DEFB114 protein enhances host resistance to fungal infection through the NOD1/2-ATG16L1-NF-κB signaling pathway.

The overuse of antibiotics has led to the enhanced resistance of many pathogenic bacteria, posing a threat to human health. Therefore, there is a need to develop green and safe alternatives to antibiotics. Beta-defensins play a crucial role in host defense against pathogens and have multifunctional properties, exerting key roles in innate and adaptive immunity, as well as non-immune processes. In this study, a 210 bp long cDNA sequence of yak DEFB114 gene was amplified and successfully expressed in a prokaryotic system. The DEFB114 protein exhibited significant inhibitory effects on the growth of Aspergillus fumigatus in vitro. When co-cultured with yak macrophages, DEFB114 protein enhanced macrophage phagocytic activity and increased nucleic acid fluorescence intensity (P < 0.05). DEFB114 protein also enhanced the activity of yak macrophages stimulated by inactivated Aspergillus fumigatus spores, increased the release of nitric oxide (NO), and promoted the expression of genes such as γ-actin, Lgals, Man2b, and Capg (P < 0.05). In mice experiments, DEFB114 protein promoted resistance against Aspergillus fumigatus infection, by regulating the NOD1/2-ATG16L1-NF-κB pathway to modulate the host immune response and exert its anti-infective effects. In summary, the yak DEFB114 protein could inhibit the growth of Aspergillus fumigatus and enhance the animal's resistance to pathogenic microorganisms, thereby having significant implications in the treatment and prevention of fungal infections.

A one-two punch targeting reactive oxygen species and fibril for rescuing Alzheimer's disease.

Toxic amyloid-beta (Aß) plaque and harmful inflammation are two leading symptoms of Alzheimer's disease (AD). However, precise AD therapy is unrealizable due to the lack of dual-targeting therapy function, poor BBB penetration, and low imaging sensitivity. Here, we design a near-infrared-II aggregation-induced emission (AIE) nanotheranostic for precise AD therapy. The anti-quenching emission at 1350 nm accurately monitors the in vivo BBB penetration and specifically binding of nanotheranostic with plaques. Triggered by reactive oxygen species (ROS), two encapsulated therapeutic-type AIE molecules are controllably released to activate a self-enhanced therapy program. One specifically inhibits the Aß fibrils formation, degrades Aß fibrils, and prevents the reaggregation via multi-competitive interactions that are verified by computational analysis, which further alleviates the inflammation. Another effectively scavenges ROS and inflammation to remodel the cerebral redox balance and enhances the therapy effect, together reversing the neurotoxicity and achieving effective behavioral and cognitive improvements in the female AD mice model.

Autoimmune glial fibrillary acidic protein astrocytopathy complicated with low flow perimedullary arteriovenous fistula: a case report.

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy and low-flow perimedullary arteriovenous fistulas (PMAVFs) may cause longitudinal widespread myelopathy. We report a middle-aged male patient with autoimmune GFAP astrocytopathy complicated with low flow PMAVFs disease, presenting with lower extremity weakness and dysuria. Magnetic resonance imaging (MRI) of the spinal cord revealed a significant longitudinal extent of T2 high signal from T11 to L1, with the lesion located proximal to the vascular territory supplied by the anterior spinal artery. Multiple patchy abnormal signals were seen adjacent to the anterior and posterior horns of the lateral ventricles bilaterally and at the centers of the semi-ovals on MRI of the cranial brain, with iso signal in T1Flair, the high signal in T2WI, and no high signal seen in Diffusion Weighted Imaging (DWI). Subsequently, the presence of anti-GFAP antibodies was detected in the cerebrospinal fluid (CSF), and the diagnosis of autoimmune GFAP astrocytopathy in conjunction with low-flow PMAVFs was confirmed through spinal digital subtraction angiography (DSA). This case report aims to increase neurologists' awareness of this disease and avoid missed or misdiagnosed cases that may lead to delayed treatment.

Study of the Anti-Inflammatory Mechanism of ß-Carotene Based on Network Pharmacology.

ß-carotene is known to have pharmacological effects such as anti-inflammatory, antioxidant, and anti-tumor properties. However, its main mechanism and related signaling pathways in the treatment of inflammation are still unclear. In this study, component target prediction was performed by using literature retrieval and the SwissTargetPrediction database. Disease targets were collected from various databases, including DisGeNET, OMIM, Drug Bank, and GeneCards. A protein-protein interaction (PPI) network was constructed, and enrichment analysis of gene ontology and biological pathways was carried out for important targets. The analysis showed that there were 191 unique targets of ß-carotene after removing repeat sites. A total of 2067 targets from the three databases were integrated, 58 duplicate targets were removed, and 2009 potential disease action targets were obtained. Biological function enrichment analysis revealed 284 biological process (BP) entries, 31 cellular component (CC) entries, 55 molecular function (MF) entries, and 84 cellular pathways. The biological processes were mostly associated with various pathways and their regulation, whereas the cell components were mainly membrane components. The main molecular functions included RNA polymerase II transcription factor activity, DNA binding specific to the ligand activation sequence, DNA binding, steroid binding sequence-specific DNA binding, enzyme binding, and steroid hormone receptors. The pathways involved in the process included the TNF signaling pathway, sphingomyelin signaling pathway, and some disease pathways. Lastly, the anti-inflammatory signaling pathway of ß-carotene was systematically analyzed using network pharmacology, while the molecular mechanism of ß-carotene was further explored by molecular docking. In this study, the anti-inflammatory mechanism of ß-carotene was preliminarily explored and predicted by bioinformatics methods, and further experiments will be designed to verify and confirm the predicted results, in order to finally reveal the anti-inflammatory mechanism of ß-carotene.

Methionine-CBS axis promotes intracellular ROS levels by reprogramming serine metabolism.

As a non-essential amino acid, cysteine could be obtained through both exogenous uptake and endogenous de novo synthesis pathways. Research has demonstrated that restricting the uptake of cystine could result in a depletion of intracellular cysteine and glutathione, ultimately leading to an increase in intracellular reactive oxygen species (ROS) levels. However, the role of methionine in regulating intracellular ROS levels is currently unclear. Here, we want to explore the role of methionine in regulating intracellular ROS levels. We found that methionine restriction could lead to a decrease in intracellular ROS levels, while supplementation with SAM can restore these levels through flow cytometry. Mechanically, we found that the methionine-SAM axis relies on CBS when regulating intracellular ROS levels. Furthermore, we speculate and prove that the methionine-SAM-CBS axis alters the metabolism of serine, thereby reducing intracellular reductive power, therefore promoting intracellular ROS levels through changing metabolite levels and genetic methods. Finally, our study revealed that high expression of CBS in tumor cells could lead to increased intracellular ROS levels, ultimately resulting in faster proliferation rates. Together, our study confirmed that methionine plays a promoting role in the regulation of intracellular ROS levels.

Aberrant resting-state functional connectivity of the globus pallidus interna in first-episode schizophrenia.

BACKGROUND: The striatal-pallidal pathway plays an important role in cognitive control and modulation of behaviors. Globus pallidus interna (GPi), as a primary output structure, is crucial in modulating excitation and inhibition. Studies of GPi in psychiatric illnesses are lacking given the technical challenges of examining this small and functionally diverse subcortical structure. METHODS: 71 medication-naïve first episode schizophrenia (FES) participants and 73 healthy controls (HC) were recruited at the Shanghai Mental Health Center. Clinical symptoms and imaging data were collected at baseline and, in a subset of patients, 8 weeks after initiating treatment. Resting-state functional connectivity of sub-regions of the GP were assessed using a novel mask that combines two atlases to create 8 ROIs in the GP. RESULTS: Baseline imaging data from 63 FES patients and 55 HC met quality standards and were analyzed. FES patients exhibited less negative connectivity and increased positive connectivity between the right anterior GPi and several cortical and subcortical areas at baseline compared to HC (PFWE < 0.05). Positive functional connectivity between the right anterior GPi and several brain areas, including the right dorsal anterior cingulate gyrus, was associated with severity of positive symptoms (PFWE < 0.05) and predicted treatment response after 8 weeks (n = 28, adjusted R2 = 0.486, p < 0.001). CONCLUSIONS: Our results implicate striatal-pallidal-thalamic pathways in antipsychotic efficacy. If replicated, these findings may reflect failure of neurodevelopmental processes in adolescence and early adulthood that decrease functional connectivity as an index of failure of the limbic/associative GPi to appropriately inhibit irrelevant signals in psychosis.

Study on bioactive compounds of microalgae as antioxidants in a bibliometric analysis and visualization perspective.

Natural antioxidants are more attractive than synthetic chemical oxidants because of their non-toxic and non-harmful properties. Microalgal bioactive components such as carotenoids, polysaccharides, and phenolic compounds are gaining popularity as very effective and long-lasting natural antioxidants. Few articles currently exist that analyze microalgae from a bibliometric and visualization point of view. This study used a bibliometric method based on the Web of Science Core Collection database to analyze antioxidant research on bioactive compounds in microalgae from 1996 to 2022. According to cluster analysis, the most studied areas are the effectiveness, the antioxidant mechanism, and use of bioactive substances in microalgae, such as carotene, astaxanthin, and tocopherols, in the fields of food, cosmetics, and medicine. Using keyword co-occurrence and keyword mutation analysis, future trends are predicted to improve extraction rates and stability by altering the environment of microalgae cultures or mixing extracts with chemicals such as nanoparticles for commercial and industrial applications. These findings can help researchers identify trends and resources to build impactful investigations and expand scientific frontiers.

Influence of deposition temperature on microstructure and gas-barrier properties of Al2O3 prepared by plasma-enhanced atomic layer deposition on a polycarbonate substrate.

We prepared polymer-based encapsulation films by plasma-enhanced atomic layer deposition (PEALD) of Al2O3 film on a polycarbonate (PC) substrate at 80-160 °C to fabricate Al2O3/PC barrier films. The thermal and dynamic mechanical properties of the PC substrate, the structural evolution of PEALD Al2O3 films, the optical transmission, surface morphology, and gas-barrier properties of Al2O3/PC film are all studied in this work as a function of temperature. The glass transition temperature T g of the PC substrate is about 140 °C, and the coefficient of thermal expansion increases significantly when the temperature exceeds T g. Increasing the deposition temperature from 80 to 160 °C for Al2O3 film deposited over 300 cycles increases the density from 3.24 to 3.45 g cm-3, decreases the thickness from 44 to 40 nm, and decreases the O/Al content ratio from 1.525 to 1.406. Al2O3/PC films deposited at 80-120 °C have no surface cracks, whereas surface cracks appear in samples deposited near or above 140 °C. Upon increasing the deposition temperature, the water vapor transmission rate (WVTR) and oxygen transmission rate (OTR) of Al2O3/PC films decrease significantly at temperatures below T g, and then increase at temperatures near to or above T g due to cracks in the films. The optimal deposition temperature is 120 °C, and the minimum WVTR and OTR of Al2O3/PC film are 0.00132 g per (m2 24 h) and 0.11 cm3 per (m2 24 h 0.1 MPa), respectively. The gas-barrier properties of the Al2O3/PC films are attributed to both the densification of the Al2O3 film and the cracks, which are caused by the shrinkage of the PC substrate.

Investigation into Rheological Behavior of Warm-Mix Recycled Asphalt Binders with High Percentages of RAP Binder.

The rheological properties of warm-mix recycled asphalt binders are critical to enhancing design quality and interpreting the performance mechanisms of the corresponding mixtures. This study investigated the rheological behavior of warm-mix recycled asphalt binders with high percentages of RAP binder. The effects of two warm-mix additives [wax-based Sasobit (S) and surfactant-based Evotherm-M1 (E)], a rejuvenating aging [ZGSB (Z)], four RAP binder contents (0%, 30%, 50% and 70%), and three aging states (unaged, short-term aged and long-term aged) were evaluated in detail using the dynamic shear rheometer (DSR), bending beam rheometer (BBR) and Brookfield rotational viscometer tests as well as conventional performance tests over the whole range of temperatures. The results showed that the rejuvenating agent Z effectively alleviated the aging effect of the RAP binder; however, it could hardly eliminate entirely this negative impact, especially at higher RAP binder contents. The addition of S remarkably lowered the apparent viscosity of the warm-mix recycled binders by up to 35.0%, whereas E had little influence on the binder viscosity due to its surfactant nature. Besides, S performed much better in improving rutting resistance (with the increase of up to 411.3% in |G*|/sinδ) than E, while E exhibited superior fatigue performance (with the reduction of up to 42.3% in |G*|·sinδ) to that of S. In terms of the thermal cracking resistance, E had very slight influence and S even yielded an adverse impact (with the increase of up to 70.2% in Sa and the decrease of up to 34.1% in m-value). Further, S broadened the ranges of pavement service temperatures by about 12 °C, whereas E almost did not change the PG grades of the binders. Finally, regarding the characteristics of viscoelastic master curves, S considerably improved the dynamic modulus and lowered the phase angle of the binders over a wide range of frequencies and temperatures but led to the failure of the time-temperature superposition principle due to its thermorheologically complex nature. Nevertheless, in this regard, the effect of E was found very mild.

Corrigendum: Influence of carrier effect on Pd/Al2O3 for methane complete catalytic oxidation.

[This corrects the article DOI: 10.3389/fchem.2022.978698.].

Genistein Promotes Skeletal Muscle Regeneration by Regulating miR-221/222.

Genistein (GEN), a phytoestrogen, has been reported to regulate skeletal muscle endocrine factor expression and muscle fiber type switching, but its role in skeletal muscle regeneration is poorly understood. As a class of epigenetic regulators widely involved in skeletal muscle development, microRNAs (miRNAs) have the potential to treat skeletal muscle injury. In this study, we identified miR-221 and miR-222 and their target genes MyoG and Tnnc1 as key regulators during skeletal muscle regeneration, and both were regulated by GEN. C2C12 myoblasts and C2C12 myotubes were then used to simulate the proliferation and differentiation of muscle satellite cells during skeletal muscle regeneration. The results showed that GEN could inhibit the proliferation of satellite cells and promote the differentiation of satellite cells by inhibiting the expression of miR-221/222. Subsequent in vitro and in vivo experiments showed that GEN improved skeletal muscle regeneration mainly by promoting satellite cell differentiation in the middle and late stages, by regulating miR-221/222 expression. These results suggest that miR-221/222 and their natural regulator GEN have potential applications in skeletal muscle regeneration.

Thrombin induces IL-8/CXCL8 expression by DCLK1-dependent RhoA and YAP activation in human lung epithelial cells.

BACKGROUND: Doublecortin-like kinase 1 (DCLK1) has been recognized as a marker of cancer stem cell in several malignancies. Thrombin is crucial in asthma severity as it can promote IL-8/CXCL8 production in lung epithelial cells, which is a potent chemoattractant for neutrophils. However, the pathologic role of DCLK1 in asthma and its involvement in thrombin-stimulated IL-8/CXCL8 expression remain unknown. METHODS: IL-8/CXCL8, thrombin, and DCLK1 expression were observed in the lung tissues of severe asthma patients and ovalbumin (OVA)-induced asthmatic mice model. A549 and BEAS-2B cells were either pretreated with inhibitors or small interfering RNAs (siRNAs) before being treated with thrombin. IL-8/CXCL8 expression and the molecules involved in signaling pathway were performed using ELISA, luciferase activity assay, Western blot, or ChIP assay. RESULTS: IL-8/CXCL8, thrombin, and DCLK1 were overexpressed in the lung tissues of severe asthma patients and ovalbumin (OVA)-induced asthmatic mice model. Our in vitro study found that DCLK siRNA or LRKK2-IN-1 (DCLK1 inhibitor) attenuated IL-8/CXCL8 release after thrombin induction in A549 and BEAS-2B cells. Thrombin activated DCLK1, RhoA, and YAP in a time-dependent manner, in which DCLK1 siRNA inhibited RhoA and YAP activation. YAP was dephosphorylated on the Ser127 site after thrombin stimulation, resulting in YAP translocation to the nucleus from the cytosol. DCLK1, RhoA and YAP activation following thrombin stimulation were inhibited by U0126 (ERK inhibitor). Moreover, DCLK1 and YAP siRNA inhibited κB-luciferase activity. Thrombin stimulated the recruitment of YAP and p65 to the NF-κB site of the IL-8/CXCL8 promoter and was inhibited by DCLK1 siRNA. CONCLUSIONS: Thrombin activates the DCLK1/RhoA signaling pathway, which promotes YAP activation and translocation to the nucleus from the cytosol, resulting in YAP/p65 formation, and binding to the NF-κB site, which enhances IL-8/CXCL8 expression. DCLK1 might be essential in thrombin-stimulated IL-8/CXCL8 expression in asthmatic lungs and indicates a potential therapeutic strategy for severe asthma treatment.

Generalizable deep learning model for early Alzheimer's disease detection from structural MRIs.

Early diagnosis of Alzheimer's disease plays a pivotal role in patient care and clinical trials. In this study, we have developed a new approach based on 3D deep convolutional neural networks to accurately differentiate mild Alzheimer's disease dementia from mild cognitive impairment and cognitively normal individuals using structural MRIs. For comparison, we have built a reference model based on the volumes and thickness of previously reported brain regions that are known to be implicated in disease progression. We validate both models on an internal held-out cohort from The Alzheimer's Disease Neuroimaging Initiative (ADNI) and on an external independent cohort from The National Alzheimer's Coordinating Center (NACC). The deep-learning model is accurate, achieved an area-under-the-curve (AUC) of 85.12 when distinguishing between cognitive normal subjects and subjects with either MCI or mild Alzheimer's dementia. In the more challenging task of detecting MCI, it achieves an AUC of 62.45. It is also significantly faster than the volume/thickness model in which the volumes and thickness need to be extracted beforehand. The model can also be used to forecast progression: subjects with mild cognitive impairment misclassified as having mild Alzheimer's disease dementia by the model were faster to progress to dementia over time. An analysis of the features learned by the proposed model shows that it relies on a wide range of regions associated with Alzheimer's disease. These findings suggest that deep neural networks can automatically learn to identify imaging biomarkers that are predictive of Alzheimer's disease, and leverage them to achieve accurate early detection of the disease.

N-Tools-Browser: Web-Based Visualization of Electrocorticography Data for Epilepsy Surgery.

Epilepsy affects more than three million people in the United States. In approximately one-third of this population, anti-seizure medications do not control seizures. Many patients pursue surgical treatment that can include a procedure involving the implantation of electrodes for intracranial monitoring of seizure activity. For these cases, accurate mapping of the implanted electrodes on a patient's brain is crucial in planning the ultimate surgical treatment. Traditionally, electrode mapping results are presented in static figures that do not allow for dynamic interactions and visualizations. In collaboration with a clinical research team at a Level 4 Epilepsy Center, we developed N-Tools-Browser, a web-based software using WebGL and the X-Toolkit (XTK), to help clinicians interactively visualize the location and functional properties of implanted intracranial electrodes in 3D. Our software allows the user to visualize the seizure focus location accurately and simultaneously display functional characteristics (e.g., results from electrical stimulation mapping). Different visualization modes enable the analysis of multiple electrode groups or individual anatomical locations. We deployed a prototype of N-Tools-Browser for our collaborators at the New York University Grossman School of Medicine Comprehensive Epilepsy Center. Then, we evaluated its usefulness with domain experts on clinical cases.

Comparison of reference gene expression stability in mouse skeletal muscle via five algorithms.

Real-time quantitative PCR (RT-qPCR) is a widely applied technique for relative quantification of gene expression. In this context, the selection of a suitable reference gene (RG) is an essential step for obtaining reliable and biologically relevant RT-qPCR results. The present study aimed to determine the expression stability of commonly used RGs in mouse skeletal muscle tissue. The expression pattern of eight RGs (ACTB, GAPDH, HPRT, YWHAZ, B2M, PPIA, TUBA and 18S) were evaluated by RT-qPCR in different sample groups classified based on genetic background, muscle tissue type, and growth stage, as well as in a C2C12 myoblast cell line model. Five computational programs were included in the study (comparative ΔCq value, NormFinder, BestKeeper, geNorm, RefFinder) to evaluate the expression stability of RGs. Furthermore, the normalization effects of RGs in soleus (SOL) and gastrocnemius (GAS) muscle tissue were evaluated. Collectively, ACTB, HPRT and YWHAZ were shown to be the most stable RGs, while GADPH and 18S were the least stable. Therefore, the combined use of ACTB, HPRT and YWHAZ is recommended for the normalization of gene expression results in experiments with murine skeletal muscle. The results discussed herein provide a foundation for gene expression analysis by RT-qPCR in mammalian skeletal muscle.

Influence of carrier effect on Pd/Al2O3 for methane complete catalytic oxidation.

Pd/Al2O3 catalysts modified by different chemical elements (Mg, Si, Ce, and Zr) were tested for methane (CH4) catalytic combustion, and PdO nanoparticles loaded on modified Al2O3 were systematically studied. These conditions assess the carrier effects of Pd/Al2O3 and acid strength influences on CH4 combustion. We observed carrier effects on activation energy through tuning Pd 3d binding energies (BEs) and on pre-exponential factors (A) through Pd dispersion and acidity on supports. When the BE of Pd 3d5/2 is 337.3 eV, PdO nanoparticles loaded on modified Al2O3 have excellent activity in cracking the C-H bond of CH4, which leads to the lowest activation energy (E a ), regardless of the size effect of the PdO nanoparticle. Furthermore, a theoretical construction that acid sites on catalysts promote the reversible elementary step (2Pd-OH ↔ Pd-O* + Pd* + H2O) right shifts improving the A dependency on the quantity of exposed Pd* and Pd-O*. As a result, Al2O3, as the carrier, not only modifies the electronic characteristics and size of supported PdO nanoparticles but also participates in the reaction process via acid sites on the surface of Al2O3.

A Novel Metabolism-Related Gene Signature for Predicting the Prognosis of HBV-Infected Hepatocellular Carcinoma.

Metabolic reprogramming is one of the crucial hallmarks of cancer. Hepatocellular carcinoma (HCC) resulting from hepatitis B has various altered metabolic features. However, the impact of such alterations on the tumor microenvironment (TME) and immunotherapy efficacy is still unclear. Here, a prognostic signature of metabolism-related gene (MRG) composition was constructed, and the immune profile of different subgroups and potential response to immunotherapy were described. Based on the HCC gene dataset, we used weighted gene coexpression network analysis for identifying MRGs linked to hepatitis B. An MRG prognostic index (MRGPI) with two genes, ATIC and KIF2C, was constructed using Cox regression analysis, an independent prognostic factor. In addition, the model was validated using the GEO dataset. The immune profile and prediction of HCC response to immunotherapy in different subgroups were analyzed using CIBERSORT and TIDE. Based on the outcomes, the distributions of memory B cells, monocytes, resting mast cells, and M0 macrophages in TME were different with a greater benefit of immunotherapy in the low MRGPI risk group. In addition, the MRGPI risk groups showed substantial differences in sensitivity to conventional drug therapy. This study concludes that MRGPI is an effective biomarker for predicting the prognoses of patients with HCC resulting from hepatitis B virus infections and determining the efficacy of immunotherapy and conventional medical therapy.

Reduced white matter venous density on MRI is associated with neurodegeneration and cognitive impairment in the elderly.

High-resolution susceptibility weighted imaging (SWI) provides unique contrast to small venous vasculature. The conspicuity of these mesoscopic veins, such as deep medullary veins in white matter, is subject to change from SWI venography when venous oxygenation in these veins is altered due to oxygenated blood susceptibility changes. The changes of visualization in small veins shows potential to depict regional changes of oxygen utilization and/or vascular density changes in the aging brain. The goal of this study was to use WM venous density to quantify small vein visibility in WM and investigate its relationship with neurodegenerative features, white matter hyperintensities (WMHs), and cognitive/functional status in elderly subjects (N = 137). WM venous density was significantly associated with neurodegeneration characterized by brain atrophy (ß = 0.046± 0.01, p < 0.001), but no significant association was found between WM venous density and WMHs lesion load (p = 0.3963). Further analysis of clinical features revealed a negative trend of WM venous density with the sum-of-boxes of Clinical Dementia Rating and a significant association with category fluency (1-min animal naming). These results suggest that WM venous density on SWI can be used as a sensitive marker to characterize cerebral oxygen metabolism and different stages of cognitive and functional status in neurodegenerative diseases.