A simulation study of transcranial magnetoacoustic stimulation of the basal ganglia thalamic neural network to improve pathological beta oscillations in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a common neurodegenerative disease. Transcranial magnetoacoustic stimulation (TMAS) is a new therapy that combines a transcranial focused acoustic pressure field with a magnetic field to excite or inhibit neurons in targeted area, which suppresses the abnormally elevated beta band amplitude in PD states, with high spatial resolution and non-invasively. OBJECTIVE: To study the effective stimulation parameters of TMAS mononuclear and multinuclear stimulation for the treatment of PD with reduced beta band energy, improved abnormal synchronization, and no thermal damage. METHODS: The TMAS model is constructed based on the volunteer's computed tomography, 128 arrays of phase-controlled transducers, and permanent magnets. A basal ganglia-thalamic (BG-Th) neural network model of the PD state was constructed on the basis of the Izhikevich model and the acoustic model. An ultrasound stimulation neuron model is constructed based on the Hodgkin-Huxley model. Numerical simulations of transcranial focused acoustic pressure field, temperature field and induced electric field at single and dual targets were performed using the locations of STN, GPi, and GPe in the human brain as the main stimulation target areas. And the acoustic and electric parameters at the focus were extracted to stimulate mononuclear and multinuclear in the BG-Th neural network. RESULTS: When the stimulating effect of ultrasound is ignored, TMAS-STN simultaneously inhibits the beta-band amplitude of the GPi nucleus, whereas TMAS-GPi fails to simultaneously have an inhibitory effect on the STN. TMAS-STN&GPi can reduce the beta band amplitude. TMAS-STN&GPi&GPe suppressed the PD pathologic beta band amplitude of each nucleus to a greater extent. When considering the stimulatory effect of ultrasound, lower sound pressures of ultrasound do not affect the neuronal firing state, but higher sound pressures may promote or inhibit the stimulatory effect of induced currents. CONCLUSIONS: At 9 T static magnetic field, 0.5-1.5 MPa and 1.5-2.0 MPa ultrasound had synergistic effects on individual STN and GPi neurons. TMAS multinuclear stimulation with appropriate ultrasound intensity was the most effective in suppressing the amplitude of pathological beta oscillations in PD and may be clinically useful.

Lefamulin Overcomes Acquired Drug Resistance via Regulating Mitochondrial Homeostasis by Targeting ILF3 in Hepatocellular Carcinoma.

Acquired resistance represents a critical clinical challenge to molecular targeted therapies such as tyrosine kinase inhibitors (TKIs) treatment in hepatocellular carcinoma (HCC). Therefore, it is urgent to explore new mechanisms and therapeutics that can overcome or delay resistance. Here, a US Food and Drug Administration (FDA)-approved pleuromutilin antibiotic is identified that overcomes sorafenib resistance in HCC cell lines, cell line-derived xenograft (CDX) and hydrodynamic injection mouse models. It is demonstrated that lefamulin targets interleukin enhancer-binding factor 3 (ILF3) to increase the sorafenib susceptibility of HCC via impairing mitochondrial function. Mechanistically, lefamulin directly binds to the Alanine-99 site of ILF3 protein and interferes with acetyltransferase general control non-depressible 5 (GCN5) and CREB binding protein (CBP) mediated acetylation of Lysine-100 site, which disrupts the ILF3-mediated transcription of mitochondrial ribosomal protein L12 (MRPL12) and subsequent mitochondrial biogenesis. Clinical data further confirm that high ILF3 or MRPL12 expression is associated with poor survival and targeted therapy efficacy in HCC. Conclusively, this findings suggest that ILF3 is a potential therapeutic target for overcoming resistance to TKIs, and lefamulin may be a novel combination therapy strategy for HCC treatment with sorafenib and regorafenib.

Ginsenoside compound K plays an anti-inflammatory effect without inducing glucose metabolism disorder in adjuvant-induced arthritis rats.

Ginsenoside compound K (GCK) possesses a glucocorticoid (GC)-like structure and functions as an agonist of the glucocorticoid receptor (GR), thereby exerting anti-inflammatory effects through GR activation. However, it remains unclear whether GCK leads to hyperglycemia, which is a known adverse reaction associated with classical GCs. In this study, we have successfully demonstrated that GCK exerts its anti-inflammatory effects in a rat model of adjuvant arthritis without impacting gluconeogenesis and pentose phosphate pathways, thus avoiding any glucose metabolism disorders. By employing the GR mutant plasmid, we have identified the binding site between GCK and GR as GRM560T, which differs from the binding site shared by dexamethasone (DEX) and GR. Notably, compared to DEX, GCK induces distinct levels of phosphorylation at S211 on GR upon binding to activate steroid receptor coactivator 1 (SRC1)-a co-factor responsible for mediating anti-inflammatory effects-while not engaging peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α)-an associated coactivator involved in gluconeogenesis.

Mefunidone ameliorates acute liver failure in mice by inhibiting MKK4-JNK pathway.

Acute liver failure (ALF) is a critical condition that can lead to substantial liver dysfunction. It is characterized by complex clinical manifestations and rapid progression, presenting significant challenges in diagnosis and treatment. We investigated the protective effect of mefunidone (MFD), a novel antifibrosis pyridone agent, on ALF in mice, and explored its potential mechanism of action. MFD pretreatment can alleviate lipopolysaccharide (LPS) and d-galactosamine (D-GalN)-induced ALF, reduce hepatocyte apoptosis, and reduce inflammation and oxidative stress. Additionally, MFD alleviated LPS/D-GalN-stimulated reactive oxygen species (ROS) production and cell death in AML12 cells. RNA sequencing enrichment analysis showed that MFD significantly affected the Mitogen-Activated Protein Kinase (MAPK) pathway. In vivo and in vitro experiments showed that MFD inhibited MKK4 and JNK phosphorylation. JNK activation caused by MKK4 and JNK activators could eliminate the therapeutic effect of MFD on AML12. In addition, MFD pretreatment alleviated ConA-induced ALF, reduced inflammation and oxidative stress in mice, and reduced mouse mortality. These results suggest that MFD can potentially protect against ALF, partially by inhibiting the MKK4-JNK pathway, and is a promising new therapeutic drug for ALF.

Research progress in the treatment of inflammatory bowel disease with natural polysaccharides and related structure-activity relationships.

Inflammatory bowel disease (IBD) comprises a group of highly prevalent and chronic inflammatory intestinal tract diseases caused by multiple factors. Despite extensive research into the causes of the disease, IBD's pathogenic mechanisms remain unclear. Moreover, side effects of current IBD therapies restrict their long-term clinical use. In contrast, natural polysaccharides exert beneficial anti-IBD effects and offer advantages over current anti-IBD drugs, including enhanced safety and straightforward isolation from abundant and reliable sources, and thus may serve as components of functional foods and health products for use in IBD prevention and treatment. However, few reviews have explored natural polysaccharides with anti-IBD activities or the relationship between polysaccharide conformation and anti-IBD biological activity. Therefore, this review aims to summarize anti-IBD activities and potential clinical applications of polysaccharides isolated from plant, animal, microorganismal, and algal sources, while also exploring the relationship between polysaccharide conformation and anti-IBD bioactivity for the first time. Furthermore, potential mechanisms underlying polysaccharide anti-IBD effects are summarized, including intestinal microbiota modulation, intestinal inflammation alleviation, and intestinal barrier protection from IBD-induced damage. Ultimately, this review provides a theoretical foundation and valuable insights to guide the development of natural polysaccharide-containing functional foods and nutraceuticals for use as dietary IBD therapies.

Genome-wide identification, expression and function analysis of the MTP gene family in tulip (Tulipa gesneriana).

Currently, soil heavy metal contamination is a severe issue, particularly with Cd pollution. The metal tolerance protein (MTP) proteins, as plant divalent cation transporters, play a crucial role in the transport and tolerance of heavy metals in plants. This study conducted comprehensive identification and characterization of the MTP gene family in the tulip. A total of 11 TgMTP genes were identified and phylogenetically classified into three subfamilies. Conserved motif and gene structure analyses unveiled commonalities and variations among subfamily members. Expression profiling demonstrated several TgMTPs were markedly upregulated under Cd exposure, including the TgMTP7.1. Heterologous expression in yeast validated that TgMTP7.1 could ameliorate Cd sensitivity and enhance its tolerance. These results provide primary insights into the MTP gene family in tulip. Phylogenetic relationships and functional analyses establish a framework for elucidating the transporters and molecular mechanisms governing Cd accumulation and distribution in tulip. Key TgMTPs identified, exemplified by TgMTP7.1, may illuminate molecular breeding efforts aimed at developing Cd-tolerant cultivars for the remediation of soil Cd contamination.

Luminescence properties and Judd-Ofelt analysis of Tb3+ doped Sr2YTaO6 double perovskite phosphors for white LED applications.

A series of Tb3+-doped Sr2YTaO6 double perovskite phosphors (SYT:Tb3+) were synthesized using a conventional solid-state reaction method. A strong green emission was observed in the SYT:Tb3+ phosphors, and the optimal doping concentration of Tb3+ was confirmed to be 5 mol%. The electric dipole-dipole interaction was ascribed to be the main mechanism for the luminescence concentration quenching. Analysis of the concentration-dependent fluorescence decay confirmed that the self-generated quenching model holds for the dynamic process of Tb3+ decays in SYT. Furthermore, the internal quantum efficiencies, non-radiative transition rates, and energy transfer rates of the 5D4 level for the SYT:Tb3+ samples were estimated, respectively. The luminescence thermal stability of the sample was also evaluated based on the Arrhenius model. The chromaticity shift of the SYT:5 mol% Tb3+ phosphor was examined to be 0.013 when the sample temperature was increased from 303 to 483 K, thus indicating excellent chromaticity shifting resistance under high temperature conditions. Moreover, the Judd-Ofelt parameters were calculated from the emission spectra of SYT:Tb3+ to be Ω2 = 0.29 × 10-20, Ω4 = 0.45 × 10-20, and Ω6 = 0.72 × 10-20 cm2, respectively. The fluorescence branching ratios and radiative transition rates for the 5D4 level were calculated based on the obtained Judd-Ofelt parameters. Finally, a white light-emitting diode (LED) prototype was assembled using a 310 nm LED chip combined with a prepared green SYT:Tb3+ phosphor and two other commercial blue and red phosphors. The obtained warm white light exhibits good chromaticity coordinates (0.32, 0.32) and a high color rendering index of 96.1. Based on the above results, it can be known that the prepared SYT:Tb3+ phosphors have a potential application as green emitting phosphors in white LEDs.

Green R & D investment, ESG reporting, and corporate green innovation performance.

Given the contradictory empirical evidence on the relationship between green R&D expenditure and corporate Green Innovation performance (GIP), The present research study is a distinctive investigation into the moderating impacts of ESG reporting on this relationship. We utilized a data collection of 3,846, firm-year observations of A-share listed firms in China from 2016 to 2022 from CSMAR and Bloomberg databases. The firm's Corporate GIP is assessed and measured by looking at the total quantity of green patents. Lastly, models with multiple regression analyses and fixed effects were employed. The findings show that ESG reporting has a positive and significant impact on the association between corporate GIP and green R&D expenditure, implying its compensating and supportive function in the form of green signals in green outputs. This research could help executives and lawmakers, especially in developing countries to build innovative environmental strategies for business sustainability.

Identification of glycosyltransferase-related genes signature and integrative analyses in patients with ovarian cancer.

BACKGROUND: Glycosyltransferases (GT) play a crucial role in glycosylation reactions, and aberrant expression of glycosyltransferase-related genes (GTs) leads to abnormal glycosylation, which is associated with tumor progression. However, the prognostic value of aberrant expression of GTs in ovarian cancer (OC) and the correlation between GTs and tumor microenvironment (TME) remain unknown. METHODS: TCGA and GSE53963 databases were used to obtain data on OC patient samples. The association of GTs with OC was analyzed. Molecular subtypes were identified by consensus unsupervised clustering, followed by immune infiltration and functional enrichment analyses. Survival analysis was performed using Kaplan-Meier curves and log-rank tests. Least Absolute Shrinkage and Selection Operator (LASSO) and multifactorial cox regression were used to screen for signature genes associated with OC and used to establish prognostic models. RESULT: OC patients were categorized into 5 GTs clusters using consensus unsupervised cluster analysis. Clusters D and E showed significant differences between survival, signaling pathways and immune infiltration. Then, a risk model was developed based on the 12 signature genes, which provides a more accurate evaluation of the prognosis of OC patients. We categorized patients into high-risk and low-risk groups based on the risk score and found that the survival of patients in the high-risk group was significantly lower than that in the low-risk group. Moreover, the risk score was significantly correlated with tumor microenvironment, immune infiltration, and chemotherapy sensitivity. CONCLUSION: Overall, we performed a comprehensive analysis of GTs in OC patients and developed a risk model for OC. Our findings will provide a new insight to OC prognosis and treatment.

Multicolor-emitting Er3+ and Er3+/Yb3+ doped Zn2GeO4 phosphors combining static and dynamic identifications for advanced anti-counterfeiting application.

Anti-counterfeiting labels based on luminescence materials are a newly emerging technique for protecting legal goods and intellectual property. In the anti-counterfeiting field to prevent forgery and cloning, luminescence materials with properties different from the commercialized and traditional ones are in urgent need. In this work, multicolor-emitting Er3+ single-doped and Er3+/Yb3+ co-doped Zn2GeO4 phosphors combining static and dynamic identifications were developed in order to achieve advanced anti-counterfeiting application. The variation of trap content with increasing the doping content of rare earth ions was analyzed through X - ray photoelectron spectroscopy, thermoluminescence analysis. It was found that there are two types of traps with different depth in Zn2GeO4 phosphors. The depths of the traps were experimentally confirmed to be 0.68 and 0.79 eV, respectively. The transient photocurrent response measurement confirmed the existence of charge carriers, and the mechanism for long persistent luminescence was deduced. The multicolor upconversion mechanisms under 980 and 1550 nm excitation were also discovered. Based on the multicolor steady and transient emission features, an anti-counterfeiting pattern was designed using the phosphors. Static and dynamic identification was demonstrated and presented in detail. Finally, it is indicated that the studied phosphors are excellent candidates for potential applications in luminescence anti-counterfeiting labels.

Transcranial dipole localization and decoding study based on ultrasonic phased array for acoustoelectric brain imaging.

Objective. Neuroimaging is one of the effective tools to understand the functional activities of the brain, but traditional non-invasive neuroimaging techniques are difficult to combine both high temporal and spatial resolution to satisfy clinical needs. Acoustoelectric brain imaging (ABI) can combine the millimeter spatial resolution advantage of focused ultrasound with the millisecond temporal resolution advantage of electroencephalogram signals.Approach. In this study, we first explored the transcranial modulated acoustic field distribution based on ABI, and further localized and decoded single and double dipoles signals.Main results. The results show that the simulation-guided acoustic field modulation results are significantly better than those of self-focusing, which can realize precise modulation focusing of intracranial target focusing. The single dipole transcranial localization error is less than 0.4 mm and the decoding accuracy is greater than 0.93. The double dipoles transcranial localization error is less than 0.2 mm and the decoding accuracy is greater than 0.89.Significance. This study enables precise focusing of transcranial acoustic field modulation, high-precision localization of source signals and decoding of their waveforms, which provides a technical method for ABI in localizing evoked excitatory neuron areas and epileptic focus.

Dynamic ultrasound molecular-targeted imaging of senescence in evaluation of lapatinib resistance in HER2-positive breast cancer.

BACKGROUND: Prolonged treatment of HER2+ breast cancer with lapatinib (LAP) causes cellular senescence and acquired drug resistance, which often associating with poor prognosis for patients. We aim to explore the correlation between cellular senescence and LAP resistance in HER2+ breast cancer, screen for molecular marker of reversible senescence, and construct targeted nanobubbles for ultrasound molecular imaging to dynamically evaluate LAP resistance. METHODS AND RESULTS: In this study, we established a new cellular model of reversible cellular senescence using LAP and HER2+ breast cancer cells and found that reversible senescence contributed to LAP resistance in HER2+ breast cancer. Then, we identified ecto-5'-nucleotidase (NT5E) as a marker of reversible senescence in HER2+ breast cancer. Based on this, we constructed NT5E-targeted nanobubbles (NT5E-FITC-NBs) as a new molecular imaging modality which could both target reversible senescent cells and be used for ultrasound imaging. NT5E-FITC-NBs showed excellent physical and imaging characteristics. As an ultrasound contrast agent, NT5E-FITC-NBs could accurately identify reversible senescent cells both in vitro and in vivo. CONCLUSIONS: Our data demonstrate that cellular senescence-based ultrasound-targeted imaging can identify reversible senescence and evaluate LAP resistance effectively in HER2+ breast cancer cells, which has the potential to improve cancer treatment outcomes by altering therapeutic strategies ahead of aggressive recurrences.

Ice-confined synthesis of highly ionized 3D-quasilayered polyamide nanofiltration membranes.

Existing polyamide (PA) membrane synthesis protocols are underpinned by controlling diffusion-dominant liquid-phase reactions that yield subpar spatial architectures and ionization behavior. We report an ice-confined interfacial polymerization strategy to enable the effective kinetic control of the interfacial reaction and thermodynamic manipulation of the hexagonal polytype (Ih) ice phase containing monomers to rationally synthesize a three-dimensional quasilayered PA membrane for nanofiltration. Experiments and molecular simulations confirmed the underlying membrane formation mechanism. Our ice-confined PA nanofiltration membrane features high-density ionized structure and exceptional transport channels, realizing superior water permeance and excellent ion selectivity.

Nitrogen-Doped Carbon Dots Encapsulated a Polyoxomolybdate-Based Coordination Polymer as a Sensitive Platform for Trace Tetracycline Determination in Water.

The requirement of simple, efficient and accurate detection of tetracycline (TC) in water environments poses new challenges for sensing platform development. Here, we report a simple method for TC sensing via fluorescence detection based on metal-organic coordination polymers (MOCPs, (4-Hap)4(Mo8O26)) coated with nitrogen-doped carbon dots (NCDs). These NCDs@(4-Hap)4(Mo8O26) composites showed excellent luminescence features of NCDs with stable bright-blue emission under UV light. The results of the sensing experiment showed that the fluorescence of NCDs@(4-Hap)4(Mo8O26) can be quenched by TC (166 µM) with 94.1% quenching efficiency via the inner filter effect (IFE) in a short time (10 s), with a detection limit (LOD) of 33.9 nM in a linear range of 8-107 µM. More significantly, NCDs@(4-Hap)4(Mo8O26) showed a high selectivity for TC sensing in the presence of anions and metal cations commonly found in water environments and can be reused in at least six cycles after washing with alcohol. The potential practicality of NCDs@(4-Hap)4(Mo8O26) was verified by sensing TC in real water samples with the standard addition method, and satisfactory recoveries from 91.95% to 104.72% were obtained.

A cell image segmentation method based on edge feature residual fusion.

In recent years, cancer has seriously damaged human health, and the morphological structure of cells serves as an important basis for cancer diagnosis and grading. Automatic cell segmentation based on deep learning has become an important means of computer-aided pathological diagnosis. Aiming at the existing problems of rough segmentation boundaries and inaccurate segmentation in cell image segmentation, this paper designs a cell image segmentation network model (ERF-TransUNet) based on edge feature residual fusion from the perspective of mutual complementarity and constraint between edge features and object features. The model uses a hybrid architecture of CNN and Transformer to extract multi-scale features from cell images, and adds independent edge feature extraction modules and residual fusion modules to enhance the extraction of edge features and their constraints when fusing with cell object features, improving the accuracy of cell contour positioning. Through experiments on two gland cell datasets, CRAG and Glas, and comparing the segmentation effects with current popular deep learning models, the network model proposed in this paper has achieved good performance in both Dice coefficient and Hausdorff distance, which can effectively improve the segmentation effect of cell images.

TfOH-Catalyzed Cascade Reaction: Metal-Free Access to 3,3-Disubstituted Phthalides from o-Alkynylbenzoic Acids.

A facile new method for the synthesis of 3,3-disubstituted phthalides is reported. A successive reaction process begins with the TfOH-catalyzed cyclization of o-alkynylbenzoic acids followed by an ortho-regioselective electrophilic alkylation of various electron-rich aromatic compounds or alkenes, which has been successfully developed. The corresponding regioselective products of 3-substituted phthalide were obtained in good to high yields.

Aerosolization inhalation of non-typeable Haemophilus influenzae outer membrane vesicles contributing to neutrophilic asthma.

Background: Neutrophilic asthma is poorly responsive to corticosteroids, and the mechanism underlying its pathogenesis remains unclear. Non-typeable Haemophilus influenzae (NTHi) is the most common bacterium found in induced sputum from patients with neutrophilic asthma. NTHi can release outer membrane vesicles (OMVs), which transfer biomolecules to host cells and the external environment. However, the role and mechanisms of NTHi OMVs in the pathogenesis of neutrophilic asthma remain unclear. Methods: We conducted assays to investigate whether NTHi OMVs can induce neutrophilic asthma when inhaled. We isolated and purified NTHi OMVs and administered them via a nebulizer to ovalbumin (OVA)-sensitized mice. We collected and sequenced serum, blood, bronchoalveolar lavage fluid, and lung tissue from each group and gathered lung function data. Results: Inhaled NTHi OMVs-induced neutrophilic asthma in OVA-sensitized mice. High-throughput sequencing revealed that NTHi OMV inhalation in OVA-sensitized mice significantly enriched inflammatory and immune-related signaling pathways. We found increased transcription and secretion of interleukin (IL)-1ß and IL-17, which may contribute to neutrophilic asthma. Furthermore, we discovered that airway epithelium is the first receptor cell of NTHi OMVs and releases IL-1ß. These findings suggest that NTHi OMVs could be a potential target for neutrophilic asthma therapy.

Stability and Rheological Behavior of Mayonnaise-like Emulsion Co-Emulsified by Konjac Glucomannan and Whey Protein.

The aim of this work was to study the physical stability and rheological properties of an oil-in-water emulsion stabilized by a konjac glucomannan-whey protein (KGM-WP) mixture at a konjac glucomannan concentration of 0.1-0.5% (w/w) and a whey protein concentration of 1.0-3.0% (w/w). The droplet size, microstructure, stackability, flow behavior, and viscoelastic properties were measured. The experimental results showed that with an increase in KGM and WP concentrations, the droplet size (D4,3) of the emulsion gradually decreased to 12.9 µm, and the macroscopic performance of the emulsion was a gel-like structure that can be inverted and resist flow and can also be extruded and stacked. The static shear viscosity and viscoelasticity generally increased with the increase of konjac glucomannan and whey protein concentration. Emulsions were pseudo-plastic fluids with shear thinning behavior (flow behavior index: 0.15 ≤ n ≤ 0.49) and exhibited viscoelastic behavior with a storage modulus (G') greater than their loss modulus (G″), indicating that the samples all had gel-like behavior (0.10 < n' < 0.22). Moreover, storage modulus and loss modulus of all samples increased with increasing KGM and WP concentrations. When the concentration of konjac glucomannan was 0.3% w/w, the emulsion had similar rheological behavior to commercial mayonnaise. These results suggested that the KGM-WP mixture can be used as an effective substitute for egg yolk to make a cholesterol-free mayonnaise-like emulsion. The knowledge obtained here had important implications for the application of protein-polysaccharide mixtures as emulsifiers/stabilizers to make mayonnaise-like emulsions in sauce and condiments.