Vitamin D Receptor Activation Reduces Hepatic Inflammation via Enhancing Macrophage Autophagy in Cholestatic Mice.

Macrophage autophagy dysfunction aggravates liver injury by activating inflammasomes, which can cleave pro-IL-1ß to its active, secreted form. We investigated whether the vitamin D/vitamin D receptor (VDR) axis could up-regulate macrophage autophagy function to inhibit the activation of inflammasome-dependent IL-1ß during cholestasis. Paricalcitol (PAL; VDR agonist) was intraperitoneally injected into bile duct-ligated mice for 5 days. Up-regulation of VDR expression by PAL reduced liver injury by reducing the oxidative stress-induced inflammatory reaction in macrophages. Moreover, PAL inhibited inflammasome-dependent IL-1ß generation. Mechanistically, the knockdown of VDR increased IL-1ß generation, whereas VDR overexpression exerted the opposite effect following tert-butyl hydroperoxide treatment. The inflammasome antagonist glyburide, the caspase-1-specific inhibitor YVAD, and the reactive oxygen species (ROS) scavenger N-acetyl-l-cysteine (NAC) blocked the increase in Vdr shRNA-induced IL-1ß production. Interestingly, up-regulation of VDR also enhanced macrophage autophagy. Autophagy reduction impaired the up-regulation of VDR-inhibited macrophage inflammasome-generated IL-1ß, whereas autophagy induction showed a synergistic effect with VDR overexpression through ROS-p38 mitogen-activated protein kinase (MAPK) pathway. This result was confirmed by p38 MAPK inhibitor, MAPK activator, and ROS inhibitor NAC. Collectively, PAL triggered macrophage autophagy by suppressing activation of the ROS-p38 MAPK pathway, which, in turn, suppressed inflammasome-generated cleaved, active forms of IL-1ß, eventually leading to reduced inflammation. Thus, triggering the VDR may be a potential target for the anti-inflammatory treatment of cholestatic liver disease.

Astrocyte-derived lactoferrin inhibits neuronal ferroptosis by reducing iron content and GPX4 degradation in APP/PS1 transgenic mice.

Increased astrocytic lactoferrin (Lf) expression was observed in the brains of elderly individuals and Alzheimer's disease (AD) patients. Our previous study revealed that astrocytic Lf overexpression improved cognitive capacity by facilitating Lf secretion to neurons to inhibit ß-amyloid protein (Aß) production in APP/PS1 mice. Here, we further discovered that astrocytic Lf overexpression inhibited neuronal loss by decreasing iron accumulation and increasing glutathione peroxidase 4 (GPX4) expression in neurons within APP/PS1 mice. Furthermore, human Lf (hLf) treatment inhibited ammonium ferric citrate (FAC)-induced ferroptosis by chelating intracellular iron. Additionally, machine learning analysis uncovered a correlation between Lf and GPX4. hLf treatment boosted low-density lipoprotein receptor-related protein 1 (LRP1) internalization and facilitated its interaction with heat shock cognate 70 (HSC70), thereby inhibiting HSC70 binds to GPX4, and eventually attenuating GPX4 degradation and FAC-induced ferroptosis. Overall, astrocytic Lf overexpression inhibited neuronal ferroptosis through two pathways: reducing intracellular iron accumulation and promoting GPX4 expression via inhibiting chaperone-mediated autophagy (CMA)-mediated GPX4 degradation. Hence, upregulating astrocytic Lf expression is a promising strategy for combating AD.

From zinc homeostasis to disease progression: Unveiling the neurodegenerative puzzle.

Zinc is a crucial trace element in the human body, playing a role in various physiological processes such as oxidative stress, neurotransmission, protein synthesis, and DNA repair. The zinc transporters (ZnTs) family members are responsible for exporting intracellular zinc, while Zrt- and Irt-like proteins (ZIPs) are involved in importing extracellular zinc. These processes are essential for maintaining cellular zinc homeostasis. Imbalances in zinc metabolism have been linked to the development of neurodegenerative diseases. Disruptions in zinc levels can impact the survival and activity of neurons, thereby contributing to the progression of neurodegenerative diseases through mechanisms like cell apoptosis regulation, protein phase separation, ferroptosis, oxidative stress, and neuroinflammation. Therefore, conducting a systematic review of the regulatory network of zinc and investigating the relationship between zinc dysmetabolism and neurodegenerative diseases can enhance our understanding of the pathogenesis of these diseases. Additionally, it may offer new insights and approaches for the treatment of neurodegenerative diseases.

A Message Passing-Assisted Iterative Noise Cancellation Method for Clipped OTFS-BFDM Systems.

Compared with orthogonal frequency division multiplexing (OFDM) systems, orthogonal time frequency space systems based on bi-orthogonal frequency division multiplexing (OTFS-BFDM) have lower out-of-band emission (OOBE) and better robustness to high-mobility scenarios, but suffer from a higher peak-to-average ratio (PAPR) in large data packets. In this paper, one-iteration clipping and filtering (OCF) is adopted to reduce the PAPR of OTFS-BFDM signals. However, the extra noise introduced by the clipping process, i.e., clipping noise, will distort the desired signal and increase the bit error rate (BER). We propose a message passing (MP)-assisted iterative cancellation (MP-AIC) method to cancel the clipping noise based on the traditional MP decoding at the receiver, which incorporates with the (OCF) at the transmitter to keep the sparsity of the effective channel matrix. The main idea of MP-AIC is to extract the residual signal fed to the MP detector by iteratively constructing reference clipping noise at the receiver. During each iteration, the variance of residual signal and channel noise are taken as input parameters of MP decoding to improve the BER. Moreover, the convergence probability of the modulation alphabet after MP decoding in the current iteration is used as the initial probability of MP decoding in the next iteration to accelerate the convergence rate of MP decoding. Simulation results show that the proposed MP-AIC method significantly improves MP-decoding accuracy while accelerating the BER convergence in the clipped OTFS-BFDM system. In the clipped OTFS-BFDM system with rectangular pulse shaping, the BER of MP-AIC with two iterations can be reduced by 72% more than that without clipping noise cancellation.

Slope with Predetermined Shear Plane Stability Predictions under Cyclic Loading with Innovative Time Series Analysis by Mechanical Learning Approach.

We propose a mechanical learning method that can be used to predict stability coefficients for slopes where slopes with predetermined shear planes are subjected to cyclic seismic loads under undrained conditions. Firstly, shear tests with cyclic loading of different parameters were simulated on designated slip zone soil specimens, in which the strain softening process leading to landslide occurrence was closely observed. At the same time, based on the limit equilibrium analysis of the Sarma method, the variation of slope stability coefficients under different cyclic loads was investigated. Finally, a Box-Jenkins' modeling approach is used to predict the data from the time series of slope stability coefficients using a mechanical learning approach. The simulation results show that (1) reduction in coordination number can be an accurate indicator of the level of strain softening and evolutionary processes; (2) the gradual reduction of shear stress facilitates the soil strain softening process, while different cyclic loading stress amplitudes will result in rapid penetration or non-penetration of the fracture zone by means of particulate flow. Although the confining pressure of the slip zone soil can inhibit the increase of fractures, it has a limited inhibitory effect on strain softening; (3) based on field observations of the slope stability factor and stress field, two possible landslide triggering mechanisms are described. (4) Mechanical learning of time series can accurately predict the changing pattern of stability coefficients of slopes without loading. This study establishes a potential bridge between the geological investigation of landslides and the theoretical background of landslide stability coefficient prediction.

Determination of Blasting Vibration Safety Criterion for HDPE Pipeline Using Vibration and Strain Data in a Coastal Metro Line.

A key aspect of urban blasting engineering is evaluating the safety of the blasting dynamic load on the adjacent high-density polyethylene water supply pipeline and controlling the negative impact of the blasting vibration load on the pipeline. According to the special characteristics of the soil layer in Shenzhen coastal city, a field blasting test of a full-scale pre-buried HDPE pipeline was carried out, and the distribution characteristics of the blasting vibration velocity and dynamic strain were analyzed. The finite element model was established by LSDYNA, and the reliability of the calculation model and parameters was verified by comparing with the field test data. At the same time, the dynamic response characteristics of pipelines with different buried depths, operating water conveyance pressures, and diameters under blasting vibration loads were studied. Combined with the circumferential allowable stress control criterion of the pipeline, the safety control standard of the blasting vibration velocity of the HDPE water supply pipeline under different working conditions was proposed. The results show that the circumferential compressive strain of the HDPE pipe is the most affected by blasting vibration, and the pipe with the shortest blasting center distance has the largest response. The vibration velocity and equivalent stress of the pipeline increase with the increase of buried depth, internal pressure, and diameter. The vibration velocity and equivalent stress of the explosion side at the same section of the pipeline are greater than those of the back explosion side. Based on the dimensionless analysis, the vibration velocity prediction model of the buried depth, operating pressure, and diameter of the pipeline is proposed. The safety control velocity of the pipeline is 25 cm/s, and the vibration velocity of the upper surface is 22.5 cm/s according to the Mises yield strength criterion.

Potential Application Prospects of Biomolecule-Modified Two-Dimensional Chiral Nanomaterials in Biomedicine.

Chirality, one of the most fundamental properties of natural molecules, plays a significant role in biochemical reactions. Nanomaterials with chiral characteristics have superior properties, such as catalytic properties, optoelectronic properties, and photothermal properties, which have significant potential for specific applications in nanomedicine. Biomolecular modifications such as nucleic acids, peptides, proteins, and polysaccharides are sources of chirality for nanomaterials with great potential for application in addition to intrinsic chirality, artificial macromolecules, and metals. Two-dimensional (2D) nanomaterials, as opposed to other dimensions, due to proper surface area, extensive modification sites, drug loading potential, and simplicity of preparation, are prepared and utilized in diagnostic applications, drug delivery research, and tumor therapy. Current advanced studies on 2D chiral nanomaterials for biomedicine are focused on novel chiral development, structural control, and materials sustainability applications. However, despite the advances in biomedical research, chiral 2D nanomaterials still confront challenges such as the difficulty of synthesis, quality control, batch preparation, chiral stability, and chiral recognition and selectivity. This review aims to provide a comprehensive overview of the origins, synthesis, applications, and challenges of 2D chiral nanomaterials with biomolecules as cargo and chiral modifications and highlight their potential roles in biomedicine.

Osmundacetone ameliorates Alzheimer's-like pathologies by inhibiting ß-amyloid fibrillation, oxidative damage and neuroinflammation in APP/PS1 transgenic mice.

BACKGROUND: ß-Amyloid (Aß) fibrillation is critical for Aß deposition and cytotoxicity during the progression of Alzheimer's disease (AD). Consequently, anti-Aß monoclonal antibody drugs targeting Aß oligomers and aggregation are considered potential therapeutic strategies for AD treatment. Similar to the working mechanisms of anti-Aß monoclonal antibody drugs, our study identified osmundacetone (OAC), a small-molecule compound isolated from the traditional Chinese medicine Rhizoma Osmundae, as exerting anti-AD effects by targeting Aß. PURPOSE: This study sought to determine whether OAC influences the Aß burden in APP/PS1 mice and to identify potential regulatory mechanisms. METHODS: Five-month-old APP/PS1 mice were injected intraperitoneally with OAC at a dose of 1 mg/kg for 12 weeks. The cognitive functions of the mice were assessed via the Morris water maze test and the open field test. Osmundacetone was analyzed via molecular docking, an isothermal dose‒response fingerprint-cellular context thermal shift assay, a thioflavine T fluorescence assay, and an atomic force microscopy assay to analyze the effects of OAC on Aß fibrillation. Immunofluorescence, immunoblotting, and immunohistochemistry were used to assess Aß clearance, AD pathology, oxidative stress, and inflammatory responses. RESULTS: The innovative biochemical and physical data illustrated that the ability of OAC to inhibit Aß fibrillation was accomplished by binding directly to Aß, which differed from the majority of previously reported natural polyphenols that modulate the Aß content and structure in an indirect manner. The inhibition of Aß fibrosis by OAC subsequently promoted Aß lysosomal degradation, resulting in a decreased Aß burden in APP/PS1 mice. Furthermore, OAC treatment inhibited oxidative damage by upregulating glutathione peroxidase expression and attenuated the production of inflammatory factors by downregulating nuclear factor-kB phosphorylation in APP/PS1 mice. CONCLUSION: These findings demonstrate, for the first time, that OAC could reduce the brain Aß burden in APP/PS1 mice by inhibiting Aß fibrillation through direct binding to Aß and improve cognitive dysfunction by attenuating oxidative damage and neuroinflammation. These findings indicate that OAC may be a promising candidate for the treatment of AD.

Astrocyte-derived lactoferrin reduces ß-amyloid burden by promoting the interaction between p38 kinase and PP2A phosphatase in male APP/PS1 transgenic mice.

BACKGROUND AND PURPOSE: Overexpression of astrocytic lactoferrin (Lf) was observed in the brain of Alzheimer's disease (AD) patients, whereas the role of astrocytic Lf in AD progression remains unexplored. In this study, we aimed to evaluate the effects of astrocytic Lf on AD progression. EXPERIMENTAL APPROACH: Male APP/PS1 mice with astrocytes overexpressing human Lf were developed to evaluate the effects of astrocytic Lf on AD progression. N2a-sw cells also were employed to further uncover the mechanism of astrocytic Lf on ß-amyloid (Aß) production. KEY RESULTS: Astrocytic Lf overexpression increased protein phosphatase 2A (PP2A) activity and reduced amyloid precursor protein (APP) phosphorylation, Aß burden and tau hyperphosphorylation in APP/PS1 mice. Mechanistically, astrocytic Lf overexpression promoted the uptake of astrocytic Lf into neurons in APP/PS1 mice, and conditional medium from astrocytes overexpressing Lf inhibited p-APP (Thr668) expression in N2a-sw cells. Furthermore, recombinant human Lf (hLf) significantly enhanced PP2A activity and inhibited p-APP expression, whereas inhibition of p38 or PP2A activities abrogated the hLf-induced p-APP down-regulation in N2a-sw cells. Additionally, hLf promoted the interaction of p38 and PP2A via p38 activation, thereby enhancing PP2A activity, and low-density lipoprotein receptor-related protein 1 (LRP1) knockdown significantly reversed the hLf-induced p38 activation and p-APP down-regulation. CONCLUSIONS AND IMPLICATIONS: Our data suggested that astrocytic Lf promoted neuronal p38 activation, via targeting to LRP1, subsequently promoting p38 binding to PP2A to enhance PP2A enzyme activity, which finally inhibited Aß production via APP dephosphorylation. In conclusion, promoting astrocytic Lf expression may be a potential strategy against AD. LINKED ARTICLES: This article is part of a themed issue From Alzheimer's Disease to Vascular Dementia: Different Roads Leading to Cognitive Decline. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.6/issuetoc.

Identification of AS1842856 as a novel small-molecule GSK3α/ß inhibitor against Tauopathy by accelerating GSK3α/ß exocytosis.

Glycogen synthase kinase-3α/ß (GSK3α/ß) is a critical kinase for Tau hyperphosphorylation which contributes to neurodegeneration. Despite the termination of clinical trials for GSK3α/ß inhibitors in Alzheimer's disease (AD) treatment, there is a pressing need for novel therapeutic strategies targeting GSK3α/ß. Here, we identified the compound AS1842856 (AS), a specific forkhead box protein O1 (FOXO1) inhibitor, reduced intracellular GSK3α/ß content in a FOXO1-independent manner. Specifically, AS directly bound to GSK3α/ß, promoting its translocation to the multivesicular bodies (MVBs) and accelerating exocytosis, ultimately decreasing intracellular GSK3α/ß content. Expectedly, AS treatment effectively suppressed Tau hyperphosphorylation in cells exposed to okadaic acid or expressing the TauP301S mutant. Furthermore, AS was visualized to penetrate the blood-brain barrier (BBB) using an imaging mass microscope. Long-term treatment of AS enhanced cognitive function in P301S transgenic mice by mitigating Tau hyperphosphorylation through downregulation of GSK3α/ß expression in the brain. Altogether, AS represents a novel small-molecule GSK3α/ß inhibitor that facilitates GSK3α/ß exocytosis, holding promise as a therapeutic agent for GSK3α/ß hyperactivation-associated disorders.

Operation characteristics of soil blasting vibration test device under vibration load.

To improve the accuracy of vibration velocity monitoring during blasting in soil layers, this paper provides a method and device for data correction by combining finite element software and actual engineering test data. Based on the length of the test pedestal exposed to the surface of the geotechnical body, the finite element structural model corresponding to each length of the test pedestal is established. Moreover, a predetermined external excitation load is applied outside the finite element model and the correction function of the vibration data is obtained by analysis of the stress and vibration data. The device solves the problem of low accuracy of vibration velocity measurement in soil and establishes a correction method for measurement data. The results show the following: (1) With the propagation of blasting seismic waves, the maximum stress values of the test device appear in the footwall position, the middle of the extension rod, and the bottom position in that order. (2) At the end of the test, there is an obvious phenomenon of speed amplification at the top of the test device. (3) As the length of the test device exposed to the ground increases, the particle peak vibration velocity (PPV) of the test device varies exponentially with the PPV of the ground and the range of variation of the vibration velocity in the X-direction is the largest.

Theoretical analysis of the deformation for steel gas pipes taking into account shear effects under surface explosion loads.

Ground blast loads are of great importance to the safe operation of steel and gas pipelines, and the results obtained from traditional theoretical formulas for pipeline safety prediction are in error with the actual measured data. In this paper, full-size field tests and corresponding numerical simulations are carried out using Timoshenko beam theory and explosion stress wave theory, which consider shear effects. At the same time, combined with the theory of foundation stiffness and pipeline stiffness flexibility ratio, a modified theoretical model is obtained in line with the actual conditions of the site, which can accurately calculate the deformation and displacement of pipeline underground explosion load, and greatly reduce the error of theoretical prediction results. The innovation of the research results in this paper is that the theoretical stress in the Timoshenko beam can be replaced by the circumferential strain. On the other hand, the modified theoretical solution can obtain the critical weight of explosives to prevent pipeline damage at different buried depths. It provides a theoretical basis for the protection of pipelines' underground blast loads and provides research ideas for the safe protection and design of pipelines.

Activation of vitamin D receptor inhibits Tau phosphorylation is associated with reduction of iron accumulation in APP/PS1 transgenic mice.

Vitamin D deficiency and iron accumulation are prevalent in the brains of Alzheimer's disease (AD) patients, however, whether Vitamin D has a role in the regulations of iron metabolism in the condition of AD remains unknown. Our previous studies revealed that vitamin D deficiency promotes ß-amyloid (Aß) deposition in the APP/PS1 mouse brains, while supplemented with a specific agonist of vitamin D receptor (VDR), paricalcitol (PAL), significantly reduced Aß production via promoting the lysosomal degradation of ß-site APP cleavage enzyme 1 (BACE1). In this study, our data suggested that activation of VDR by PAL significantly reduced the iron accumulation in the cortex and hippocampus of APP/PS1 mice through downregulation of Transferrin receptor (TFR) by reducing iron-regulatory protein 2 (IRP2) expression. Furthermore, activation of VDR effectively reduced the phosphorylations of Tau at Ser396 and Thr181 sites via inhibiting the GSK3ß phosphorylation (Tyr216). Taken together, our data suggest that activation of VDR could inhibit the phosphorylations of Tau possibly by repressing the iron accumulation-induced upregulation of GSK3ß activity in the brains of APP/PS1 mice. Thus, activation of VDR may be an effective strategy for treating AD.

The Effect of Polysaccharides on Preventing Proteins and Cholesterol from Being Adsorbed on the Surface of Orthokeratology Lenses.

The adsorption of tear film compositions such as proteins and lipids on the orthokeratology lenses often lead to infection or corneal damage. In order to investigate whether polysaccharides could prevent tear compositions from being adsorbed on the lens, alginic acid and lambda-carrageenan were added into artificial tear solution. By measuring daily adsorption of cholesterol, lysozyme, and albumin, our results showed that polysaccharides could weakly prevent cholesterol adsorption. In addition, polysaccharides could also reduce albumin deposition over time. Although the effect of polysaccharides on lysozyme adsorption was distinct depending on the concentrations of polysaccharides, the overall results demonstrated that polysaccharides could decrease protein deposition over time. Our results provided an in vitro evidence that polysaccharides may be applied as coating materials on the lens or as the composition of artificial tear solutions or eyedrops, in order to prevent adsorption of tear film compositions that may lead to a reduced incidence of infection or corneal damage for orthokeratology lens wearers.

An innovative test equipment with rate-dependence in interface damage and its operation under cyclic loading.

An innovative test equipment for analyzing the dynamic damage at the interface of geosynthetic materials is introduced. It provides a result of shear damage on the structural surface of a geosynthetic material that has been subjected to cyclic loading of different amplitudes. First, the experimental data of geosynthetics under cyclic loading are obtained based on the innovative test equipment mentioned above, and a mathematical identification method for the relationship between cyclic loading parameters and shear mechanical behavior of geosynthetics is proposed based on the Mohr-Coulomb criterion, assuming that the micro-element strength of geosynthetics follows Weibull distribution. Moreover, the proposed model, which takes into account repeated loading-unloading conditions, enables this simulated damage process to have properties of reoccurring load cycles, and the proposed method was evaluated by experimental datasets from this study and the existing literature and proved to have a satisfying performance in predicting mechanical behavior of shear stress in geosynthetics under different cyclic loadings. Second, the self-developed test instrument can well solve the direct shear parameters of geosynthetics under dynamic load and can be obtained as a new dynamic statistical model with rate-dependence in interface damage.

Robust Scalable-Manufactured Smart Fabric Surfaces Based on Azobenzene-Containing Maleimide Copolymers for Rewritable Information Storage and Hydrogen Fluoride Visual Sensor.

Functionalized materials with reversible color switching are highly attractive in many application fields, especially as rewritable media for information storage. It is critical yet challenging to develop a cost-effective strategy for the fabrication of stimulus-responsive chromogenic systems. Herein, we present a versatile dip-coating approach to fabricate robust smart textile with acid/base-driven chromotropic capability. Owing to the introduction of novel maleimide-based copolymers bearing azobenzene derivative moieties, smart textiles possess rapid color switching between yellow and orange-red, which is triggered by acid-base stimulations with the resulting reversible protonation/deprotonation of maleimide moieties. As a proof of concept of the application of the smart textile for high-performance rewritable media, various rewritable elaborate patterns can be fast trifluoroacetic acid-printed/triethylamine-erased (within 20 s) with excellent cycling stability and long legible duration (>30 days). Meanwhile, the smart textile can be employed as a visual sensor for the detection of hydrogen fluoride gas leakage. It is highlighted that the as-prepared robust smart textiles with superhydrophobic surfaces have excellent antifouling properties and chemical/mechanical stabilities, which can tolerate harsh environmental conditions and repetitive mechanical deformation. The robust smart textiles with simple low-cost large-scale production may find more advanced potential applications besides information storage and sensors demonstrated.

Vitamin D deficiency exacerbates Alzheimer-like pathologies by reducing antioxidant capacity.

Vitamin D (VD) deficiency is prevalent among aging people and Alzheimer's disease (AD) patients. However, the roles of VD deficiency in the pathology of AD remain largely unexplored. In this study, APP/PS1 mice were fed a VD-deficient diet for 13 weeks to evaluate the effects of VD deficiency on the learning and memory functions and the neuropathological characteristics of the mice. Our study revealed that VD deficiency accelerated cognitive impairment in the APP/PS1 mice. Mechanistic studies revealed that VD deficiency promoted glial activation and increased inflammatory factor secretion. Furthermore, VD deficiency increased the production and deposition of Aß by elevating the expression levels of amyloid precursor protein (APP) and ß-site APP cleavage enzyme 1 (BACE1). In addition, VD deficiency increased the phosphorylation of Tau at Thr181, Thr205 and Ser396 by increasing the activities of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3α/ß (GSK3α/ß) and promoted synaptic dystrophy and neuronal loss. All these effects of VD deficiency may be ascribed to enhanced oxidative stress via the downregulation of superoxide dismutase 1 (SOD1), glutathione peroxidase 4 (GPx4) and cystine/glutamate exchanger (xCT). Taken together, our data suggest that VD deficiency exacerbates Alzheimer-like pathologies via promoting inflammatory stress, increasing Aß production and elevating Tau phosphorylation by decreasing antioxidant capacity in the brains of APP/PS1 mice. Hence, rescuing the VD status of AD patients should be taken into consideration during the treatment of AD.