ability on tungsten atoms, thereby accelerating alkaline Volmer and Heyrovsky reaction kinetics. Specifically, the abundance of Ov induced a transition of tungsten from a six-coordinated to highly active four-coordinated structure, which becomes the active site for HER. Consequently, an ultra-low overpotential of 41 mV at 10 mA cm-2 , and a low Tafel slope of 35 mV dec-1 are achieved. These findings offer crucial insights for the design of efficient HER electrocatalysts.

Artificial intelligence assists identification and pathologic classification of glomerular lesions in patients with diabetic nephropathy.

BACKGROUND: Glomerular lesions are the main injuries of diabetic nephropathy (DN) and are used as a crucial index for pathologic classification. Manual quantification of these morphologic features currently used is semi-quantitative and time-consuming. Automatically quantifying glomerular morphologic features is urgently needed. METHODS: A series of convolutional neural networks (CNN) were designed to identify and classify glomerular morphologic features in DN patients. Associations of these digital features with pathologic classification and prognosis were further analyzed. RESULTS: Our CNN-based model achieved a 0.928 F1-score for global glomerulosclerosis and 0.953 F1-score for Kimmelstiel-Wilson lesion, further obtained a dice of 0.870 for the mesangial area and F1-score beyond 0.839 for three glomerular intrinsic cells. As the pathologic classes increased, mesangial cell numbers and mesangial area increased, and podocyte numbers decreased (p for all < 0.001), while endothelial cell numbers remained stable (p = 0.431). Glomeruli with Kimmelstiel-Wilson lesion showed more severe podocyte deletion compared to those without (p < 0.001). Furthermore, CNN-based classifications showed moderate agreement with pathologists-based classification, the kappa value between the CNN model 3 and pathologists reached 0.624 (ranging from 0.529 to 0.688, p < 0.001). Notably, CNN-based classifications obtained equivalent performance to pathologists-based classifications on predicting baseline and long-term renal function. CONCLUSION: Our CNN-based model is promising in assisting the identification and pathologic classification of glomerular lesions in DN patients.

Clinicopathological Characteristics of Light and Heavy Chain Deposition Disease: A Case Series.

RATIONALE & OBJECTIVE: Light and heavy chain deposition disease (LHCDD) is a rare form of monoclonal immunoglobulin (Ig) deposition disease, and limited clinical data are available characterizing this condition. Here we describe the clinicopathological characteristics and outcomes of LHCDD. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: 13 patients with biopsy-proven LHCDD diagnosed between January 2008 and December 2022 at one of 2 Chinese medical centers. FINDINGS: Among the 13 patients described, 6 were men and 7 were women, with a mean age of 52.6±8.0 years. Patients presented with hypertension (76.9%), anemia (84.6%), increased serum creatinine concentrations (84.6%; median, 1.7mg/dL), proteinuria (100%; average urine protein, 3.0g/24h), nephrotic syndrome (30.8%), and microscopic hematuria (76.9%). Serum immunofixation electrophoresis showed monoclonal Ig for 11 patients (84.6%). Serum free light chain ratios were abnormal in 11 patients (84.6%), and heavy/light chain ratios were abnormal in 9 of 10 patients (90%) with available data. Five patients were diagnosed with multiple myeloma. A histological diagnosis of nodular mesangial sclerosis was made in 10 patients (76.9%). Immunofluorescence demonstrated deposits of IgG subclass in 7 patients (γ-κ, n=4; γ-λ, n=3) and IgA in 5 patients (α-κ, n=2; α-λ, n=3). Six patients underwent IgG subclass staining (γ1, n=3; γ2, n=2; γ3, n=1). The deposits of IgD-κ were confirmed by mass spectrometry in 1 patient. Among 12 patients for whom data were available during a median of 26.5 months, 11 received chemotherapy and 1 received conservative treatment. One patient died, and disease progressed to kidney failure in 3 (25%). Among the 9 patients evaluable for hematological and kidney disease progression, 5 (56%) had a hematologic response and 1 (11%) exhibited improvement in kidney disease. LIMITATIONS: Retrospective descriptive study, limited number of patients, urine protein electrophoresis or immunofixation electrophoresis test results missing for most patients. CONCLUSIONS: In this case series of LHCDD, light and heavy chain deposition in kidney tissues were most frequent with monoclonal IgG1-κ. Among patients with evaluable data, more than half had a hematologic response, but a kidney response was uncommon.

Primary immunodeficiency as a cause of immune-mediated kidney diseases.

Primary immunodeficiency (PID) is no longer defined by infections alone, and autoimmunity is an accompanying manifestation of PID. Recurrent infections may trigger autoimmunity through molecular mimicry, bystander activation, or superantigens. The diagnosis of PID is still challenging, but genetic analysis reveals the underlying link between PID and autoimmunity. Mutations in relevant genes affecting central and peripheral immune tolerance, regulatory T-cell function, expansion of autoreactive lymphocytes, antigen clearance, hyperactivation of type I interferon, and NF-κB pathways have all been implicated in triggering autoimmunity in PID. Autoimmunity in PID leads to chronic inflammation, tissue damage, and organ failure and increases the mortality of patients with PID. The kidneys are inextricably linked with the immune system, and kidney diseases can be mediated by both infection and autoimmunity/inflammation in PID patients. The manifestations of kidney involvement in PID patients are very heterogeneous and include lupus nephritis, C3 glomerulopathy, kidney thrombotic microangiopathy, vasculitis, and interstitial nephritis.Patients with PID-caused kidney diseases have defined immune function defects and may benefit from pathway-based biologics, stem cell transplantation, or gene therapy. Early diagnosis and appropriate treatment of PID are crucial for reducing the mortality rate and improving organ function and quality of life.

Sorting Out the Latest Advances in Separators and Pilot-Scale Microbial Electrochemical Systems for Wastewater Treatment: Concomitant Development, Practical Application, and Future Perspective.

To date, dozens of pilot-scale microbial fuel cell (MFC) devices have been successfully developed worldwide for treating various types of wastewater. The availability and configurations of separators are determining factors for the economic feasibility, efficiency, sustainability, and operability of these devices. Thus, the concomitant advances between the separators and pilot-scale MFC configurations deserve further clarification. The analysis of separator configurations has shown that their evolution proceeds as follows: from ion-selective to ion-non-selective, from nonpermeable to permeable, and from abiotic to biotic. Meanwhile, their cost is decreasing and their availability is increasing. Notably, the novel MFCs configured with biotic separators are superior to those configured with abiotic separators in terms of wastewater treatment efficiency and capital cost. Herein, a highly comprehensive review of pilot-scale MFCs (>100 L) has been conducted, and we conclude that the intensive stack of the liquid cathode configuration is more advantageous when wastewater treatment is the highest priority. The use of permeable biotic separators ensures hydrodynamic continuity within the MFCs and simplifies reactor configuration and operation. In addition, a systemic comparison is conducted between pilot-scale MFC devices and conventional decentralized wastewater treatment processes. MFCs showed comparable cost, higher efficiency, long-term stability, and significant superiority in carbon emission reduction. The development of separators has greatly contributed to the availability and usability of MFCs, which will play an important role in various wastewater treatment scenarios in the future.

Biosafe cerium oxide nanozymes protect human pluripotent stem cells and cardiomyocytes from oxidative stress.

BACKGROUND: Cardiovascular diseases (CVDs) have the highest mortality worldwide. Human pluripotent stem cells (hPSCs) and their cardiomyocyte derivatives (hPSC-CMs) offer a valuable resource for disease modeling, pharmacological screening, and regenerative therapy. While most CVDs are linked to significant over-production of reactive oxygen species (ROS), the effects of current antioxidants targeting excessive ROS are limited. Nanotechnology is a powerful tool to develop antioxidants with improved selectivity, solubility, and bioavailability to prevent or treat various diseases related to oxidative stress. Cerium oxide nanozymes (CeONZs) can effectively scavenge excessive ROS by mimicking the activity of endogenous antioxidant enzymes. This study aimed to assess the nanotoxicity of CeONZs and their potential antioxidant benefits in stressed human embryonic stem cells (hESCs) and their derived cardiomyocytes (hESC-CMs). RESULTS: CeONZs demonstrated reliable nanosafety and biocompatibility in hESCs and hESC-CMs within a broad range of concentrations. CeONZs exhibited protective effects on the cell viability of hESCs and hESC-CMs by alleviating excessive ROS-induced oxidative stress. Moreover, CeONZs protected hESC-CMs from doxorubicin (DOX)-induced cardiotoxicity and partially ameliorated the insults from DOX in neonatal rat cardiomyocytes (NRCMs). Furthermore, during hESCs culture, CeONZs were found to reduce ROS, decrease apoptosis, and enhance cell survival without affecting their self-renewal and differentiation potential. CONCLUSIONS: CeONZs displayed good safety and biocompatibility, as well as enhanced the cell viability of hESCs and hESC-CMs by shielding them from oxidative damage. These promising results suggest that CeONZs may be crucial, as a safe nanoantioxidant, to potentially improve the therapeutic efficacy of CVDs and be incorporated into regenerative medicine.

Genetic features and kidney morphological changes in women with X-linked Alport syndrome.

BACKGROUND: X-linked Alport syndrome (XLAS) caused by COL4A5 pathogenic variants usually has heterogeneous phenotypes in female patients. The genetic characteristics and glomerular basement membrane (GBM) morphological changes in women with XLAS need to been further investigated. METHODS: A total of 83 women and 187 men with causative COL4A5 variants were enrolled for comparative analysis. RESULTS: Women were more frequently carrying de novo COL4A5 variants compared with men (47% vs 8%, p=0.001). The clinical manifestations in women were variable, and no genotype-phenotype correlation was observed. Coinherited podocyte-related genes, including TRPC6, TBC1D8B, INF2 and MYH9, were identified in two women and five men, and the modifying effects of coinherited genes contributed to the heterogeneous phenotypes in these patients. X-chromosome inactivation (XCI) analysis of 16 women showed that 25% were skewed XCI. One patient preferentially expressing the mutant COL4A5 gene developed moderate proteinuria, and two patients preferentially expressing the wild-type COL4A5 gene presented with haematuria only. GBM ultrastructural evaluation demonstrated that the degree of GBM lesions was associated with the decline in kidney function for both genders, but more severe GBM changes were found in men compared with women. CONCLUSIONS: The high frequency of de novo variants carried by women indicates that the lack of family history tends to make them susceptible to be underdiagnosed. Coinherited podocyte-related genes are potential contributors to the heterogeneous phenotype of some women. Furthermore, the association between the degree of GBM lesions and decline in kidney function is valuable in evaluating the prognosis for patients with XLAS.

Advancing the application of the analytical renal pathology system in allograft IgA nephropathy patients.

BACKGROUND: The analytical renal pathology system (ARPS) based on convolutional neural networks has been used successfully in native IgA nephropathy (IgAN) patients. Considering the similarity of pathologic features, we aim to evaluate the performance of the ARPS in allograft IgAN patients and broaden its implementation. METHODS: Biopsy-proven allograft IgAN patients from two different centers were enrolled for internal and external validation. We implemented the ARPS to identify glomerular lesions and intrinsic glomerular cells, and then evaluated its performance. Consistency between the ARPS and pathologists was assessed using intraclass correlation coefficients. The association of digital pathological features with clinical and pathological data was measured. Kaplan-Meier survival curve and cox proportional hazards model were applied to investigate prognosis prediction. RESULTS: A total of 56 biopsy-proven allograft IgAN patients from the internal center and 17 biopsy-proven allograft IgAN patients from the external center were enrolled in this study. The ARPS was successfully applied to identify the glomerular lesions (F1-score, 0.696-0.959) and quantify intrinsic glomerular cells (F1-score, 0.888-0.968) in allograft IgAN patients rapidly and precisely. Furthermore, the mesangial hypercellularity score was positively correlated with all mesangial metrics provided by ARPS [Spearman's correlation coefficient (r), 0.439-0.472, and all p values < 0.001]. Besides, a higher allograft survival was noticed among patients in the high-level groups of the maximum and ratio of endothelial cells, as well as the maximum and density of podocytes. CONCLUSION: We propose that the ARPS could be implemented in future clinical practice with outstanding capability.

Cell-Surface GRP78-Targeted Chimeric Antigen Receptor T Cells Eliminate Lung Cancer Tumor Xenografts.

Lung cancer is one of the most common and intractable malignancies. It is associated with low survival rates despite existing treatments, indicating that new and more effective therapies are urgently needed such as the chimeric antigen receptor-T (CAR-T) cell immunotherapy. The cell-surface glucose-regulated protein 78 (csGRP78) is expressed in various hematological malignancies and solid tumor cells including lung cancer in response to cancer-related endoplasmic reticulum stress, while GRP78 is restricted to inside the normal cells. Here, we detected the prominent expression of csGRP78 in both lung cancer cell lines, A549 and H1299, as well as cancer stemlike cells derived from A549 by immunofluorescence. Next, a csGRP78-targeted CAR was constructed, and the transduced CAR-T cells were tested for their potency to kill the two lung cancer cell lines and derived stemlike cells, which was correlated with specific interferon γ release in vitro. Finally, we found that csGRP78 CAR-T cells also efficiently killed both lung cancer cells and cancer stemlike cells, resulting into the elimination of tumor xenografts in vivo, neither with any evidence of relapse after 63 days of tumor clearance nor any detrimental impact on other body organs we examined. Our study reveals the capacity of csGRP78 as a therapeutic target and offers valuable insight into the development of csGRP78 CAR-T cells as potential therapy for lung cancer.

3MCor: an integrative web server for metabolome-microbiome-metadata correlation analysis.

MOTIVATION: The metabolome and microbiome disorders are highly associated with human health, and there are great demands for dual-omics interaction analysis. Here, we designed and developed an integrative platform, 3MCor, for metabolome and microbiome correlation analysis under the instruction of phenotype and with the consideration of confounders. RESULTS: Many traditional and novel correlation analysis methods were integrated for intra- and inter-correlation analysis. Three inter-correlation pipelines are provided for global, hierarchical and pairwise analysis. The incorporated network analysis function is conducive to rapid identification of network clusters and key nodes from a complicated correlation network. Complete numerical results (csv files) and rich figures (pdf files) will be generated in minutes. To our knowledge, 3MCor is the first platform developed specifically for the correlation analysis of metabolome and microbiome. Its functions were compared with corresponding modules of existing omics data analysis platforms. A real-world dataset was used to demonstrate its simple and flexible operation, comprehensive outputs and distinctive contribution to dual-omics studies. AVAILABILITYAND IMPLEMENTATION: 3MCor is available at http://3mcor.cn and the backend R script is available at https://github.com/chentianlu/3MCorServer. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Association of regulatory T cells with renal outcomes in patients with proliferative lupus nephritis.

BACKGROUND: Despite progress in the diagnosis and treatment of proliferative lupus nephritis (PLN), the prognosis remains unfavorable. Previous investigations have suggested that the deficiency of regulatory T cells (Tregs) is involved in the pathogenesis of systemic lupus erythematosus (SLE) and lupus nephritis (LN). But the prognostic value of Tregs in PLN remains controversial. This study aimed to investigate the association of Tregs with renal outcomes in patients with PLN. METHODS: The baseline and follow-up data of patients with biopsy-proven PLN were collected in this study. All patients were divided into two groups according to whether the renal endpoint event occurred. Clinicopathologic features and therapeutic responses were compared between the two groups. Cox regression analyses curve fitting and threshold effect analysis were implemented to investigate the relationship between Tregs level and the long-term renal outcomes. The renal endpoint was defined as end-stage kidney disease (ESKD) or doubling the SCr value. RESULTS: A total of 405 PLN patients were included. After a follow-up of 71.53 (53.13-97.47) months, 42 (10.4%) patients reached the renal endpoint. The Treg cell counts (16/µL) in the renal endpoint group were significantly decreased than that in the non-renal endpoint group (p < 0.001). Univariate and multivariate Cox regression analyses showed that the high level of Tregs was an independent protective factor for the long-term renal prognosis of PLN. Smooth curve fitting of the generalized additive mixed model analysis indicated that the risk of renal endpoint first decreased with Tregs and then slightly increased along with Treg cell levels. The segmented linear model revealed that when Treg cell counts <46/µL, the risk of renal endpoint decreased by 6.8% for every 1 µL increase in Treg levels (p = 0.0029). CONCLUSION: Treg cell counts are closely related to the long-term renal outcomes of patients with PLN, and increasing Treg cell levels may play an important role in improving the prognosis of the kidney, but there may be a turning point (i.e., threshold effect) at the Treg cell counts that leads to directional changes in the renal outcomes.

HGF-Based CAR-T Cells Target Hepatocellular Carcinoma Cells That Express High Levels of c-Met.

BACKGROUND: CAR-T is emerging as an effective treatment strategy for hematologic malignancies, however its effectiveness for treating solid tumors, such as Hepatocellular Carcinoma (HCC) is limited. Here, we screened a variety of CAR-T cells that target c-Met to investigate their potential to induce HCC cell death in vitro. METHODS: Human T cells were transduced to express CARs by lentiviral vector transfection. c-Met expression in human HCC cell lines and CARs expression were monitored by flow cytometry. Tumor cell killing was evaluated by Luciferase Assay System Kit. The concentrations of cytokine were tested by Enzyme-linked immunosorbent assays. Knock down and overexpression studies targeting c-Met were conducted to assess the targeting specificity of CARs. RESULTS: We found that CAR T cells expressing a minimal amino-terminal polypeptide sequence comprising the first kringle (kringle 1) domain (denoted as NK1 CAR-T cells), efficiently killed HCC cell lines that expressed high levels of the HGF receptor c-Met. Furthermore, we report that while NK1 CAR-T cells were efficient at targeting SMMC7221 cells for destruction, and its potency was significantly attenuated in parallel experiments with cells stably expressing short hairpin RNAs (shRNAs) that suppressed c-Met expression. Correspondingly, overexpression of c-Met in the embryonic kidney cell line HEK293T led to their enhanced killing by NK1 CAR-T cells. CONCLUSION: Our studies demonstrate that a minimal amino-terminal polypeptide sequence comprising the kirngle1 domain of HGF is highly relevant to the design of effective CAR-T cell therapies that kill HCC cells expressing high levels of c-Met.

Insights into the Electron Transfer Behaviors of a Biocathode Regulated by Cathode Potentials in Microbial Electrosynthesis Cells for Biogas Upgrading.

Bioelectrochemical-based biogas upgrading is a promising technology for the storage of renewable energy and reduction of the global greenhouse gas emissions. Understanding the electron transfer behavior between the electrodes and biofilm is crucial for the development of this technology. Herein, the electron transfer pathway of the biofilm and its catalytic capability that responded to the cathode potential during the electromethanogenesis process were investigated. The result suggested that the dominant electron transfer pathway shifted from a direct (DET) to indirect (IDET) way when decreasing the cathode potential from -0.8 V (Bio-0.8 V) to -1.0 V (Bio-1.0 V) referred to Ag/AgCl. More IDET-related redox substances and high content of hydrogenotrophic methanogens (91.9%) were observed at Bio-1.0 V, while more DET-related redox substances and methanogens (82.3%) were detected at Bio-0.8 V. H2, as an important electron mediator, contributed to the electromethanogenesis up to 72.9% of total CH4 yield at Bio-1.0 V but only ∼17.3% at Bio-0.8 V. Much higher biogas upgrading performance in terms of CH4 production rate, final CH4 content, and carbon conversion rate was obtained with Bio-1.0 V. This study provides insight into the electron transfer pathway in the mixed culture constructed biofilm for biogas upgrading.

Re-evaluating the Contribution of a Fe-Based Current Collector to Bioelectrochemical Methanogenesis: Role and Mechanisms.

The metal-based current collector has been adopted as an essential component of cathodes for electron delivery in microbial electrosynthesis (MES) cells, while the effect of its corrosion on biofilm development and electromethanogenesis activity was overlooked. In this study, the corrosion of the Fe-based current collector was identified to in situ decorate cathode naturally which substantially boosted the performance of CO2 electromethanogenesis in terms of taking over two-thirds less time starting up MES and increasing the CH4 production rate by 3.5 times. Despite the low concentration of Fe (0.13 at%), the electrochemical analysis indicated that it was possible for these Fe deposits to act as electron shuttles and catalysts for H2 production to benefit methanogenesis. The Fe aggregates weakened the dependence of methanogens on electroactive bacteria (EABs) to conduct methanogenesis via interspecies electron transfer as the proportion of EABs on Bio FeCF (with Fe current collector, where CF is carbon felt) was only 25.5% of that on Bio CF (without Fe current collector). On the contrary, the abundance of genes encoding the proteins to uptake extracellular electrons of methanogens on Bio FeCF was 2.3 times higher than that on Bio CF. The enhanced energy transfer maintained high amounts of methanogens and live microorganisms. This study comprehensively explored the multiple roles of Fe-based current collectors in enhancing CO2 electromethanogenesis.

The link between the factuality of verb and the theory of mind ability of Mandarin-speaking children with high-functioning autism.

BACKGROUND: Weak theory of mind (ToM) ability is a core deficit in children with autism. A growing body of work has found that there is a close relation between complement syntax and ToM in autistic children. However, researchers have not yet investigated whether other linguistic components may explain the difficulties in ToM reasoning in autistic children. AIMS: To determine whether verb factuality (i.e., mental and action verbs) is related to ToM ability, as measured by a false belief understanding (FBU) task after controlling the effect of complement syntax for Mandarin-speaking autistic children. METHODS & PROCEDURES: Participants were verbal autistic children, aged 4-7 years. Their IQ performance (verbal, performance and total IQ) and the comprehension of complement syntax were evaluated. A total of 38 children scoring over 9 points in complement syntax test and 90 points in the verbal IQ test were selected to complete verb factuality and FBU task. The χ2 tests and correlation analyses were carried out on two relations: (1) ToM ability and understanding of verb factuality; and (2) ToM ability and comprehension of complement syntax. OUTCOMES & RESULTS: A total of 11 autistic children completed the action verb factuality task, while 14 completed the mental verb factuality task and 13 completed both tasks. Participants performed well on the verb factuality task, and their ToM performance appeared to be related to their linguistic ability, regardless of the type of verb (i.e., action or mental verb). However, complement syntax scores did not significantly predict the success of the FBU task for the autistic children. CONCLUSIONS & IMPLICATIONS: The results of this study link weaker ToM ability with the understanding of verb factuality among autistic children aged 4-7 and provide new evidence for the view that the development of language facilitates improvement of ToM skills. The findings shed new light on how language affects or determines social interactions. WHAT THIS PAPER ADDS: What is already known on the subject ToM ability is crucial for social interaction. It has been claimed that mental verb factuality (e.g., think, had thought) may play a role in the development of ToM reasoning in typically developing children, but whether there is a link between the mastery of verb factuality and ToM skills in autistic children is still unclear. What this study adds to existing knowledge Correlational analysis revealed links between verbal ToM measured by unexpected location task and factuality test of mental verbs as well as action verbs. More importantly, this study confirmed the extra role of verb factuality in explaining ToM ability after excluding the influence of the complement syntax. What are the potential or actual clinical implications of this work? This study suggests that the factuality of verbs could serve as a tool for autistic children to infer the mental states of others. Thus, training on this linguistic structure could be taken into consideration when improving the social skills of autistic children.

Immune Cell-Related Genes in Juvenile Idiopathic Arthritis Identified Using Transcriptomic and Single-Cell Sequencing Data.

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children. The heterogeneity of the disease can be investigated via single-cell RNA sequencing (scRNA-seq) for its gap in the literature. Firstly, five types of immune cells (plasma cells, naive CD4 T cells, memory-activated CD4 T cells, eosinophils, and neutrophils) were significantly different between normal control (NC) and JIA samples. WGCNA was performed to identify genes that exhibited the highest correlation to differential immune cells. Then, 168 differentially expressed immune cell-related genes (DE-ICRGs) were identified by overlapping 13,706 genes identified by WGCNA and 286 differentially expressed genes (DEGs) between JIA and NC specimens. Next, four key genes, namely SOCS3, JUN, CLEC4C, and NFKBIA, were identified by a protein-protein interaction (PPI) network and three machine learning algorithms. The results of functional enrichment revealed that SOCS3, JUN, and NFKBIA were all associated with hallmark TNF-α signaling via NF-κB. In addition, cells in JIA samples were clustered into four groups (B cell, monocyte, NK cell, and T cell groups) by single-cell data analysis. CLEC4C and JUN exhibited the highest level of expression in B cells; NFKBIA and SOCS3 exhibited the highest level of expression in monocytes. Finally, real-time quantitative PCR (RT-qPCR) revealed that the expression of three key genes was consistent with that determined by differential analysis. Our study revealed four key genes with prognostic value for JIA. Our findings could have potential implications for JIA treatment and investigation.

Krüppel-like Factor 15 Suppresses Ferroptosis by Activating an NRF2/GPX4 Signal to Protect against Folic Acid-Induced Acute Kidney Injury.

Acute kidney injury (AKI) is a common and serious disease with high morbidity and mortality, and its pathophysiological mechanisms are not fully understood. Increasing evidence suggests an important role of ferroptosis in AKI. Krüppel-like factor 15 (KLF15) is a transcription factor involved in several metabolic diseases, but its role in AKI and ferroptosis remains unclear. In this study, we explored the potential role of KLF15 using a folic acid-induced AKI model. Our study showed that KLF15 expression was reduced in kidney tissues of AKI mice, and KLF15 knockout exacerbated folic acid-induced ferroptosis and kidney injury. In vitro studies revealed that the ferroptosis inducer erastin significantly suppressed KLF15 expression in human tubular epithelial cells. Notably, the overexpression of KLF15 attenuated ferroptosis, as evidenced by a decrease in the lipid peroxidation marker of malondialdehyde and the upregulation of glutathione peroxidase 4 (GPX4), while KLF15 knockdown with shRNA exerted the opposite effect. Mechanistically, KLF15 stabilized the protein of nuclear factor erythroid 2-related factor 2 (NRF2) and subsequently increased the GPX4 level. Collectively, KLF15 plays an important role in the modulation of ferroptosis in AKI and may be a potential therapeutic target for treating AKI.

Mechanistic Understanding of Tyrosinase Inhibition by Polymeric Proanthocyanidins from Acacia confusa Stem Bark and Their Effect on the Browning Resistance of Fresh-Cut Asparagus Lettuce.

Tyrosinase inhibitors are capable of preventing unfavorable enzymatic browning of fruits and vegetables. In this study, the capacity of Acacia confusa stem bark proanthocyanidins (ASBPs) to inhibit tyrosinase activity was evaluated. ASBPs were shown to be a high-potential inhibitor of tyrosinase with IC50 values of 92.49 ± 4.70 and 61.74 ± 8.93 µg/mL when using L-tyrosine and L-DOPA as the substrate, respectively. The structural elucidation performed with UV-vis, FT-IR spectroscopy, ESI-MS and thiolysis coupled to HPLC-ESI-MS suggested that ASBPs had structural heterogeneity in monomer units and interflavan linkages and consisted mainly of procyanidins dominant with B-type linkages. To gain insights into the inhibitory mechanisms of ASBPs against tyrosinase, different spectroscopic and molecular docking methods were further conducted. Results validated that ASBPs possessed the ability to chelate copper ions and could prevent the oxidation process of substrates by tyrosinase. The hydrogen bond formed with Lys-376 residue played a key role in the binding force of ASBPs with tyrosinase that induced a certain alteration in the microenvironment and secondary structure of tyrosinase, resulting in the enzymatic activity being ultimately restricted. It was also observed that ASBPs treatment effectively inhibited the activities of PPO and POD to retard the surface browning of fresh-cut asparagus lettuce and thus extended their shelf-life. The results provided preliminary evidence supporting the exploitation of ASBPs into potential antibrowning agents for the fresh-cut food industry.