Pirfenidone and nintedanib exert additive antifibrotic effects by the SPP1-AKT pathway in macrophages and fibroblasts.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease with high mortality rates. It has been shown that pirfenidone (PFD) and nintedanib (Ofev) can slow down the decline in lung function of IPF patients, but their efficacy remains suboptimal. Some studies have suggested that the combination of PFD and Ofev may yield promising results. However, there is a lack of research on the combined application of these two medications in the treatment of IPF. A mouse model of bleomycin-induced (BLM) pulmonary fibrosis was established to investigate the impact of combination therapy on pulmonary fibrosis of mice. The findings demonstrated a significant reduction in lung tissue damage in mice treated with the combination therapy. Subsequent transcriptome analysis identified the differential gene secreted phosphoprotein 1 (SPP1), which was found to be associated with macrophages and fibroblasts based on multiple immunofluorescence staining results. Analysis of a phosphorylated protein microarray indicated that SPP1 plays a regulatory role in macrophages and fibroblasts via the AKT pathway. Consequently, the regulation of macrophages and fibroblasts in pulmonary fibrosis by the combination of PFD and Ofev is mediated by SPP1 through the AKT pathway, potentially offering a novel therapeutic option for IPF patients. Further investigation into the targeting of SPP1 for the treatment of pulmonary fibrosis is warranted.

Dynamic molecular signatures of acute myocardial infarction based on transcriptomics and metabolomics.

Acute myocardial infarction (AMI) commonly precedes ventricular remodeling, heart failure. Few dynamic molecular signatures have gained widespread acceptance in mainstream clinical testing despite the discovery of many potential candidates. These unmet needs with respect to biomarker and drug discovery of AMI necessitate a prioritization. We enrolled patients with AMI aged between 30 and 70. RNA-seq analysis was performed on the peripheral blood mononuclear cells collected from the patients at three time points: 1 day, 7 days, and 3 months after AMI. PLC/LC-MS analysis was conducted on the peripheral blood plasma collected from these patients at the same three time points. Differential genes and metabolites between groups were screened by bio-informatics methods to understand the dynamic changes of AMI in different periods. We obtained 15 transcriptional and 95 metabolite expression profiles at three time points after AMI through high-throughput sequencing. AMI-1d: enrichment analysis revealed the biological features of 1 day after AMI primarily included acute inflammatory response, elevated glycerophospholipid metabolism, and decreased protein synthesis capacity. Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) might stand promising biomarkers to differentiate post-AMI stage. Anti-inflammatory therapy during the acute phase is an important direction for preventing related pathology. AMI-7d: the biological features of this stage primarily involved the initiation of cardiac fibrosis response and activation of platelet adhesion pathways. Accompanied by upregulated TGF-beta signaling pathway and ECM receptor interaction, GP5 help assess platelet activation, a potential therapeutic target to improve haemostasis. AMI-3m: the biological features of 3 months after AMI primarily showed a vascular regeneration response with VEGF signaling pathway, NOS3 and SHC2 widely activated, which holds promise for providing new therapeutic approaches for AMI. Our analysis highlights transcriptional and metabolomics signatures at different time points after MI, which deepens our understanding of the dynamic biological responses and associated molecular mechanisms that occur during cardiac repair.

[Evidence mapping of Chinese patent medicines in treatment of premature ventricular contractions].

This study employed evidence mapping to systematically sort out the clinical studies about the treatment of premature ventricular contractions with Chinese patent medicines and to reveal the distribution of evidence in this field. The articles about the treatment of premature ventricular contractions with Chinese patent medicines were searched against PubMed, Cochrane Library, Web of Science, CNKI, Wanfang, and VIP with the time interval from January 2016 to December 2022. Evidence was analyzed and presented by charts and graphs combined with text. According to the inclusion and exclusion criteria, 164 papers were included, including 147 interventional studies, 4 observational studies, and 13 systematic reviews. A total of 27 Chinese patent medicines were involved, in which Shensong Yangxin Capsules and Wenxin Granules had high frequency. There were off-label uses in clinical practice. In recent years, the number of articles published in this field showed a decreasing trend. Eight types of outcome indicators were used in interventional studies. Ambulatory electrocardiography, clinical response rate, safety, and echocardiography had high frequency, while the rate of ß-blocker decompensation, major cardiovascular events, and pharmaceutical economic indicators were rarely reported. The evaluation was one-sided. The low quality of the included articles reduced the reliability of the findings. In the future, the clinical use of medicines should be standardized, and the quality of clinical studies should be improved. Comprehensive clinical evaluation should be carried out to provide a sound scientific basis for the treatment of premature ventricular contractions with Chinese patent medicines.

Detection of pTDP-43 via routine muscle biopsy: A promising diagnostic biomarker for amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, pathologically characterized by TDP-43 aggregates. Recent evidence has been indicated that phosphorylated TDP-43 (pTDP-43) is present not only in motor neurons but also in muscle tissues. However, it is unclear whether testing pTDP-43 aggregation in muscle tissue would assist in the diagnosis of ALS. We propose three key questions: (i) Is aggregation of pTDP-43 detectable in routine biopsied muscles? (ii) Can detection of pTDP-43 aggregation discriminate between ALS and non-ALS patients? (iii) Can pTDP-43 aggregation be observed in the early stages of ALS? We conducted a diagnostic study comprising 2 groups: an ALS group in which 18 cases underwent muscle biopsy screened from a registered ALS cohort consisting of 802 patients and a non-ALS control group, in which we randomly selected 54 muscle samples from a biospecimen bank of 684 patients. Among the 18 ALS patients, 3 patients carried pathological GGGGCC repeats in the C9ORF72 gene, 2 patients carried SOD1 mutations, and 7 patients were at an early stage with only one body region clinically affected. The pTDP-43 accumulation could be detected in routine biopsied muscles, including biceps brachii, deltoid, tibialis anterior, and quadriceps. Abnormal aggregation of pTDP-43 was present in 94.4% of ALS patients (17/18) compared to 29.6% of non-ALS controls (16/54; p < 0.001). The pTDP-43 aggregates were mainly close to the sarcolemma. Using a semi-quantified pTDP-43 aggregates score, we applied a cut-off value of 3 as a diagnostic biomarker, resulting in a sensitivity of 94.4% and a specificity of 83.3%. Moreover, we observed that accumulation of pTDP-43 occurred in muscle tissues prior to clinical symptoms and electromyographic lesions. Our study provides proof-of-concept for the detection of pTDP-43 accumulation via routine muscle biopsy which may serve as a novel biomarker for diagnosis of ALS.

SRY-Box transcription factor 9 triggers YAP nuclear entry via direct interaction in tumors.

The translocation of YAP from the cytoplasm to the nucleus is critical for its activation and plays a key role in tumor progression. However, the precise molecular mechanisms governing the nuclear import of YAP are not fully understood. In this study, we have uncovered a crucial role of SOX9 in the activation of YAP. SOX9 promotes the nuclear translocation of YAP by direct interaction. Importantly, we have identified that the binding between Asp-125 of SOX9 and Arg-124 of YAP is essential for SOX9-YAP interaction and subsequent nuclear entry of YAP. Additionally, we have discovered a novel asymmetrical dimethylation of YAP at Arg-124 (YAP-R124me2a) catalyzed by PRMT1. YAP-R124me2a enhances the interaction between YAP and SOX9 and is associated with poor prognosis in multiple cancers. Furthermore, we disrupted the interaction between SOX9 and YAP using a competitive peptide, S-A1, which mimics an α-helix of SOX9 containing Asp-125. S-A1 significantly inhibits YAP nuclear translocation and effectively suppresses tumor growth. This study provides the first evidence of SOX9 as a pivotal regulator driving YAP nuclear translocation and presents a potential therapeutic strategy for YAP-driven human cancers by targeting SOX9-YAP interaction.

Electronic Structure Modulation Via Iron-Incorporated NiO to Boost Urea Oxidation/Oxygen Evolution Reaction.

The urea-assisted water splitting not only enables a reduction in energy consumption during hydrogen production but also addresses the issue of environmental pollution caused by urea. Doping heterogeneous atoms in Ni-based electrocatalysts is considered an efficient means for regulating the electronic structure of Ni sites in catalytic processes. However, the current methodologies for synthesizing heteroatom-doped Ni-based electrocatalysts exhibit certain limitations, including intricate experimental procedures, prolonged reaction durations, and low product yield. Herein, Fe-doped NiO electrocatalysts were successfully synthesized using a rapid and facile solution combustion method, enabling the synthesis of 1.1107 g within a mere 5 min. The incorporation of iron atoms facilitates the modulation of the electronic environment around Ni atoms, generating a substantial decrease in the Gibbs free energy of intermediate species for the Fe-NiO catalyst. This modification promotes efficient cleavage of C-N bonds and consequently enhances the catalytic performance of UOR. Benefiting from the tunability of the electronic environment around the active sites and its efficient electron transfer, Fe-NiO electrocatalysts only needs 1.334 V to achieve 50 mA cm-2 during UOR. Moreover, Fe-NiO catalysts were integrated into a dual electrode urea electrolytic system, requiring only 1.43 V of cell voltage at 10 mA cm-2.

[Exosomes derived from bone marrow mesenchymal stem cells regulate NF-κB pathway and reduce lung ischemia-reperfusion injury in rats by miR-335].

This study aimed to investigate the effect of exosomes derived from bone marrow mesenchymal stem cells (BMSCs-EXO) on lung ischemia-reperfusion injury (IRI) in rats and to explore the role of miR-335. The model of rat lung IRI was established by clipping the hilum of left lung for 60 min and opening for 180 min. Forty Sprague-Dawley rats were randomly divided into sham group, IRI group, IRI+PBS group, IRI+EXO group, and IRI+miR-335 inhibitor EXO (IRI+inhibitor-EXO) group (n = 8). Rats in the sham group underwent thoracotomies without IRI. Rats in the IRI group were used to establish IRI model without any additional treatment. In the IRI+PBS, IRI+EXO, and IRI+inhibitor-EXO groups, the rats were used to establish IRI model and given PBS, EXO from BMSCs without any treatment, and EXO from BMSCs with miR-335 inhibitor treatment before reperfusion, respectively. Blood gases were analyzed during the experiment. Lung tissue wet/dry ratio (W/D), interleukin 1ß (IL-1ß), tumor necrosis factor α (TNF-α), myeloperoxidase (MPO), malondialdehyde (MDA), and superoxide dismutase (SOD) were measured at the end of reperfusion. Mitochondria were observed by electron microscopy and the Flameng scores were counted. Lung histopathology and apoptosis (TUNEL staining) were observed by light microscopy, and the lung injury scores (LIS) and apoptosis index (AI) were detected. The miR-335 expression was detected by RT-qPCR, and the expression of caspase-3, cleaved-caspase-3, caspase-9, cleaved-caspase-9, and NF-κB proteins were detected by Western blot at the end of reperfusion. The results showed that compared with the sham group, the oxygenation index, pH, and base excess (BE) were significantly lower in the IRI group and IRI+PBS group after reperfusion, whereas those indices were significantly higher in the IRI+EXO group than those in the IRI+PBS group (P < 0.05). Compared with the sham group, there were significant increases in W/D, IL-1ß, TNF-α, MPO, MDA, LIS, AI, Flameng score, caspase-3, cleaved-caspase-3, caspase-9, and cleaved-caspase-9, however significant decreases in the SOD, miR-335 and NF-κB in the IRI group (P < 0.05). These indices in the IRI and IRI+PBS groups showed no significant differences. Compared with the IRI+PBS group, there were significant decreases in W/D, IL-1ß, TNF-α, MPO, MDA, LIS, AI, Flameng score, caspase-3, cleaved-caspase-3, caspase-9, and cleaved-caspase-9, however significant increases in the SOD, miR-335 and NF-κB in the IRI+EXO group (P < 0.05). While, the changes of the above mentioned indices were reversed in the IRI+inhibitor-EXO group compared with IRI+EXO group, which were still better than those in the IRI+PBS group (P < 0.05). The results suggest that BMSCs-EXO could attenuate lung IRI in rats, activate NF-κB pathway, and maintain mitochondrial stability by up-regulating miR-335.

Analysis of the chemical characteristics and causes of high total hardness of groundwater in Jianghan Plain, China.

Familiarity with the chemical characteristics of regional groundwater can provide important guidance and reference for the development of regional groundwater exploitation. Jianghan Plain has been reported to have high groundwater total hardness (TH), resulting in the inability of local groundwater to be directly used as drinking water. In order to explore the causes of high TH, the paper analyzed the hydrochemical characteristics of shallow groundwater in Jianghan Plain combined with software of SPSS, JMP, and PHEEQC. The results showed that the cations in the groundwater in the area were mainly Ca2+, while the anions were mainly HCO3-. 20% of groundwater exceed the China national guideline for TH (i.e., 450 mg/L). The groundwater chemistry in the study area was controlled by three main factors of dissolution of carbonate rocks, human activities, and redox conditions, among which the interaction between water and rock had the greatest impact. The water carbonate rock interaction within Jianghan Plain was affected by various factors such as water flow and aquifers and showed a gradually weakening trend from west to east. This work not only strengthened the understanding of the causes of the high TH of groundwater in the region, but also provided reference value for regional groundwater environmental management.

Intracavity spatially modulated metasurfaces for a wavelength-tunable figure-9 vortex fiber laser.

Intracavity optical metasurfaces with compact and flexible light manipulation capabilities, effectively enrich the implementation of miniaturized and user-friendly orbital angular momentum (OAM) laser sources. Here we demonstrate a wavelength-tunable figure-9 Yb-doped vortex fiber laser solely with standard non-polarization-maintaining single-mode fibers, which utilizes a gap-surface plasmon (GSP) metasurface as the intracavity mode regulation component to generate OAM beams, extending the avenues and related applications for cost-effective OAM laser sources. Gained by the broadband operation range of the metasurface, the figure-9 fiber laser could emit OAM light with center wavelength tunable from 1020 nm to 1060 nm and of high mode purity (about 90%). OAM beams with different topological charges such as l = ±1 have been obtained by changing the metasurface design. The proposed fiber laser with the intracavity GSP metasurface provides a reliable and customized output of OAM beams at the laser source, holding great promise for a wide range of applications in optical communications, sensing, and super-resolution imaging.

A Long-Term Follow-Up Study on the Auditory Performance and Speech Intelligibility of Mandarin-Speaking Prelingually Deaf Children With Isolated Large Vestibular Aqueduct Syndrome After Cochlear Implantation.

PURPOSE: The purpose of this study was to evaluate the auditory performance and speech perception of 104 children with isolated large vestibular aqueduct syndrome (LVAS) and 523 children with no inner ear malformation (IEM) for 5 years after cochlear implantation, in order to explore whether isolated LVAS can affect the long-term hearing and speech rehabilitation of deaf children after cochlear implantation. METHOD: A cohort study was established consisting of 627 children who underwent cochlear implantation at Beijing Tongren Hospital from 1999 to 2016. The children were examined at 0, 6, 12, 24, 36, 48, and 60 months after cochlear implantation to assess their auditory performance and speech perception using the Categories of Auditory Performance (CAP) and Speech Intelligibility Rating (SIR) questionnaires. RESULTS: The CAP scores of the isolated LVAS group increased significantly during the baseline to the 24th month, after which they gradually rose until reaching the plateau during the 24th to the 60th month. The CAP scores of the non-IEM group increased significantly during the baseline to the 36th month and then increased steadily. The SIR scores went up significantly during the baseline to the 48th month, and increased in a gradual manner in other stages of isolated LVAS evaluation. In comparison, The SIR scores of non-IEM group grew remarkably from the baseline to the 60th month. There were no significant differences in the CAP or SIR scores between isolated LVAS and non-IEM groups in each stage of evaluation, with the only exception being the CAP score at baseline month after cochlear implantation. CONCLUSIONS: The CAP and SIR questionnaires are helpful tools for quantifying the early hearing and speech skills of younger prelingually deafened cochlear implant recipients. This long-term follow-up study shows that the speech and hearing development of children in isolated LVAS and non-IEM groups follow similar patterns, and isolated LVAS does not affect the long-term rehabilitation of deaf children after cochlear implantation.

Ir Single Atoms Boost Metal-Oxygen Covalency on Selenide-Derived NiOOH for Direct Intramolecular Oxygen Coupling.

This investigation probes the intricate interplay of catalyst dynamics and reaction pathways during the oxygen evolution reaction (OER), highlighting the significance of atomic-level and local ligand structure insights in crafting highly active electrocatalysts. Leveraging a tailored ion exchange reaction followed by electrochemical dynamic reconstruction, we engineered a novel catalytic structure featuring single Ir atoms anchored to NiOOH (Ir1@NiOOH). This novel approach involved the strategic replacement of Fe with Ir, facilitating the transition of selenide precatalysts into active (oxy)hydroxides. This elemental substitution promoted an upward shift in the O 2p band and intensified the metal-oxygen covalency, thereby altering the OER mechanism toward enhanced activity. The shift from a single-metal site mechanism (SMSM) in NiOOH to a dual-metal-site mechanism (DMSM) in Ir1@NiOOH was substantiated by in situ differential electrochemical mass spectrometry (DEMS) and supported by theoretical insights. Remarkably, the Ir1@NiOOH electrode exhibited exceptional electrocatalytic performance, achieving overpotentials as low as 142 and 308 mV at current densities of 10 and 1000 mA cm-2, respectively, setting a new benchmark for the electrocatalysis of OER.

Supported Platinum Nanoparticles Catalyzed Carbon-Carbon Bond Cleavage of Polyolefins: Role of the Oxide Support Acidity.

Supported platinum nanoparticle catalysts are known to convert polyolefins to high-quality liquid hydrocarbons using hydrogen under relatively mild conditions. To date, few studies using platinum grafted onto various metal oxide (MxOy) supports have been undertaken to understand the role of the acidity of the oxide support in the carbon-carbon bond cleavage of polyethylene under consistent catalytic conditions. Specifically, two Pt/MxOy catalysts (MxOy = SrTiO3 and SiO2-Al2O3; Al = 3.0 wt %, target Pt loading 2 wt % Pt ∼1.5 nm), under identical catalytic polyethylene hydrogenolysis conditions (T = 300 °C, P(H2) = 170 psi, t = 24 h; Mw = ∼3,800 g/mol, Mn = ∼1,100 g/mol, D = 3.45, Nbranch/100C = 1.0), yielded a narrow distribution of hydrocarbons with molecular weights in the range of lubricants (Mw = < 600 g/mol; Mn < 400 g/mol; D = 1.5). While Pt/SrTiO3 formed saturated hydrocarbons with negligible branching, Pt/SiO2-Al2O3 formed partially unsaturated hydrocarbons (<1 mol % alkenes and ∼4 mol % alkyl aromatics) with increased branch density (Nbranch/100C = 5.5). Further investigations suggest evidence for a competitive hydrocracking mechanism occurring alongside hydrogenolysis, stemming from the increased acidity of Pt/SiO2-Al2O3 compared to Pt/SrTiO3. Additionally, the products of these polymer deconstruction reactions were found to be independent of the polyethylene feedstock, allowing the potential to upcycle polyethylenes with various properties into a value-added product.

Electrically tunable topological phase transition in non-Hermitian optical MEMS metasurfaces.

Exceptional points (EPs), unique junctures in non-Hermitian open systems where eigenvalues and eigenstates simultaneously coalesce, have gained notable attention in photonics because of their enthralling physical principles and unique properties. Nonetheless, the experimental observation of EPs, particularly within the optical domain, has proven rather challenging because of the grueling demand for precise and comprehensive control over the parameter space, further compounded by the necessity for dynamic tunability. Here, we demonstrate the occurrence of optical EPs when operating with an electrically tunable non-Hermitian metasurface platform that synergizes chiral metasurfaces with piezoelectric MEMS mirrors. Moreover, we show that, with a carefully constructed metasurface, a voltage-controlled spectral space can be finely tuned to access not only the chiral EP but also the diabolic point characterized by degenerate eigenvalues and orthogonal eigenstates, thereby allowing for dynamic topological phase transition. Our work paves the way for developing cutting-edge optical devices rooted in EP physics and opening uncharted vistas in dynamic topological photonics.

Efficient Acidic Photoelectrochemical Water Splitting Enabled by Ru Single Atoms Anchored on Hematite Photoanodes.

Photoelectrochemical (PEC) water splitting in acidic media holds promise as an efficient approach to renewable hydrogen production. However, the development of highly active and stable photoanodes under acidic conditions remains a significant challenge. Herein, we demonstrate the remarkable water oxidation performance of Ru single atom decorated hematite (Fe2O3) photoanodes, resulting in a high photocurrent of 1.42 mA cm-2 at 1.23 VRHE under acidic conditions. Comprehensive experimental and theoretical investigations shed light on the mechanisms underlying the superior activity of the Ru-decorated photoanode. The presence of single Ru atoms enhances the separation and transfer of photogenerated carriers, facilitating efficient water oxidation kinetics on the Fe2O3 surface. This is achieved by creating additional energy levels within the Fe2O3 bandgap and optimizing the free adsorption energy of intermediates. These modifications effectively lower the energy barrier of the rate-determining step for water splitting, thereby promoting efficient PEC hydrogen production.

Controllable synthesis of crystalline germanium nanorods as anode for lithium-ion batteries with high cycling stability.

Germanium (Ge) nanomaterials have emerged as promising anode materials for lithium-ion batteries (LIBs) due to their higher capacity compared to commercial graphite. However, their practical application has been limited by the high cost associated with harsh preparation conditions and the poor electrode cycling stability in charging and diacharging. In this study, we successfully synthesized crystalline Ge nanorods through the reaction of intermetallic compound CaGe and ZnCl2. Ge nanorods with different morphologies and crystallinity can be obtained through precisely controlling the reaction temperature. When employed as electrodes for LIBs, the Ge nanorods demonstrate exceptional long-term cyclic stability. Even after 1000 cycles at a high rate of 2C (1C = 1600 mA g-1), it exhibits a remarkable reversible capacity of around 1000 mAh/g. Furthermore, such Ge electrode displays excellent cycling performance across a wide temperature range. And it could achieve reversible capacities of 1267, 832, and 690 mAh/g, with the rate of 1C, at temperatures of 20, 0, and -20 °C, respectively. Above all, our study offers a cost-effective approach for the synthesis of crystalline Ge nanorods, addressing the concerns associated with high production costs. And the application of Ge nanorods as anode materials in LIBs over a wide temperature range opens up new possibilities for the development of advanced energy storage systems.

Bilayer LDPC Codes Combined with Perturbed Decoding for MLC NAND Flash Memory.

This paper presents a coding scheme based on bilayer low-density parity-check (LDPC) codes for multi-level cell (MLC) NAND flash memory. The main feature of the proposed scheme is that it exploits the asymmetric properties of an MLC flash channel and stores the extra parity-check bits in the lower page, which are activated only after the decoding failure of the upper page. To further improve the performance of the error correction, a perturbation process based on the genetic algorithm (GA) is incorporated into the decoding process of the proposed coding scheme, which can convert uncorrectable read sequences into error-correctable regions of the corresponding decoding space by introducing GA-trained noises. The perturbation decoding process is particularly efficient at low program-and-erase (P/E) cycle regions. The simulation results suggest that the proposed bilayer LDPC coding scheme can extend the lifetime of MLC NAND flash memory up to 10,000 P/E cycles. The proposed scheme can achieve a better balance between performance and complexity than traditional single LDPC coding schemes. All of these findings indicate that the proposed coding scheme is suitable for practical purposes in MLC NAND flash memory.

TRIB3-TRIM8 complex drives NAFLD progression by regulating HNF4α stability.

BACKGROUND & AIMS: Endoplasmic reticulum (ER) stress of hepatocytes plays a causative role in non-alcoholic fatty liver disease (NAFLD). Reduced expression of hepatic nuclear factor 4α (HNF4α) is a critical event in the pathogenesis of NAFLD and other liver diseases. Whether ER stress regulates HNF4α expression remains unknown. The aim of this study was to delineate the machinery of HNF4α protein degradation and explore a therapeutic strategy based on protecting HNF4α stability during NAFLD progression. METHODS: Correlation of HNF4α and tribbles homologue 3 (TRIB3), an ER stress sensor, was evaluated in human and mouse NAFLD tissues. RNA-sequencing, mass spectrometry analysis, co-immunoprecipitation, in vivo and in vitro ubiquitination assays were used to elucidate the mechanisms of TRIB3-mediated HNF4α degradation. Molecular docking and co-immunoprecipitation analyses were performed to identify a cell-penetrating peptide that ablates the TRIB3-HNF4α interaction. RESULTS: TRIB3 directly interacts with HNF4α and mediates ER stress-induced HNF4α degradation. TRIB3 recruits tripartite motif containing 8 (TRIM8) to form an E3 ligase complex that catalyzes K48-linked polyubiquitination of HNF4α on lysine 470. Abrogating the degradation of HNF4α attenuated the effect of TRIB3 on a diet-induced NAFLD model. Moreover, the TRIB3 gain-of-function variant p.Q84R is associated with NAFLD progression in patients, and induces lower HNF4α levels and more severe hepatic steatosis in mice. Importantly, disrupting the TRIB3-HNF4α interaction using a cell-penetrating peptide restores HNF4α levels and ameliorates NAFLD progression in mice. CONCLUSIONS: Our findings unravel the machinery of HNF4α protein degradation and indicate that targeting TRIB3-TRIM8 E3 complex-mediated HNF4α polyubiquitination may be an ideal strategy for NAFLD therapy. IMPACT AND IMPLICATIONS: Reduced expression of hepatic nuclear factor 4α (HNF4α) is a critical event in the pathogenesis of NAFLD and other liver diseases. However, the mechanism of HNF4α protein degradation remains unknown. Herein, we reveal that TRIB3-TRIM8 E3 ligase complex is responsible for HNF4α degradation during NAFLD. Inhibiting the TRIB3-HNF4α interaction effectively stabilized HNF4α protein levels and transcription factor activity in the liver and ameliorated TRIB3-mediated NAFLD progression. Our findings demonstrate that disturbing the TRIM8-TRIB3-HNF4α interaction may provide a novel approach to treat NAFLD and even other liver diseases by stabilizing the HNF4α protein.

Efficacy of Chinese and Western Medical Techniques in Treating Diabetic Foot Ulcers With Necrotizing Fasciitis of the Lower Leg.

To analyze and evaluate the clinical efficacy of Chinese and Western medical techniques in the treatment of severe diabetic foot ulcers complicated with necrotizing fasciitis of the lower leg and summarize the treatment experience of such patients to identify a new method of limb salvage treatment. A total of 46 patients with severe diabetic foot ulcers and necrotizing fasciitis of the lower leg were treated with such techniques as surgical debridement, bone drilling, open joint fusion, and microskin implantation. Wounds were treated with moisture-exposed burn therapy (a regenerative medical treatment for burns, wounds, and ulcers) and moisture-exposed burn ointment (a traditional Chinese medicine); underlying diseases were also treated effectively. The wound healing time, rate of high amputation, and mortality of these patients were summarized, and the clinical efficacy of such treatments was evaluated. Of the 46 patients enrolled, 38 patients were cured, with a cure rate of 82.61%. The average wound healing time was 130 ± 74.37 days. Two patients underwent high amputations, with an amputation rate of 4.35%, and 4 deaths occurred, with a mortality rate of 8.70%. The combination of Chinese and Western medical techniques in the treatment of severe diabetic foot ulcers complicated with necrotizing fasciitis of the lower leg not only effectively saved patients' lives and promoted wound healing but also greatly reduced the rates of high amputation and disability.

Network-based analysis on the genes and their interactions reveals link between schizophrenia and Alzheimer's disease.

Schizophrenia (SCZ) is a heterogeneous psychiatric disorder marked by impaired thinking, emotions, and behaviors. Studies have suggested a strong connection between SCZ and Alzheimer's disease (AD), however, controversies exist and the underlying mechanisms linking these two disorders remain largely unknown. Therefore, systematic studies of SCZ- and AD-related genes will provide valuable insights into the molecular features of these two diseases and their comorbidities. In this study, we obtained 331 SCZ-related genes, 650 AD-related genes, 65 shared genes between SCZ and AD. Enrichment analysis shown that these 65 shared genes were mainly involved in cognition, neural development, synaptic transmission, drug reactions, metabolic processes and immune related processes, suggesting a complex mechanism for the co-existence of SCZ and AD. In addition, we performed pathway enrichment analysis and found a total of 57 common pathways between SCZ and AD, which could be largely grouped into three modules: immune module, neurodevelopment module and cancer module. We eventually identified the potential disease-related genes whose interactions provide clues to the overlapping symptoms between SCZ and AD.

Clinical features and visual prognosis of very late-onset neuromyelitis optica spectrum disorder-related optic neuritis.

BACKGROUND: Very late-onset neuromyelitis optica spectrum disorder-related optic neuritis is limited to a few case reports. OBJECTIVE: To investigate the clinical features and visual prognosis of very late-onset neuromyelitis optica spectrum disorder-related optic neuritis. METHODS: This study evaluated 22 patients with first-onset optic neuritis and fulfilled the 2015 diagnosis criteria for neuromyelitis optica spectrum disorders. RESULTS: The mean age at optic neuritis onset was 73.91 ± 4.71 (range: 70-82) years with a female predominance (81.8%; ratio: 4.5:1). Antinuclear antibody seropositivity and seronegativity were identified in 12 (55.5%) and 10 (45.5%) patients, respectively. Severe visual loss persisted in 19 (19/42, 45.3%) eyes at the last follow-up. Although patients with antinuclear antibody seropositivity had a significantly higher frequency of attacks (P = 0.015), but they had a longer median time to reach severe visual loss (37 vs. 26 months; log-rank test, P = 0.023). Multivariate logistic regression analysis revealed antinuclear antibody seropositivity (hazard ratio = 4.849, 95% confidence interval: 1.309-17.965, P = 0.018) as a good predictor of visual acuity improvement. CONCLUSION: Patients with very late-onset neuromyelitis optica spectrum disorder-related optic neuritis may develop severe optic neuritis, and those with antinuclear antibody seronegativity have a similar clinical presentation but worse outcome than those with seropositivity.