The Intersection of cerebral cholesterol metabolism and Alzheimer's disease: Mechanisms and therapeutic prospects.

Alzheimer's disease (AD) is a common neurodegenerative disease in the elderly, the exact pathogenesis of which remains incompletely understood, and effective preventive and therapeutic drugs are currently lacking. Cholesterol plays a vital role in cell membrane formation and neurotransmitter synthesis, and its abnormal metabolism is associated with the onset of AD. With the continuous advancement of imaging techniques and molecular biology methods, researchers can more accurately explore the relationship between cholesterol metabolism and AD. Elevated cholesterol levels may lead to vascular dysfunction, thereby affecting neuronal function. Additionally, abnormal cholesterol metabolism may affect the metabolism of ß-amyloid protein, thereby promoting the onset of AD. Brain cholesterol levels are regulated by multiple factors. This review aims to deepen the understanding of the subtle relationship between cholesterol homeostasis and AD, and to introduce the latest advances in cholesterol-regulating AD treatment strategies, thereby inspiring readers to contemplate deeply on this complex relationship. Although there are still many unresolved important issues regarding the risk of brain cholesterol and AD, and some studies may have opposite conclusions, further research is needed to enrich our understanding. However, these findings are expected to deepen our understanding of the pathogenesis of AD and provide important insights for the future development of AD treatment strategies targeting brain cholesterol homeostasis.

Deciphering the intricate linkage between the gut microbiota and Alzheimer's disease: Elucidating mechanistic pathways promising therapeutic strategies.

BACKGROUND: The gut microbiome is composed of various microorganisms such as bacteria, fungi, and protozoa, and constitutes an important part of the human gut. Its composition is closely related to human health and disease. Alzheimer's disease (AD) is a neurodegenerative disease whose underlying mechanism has not been fully elucidated. Recent research has shown that there are significant differences in the gut microbiota between AD patients and healthy individuals. Changes in the composition of gut microbiota may lead to the development of harmful factors associated with AD. In addition, the gut microbiota may play a role in the development and progression of AD through the gut-brain axis. However, the exact nature of this relationship has not been fully understood. AIMS: This review will elucidate the types and functions of gut microbiota and their relationship with AD and explore in depth the potential mechanisms of gut microbiota in the occurrence of AD and the prospects for treatment strategies. METHODS: Reviewed literature from PubMed and Web of Science using key terminologies related to AD and the gut microbiome. RESULTS: Research indicates that the gut microbiota can directly or indirectly influence the occurrence and progression of AD through metabolites, endotoxins, and the vagus nerve. DISCUSSION: This review discusses the future challenges and research directions regarding the gut microbiota in AD. CONCLUSION: While many unresolved issues remain regarding the gut microbiota and AD, the feasibility and immense potential of treating AD by modulating the gut microbiota are evident.

The Oligomeric State of Vasorin in the Plasma Membrane Measured Non-Invasively by Quantitative Fluorescence Fluctuation Spectroscopy.

Vasorin (VASN), a transmembrane protein heavily expressed in endothelial cells, has garnered recent interest due to its key role in vascular development and pathology. The oligomeric state of VASN is a crucial piece of knowledge given that receptor clustering is a frequent regulatory mechanism in downstream signaling activation and amplification. However, documentation of VASN oligomerization is currently absent. In this brief report, we describe the measurement of VASN oligomerization in its native membranous environment, leveraging a class of fluorescence fluctuation spectroscopy. Our investigation revealed that the majority of VASN resides in a monomeric state, while a minority of VASN forms homodimers in the cellular membrane. This result raises the intriguing possibility that ligand-independent clustering of VASN may play a role in transforming growth factor signaling.

The Impact of the Fluid-Solid Coupling Behavior of Macro and Microstructures in the Spiral Cochlea on Hearing.

The cilia of the outer hair cells (OHCs) are the key microstructures involved in cochlear acoustic function, and their interactions with lymph in the cochlea involve complex, highly nonlinear, coupled motion and energy conversions, including macroscopic fluid-solid coupling. Recent optical measurements have shown that the frequency selectivity of the cochlea at high sound levels is entirely mechanical and is determined by the interactions of the hair bundles with the surrounding fluid. In this paper, an analytical mathematical model of the spiral cochlea containing macro- and micromeasurements was developed to investigate how the phonosensitive function of OHCs' motions is influenced by the macrostructural and microstructural fluid-solid coupling in the spiral cochlea. The results showed that the macrostructural and microstructural fluid-solid coupling exerted the radial forces of OHCs through the flow field, deflecting the cilia and generating frequency-selective properties of the microstructures. This finding showed that microstructural frequency selectivity arises from the radial motions of stereocilia hair bundles and enhances the hearing of sound signals at specific frequencies. It also implied that the macrostructural and microstructural fluid-solid couplings influence the OHCs' radial forces and that this is a key factor in the excitation of ion channels that enables their activity in helping the brain to detect sound.

The ß2-adrenergic receptor associates with CXCR4 multimers in human cancer cells.

While the existence and functional role of class C G-protein-coupled receptors (GPCR) dimers is well established, there is still a lack of consensus regarding class A and B GPCR multimerization. This lack of consensus is largely due to the inherent challenges of demonstrating the presence of multimeric receptor complexes in a physiologically relevant cellular context. The C-X-C motif chemokine receptor 4 (CXCR4) is a class A GPCR that is a promising target of anticancer therapy. Here, we investigated the potential of CXCR4 to form multimeric complexes with other GPCRs and characterized the relative size of the complexes in a live-cell environment. Using a bimolecular fluorescence complementation (BiFC) assay, we identified the ß2 adrenergic receptor (ß2AR) as an interaction partner. To investigate the molecular scale details of CXCR4-ß2AR interactions, we used a time-resolved fluorescence spectroscopy method called pulsed-interleaved excitation fluorescence cross-correlation spectroscopy (PIE-FCCS). PIE-FCCS can resolve membrane protein density, diffusion, and multimerization state in live cells at physiological expression levels. We probed CXCR4 and ß2AR homo- and heteromultimerization in model cell lines and found that CXCR4 assembles into multimeric complexes larger than dimers in MDA-MB-231 human breast cancer cells and in HCC4006 human lung cancer cells. We also found that ß2AR associates with CXCR4 multimers in MDA-MB-231 and HCC4006 cells to a higher degree than in COS-7 and CHO cells and in a ligand-dependent manner. These results suggest that CXCR4-ß2AR heteromers are present in human cancer cells and that GPCR multimerization is significantly affected by the plasma membrane environment.

Vibration modes of three-dimensional spiral cochlea covering the organ of Corti.

So far, explaining the mechanism on active phonosensitive amplification in the cochlea is a major and difficult medical question. Among them, one of the key problems is that the motion pattern of the organ of Corti (OC) is still unknown. To this end, a multi-scale cochlear model including a three-dimensional spiral OC was established based on CT data and light source imaging experimental data, which complete combined the macroscopic and microscopic structure. On the basis of verifying the reliability of the model, acoustic-solid coupling calculation and modal analysis were performed on the model, and the vibration modes of basilar membrane (BM) and structures of the OC at different characteristic frequencies were discussed. The results show that tectorial membrane (TM) exhibits completely different vibration modes from BM at low frequencies, while the two movements gradually synchronize as the frequency increases. The amplitude position of OC's motion moves laterally with increasing frequency from Deiters' cells to Hensen's cells and then back to Deiters' cells. The OC exhibits longitudinal vibrations following BM when BM's displacement is large, while it manifests more as lateral movement of Deiters' cells when BM's displacement is small. This model can well simulate the motion process of BM and OC in the lymphatic fluid, which provides theoretical support and a numerical simulation computational platform to explore the interaction between macroscopic and microscopic tissue structures of the overall cochlea.

Pathogenic mechanism analysis of cochlear key structural lesion and phonosensitive hearing loss.

Due to ethical issues and the very fine and complex structure of the cochlea, it is difficult to directly perform experimental measurement on the human cochlea. Therefore, the finite element method has become an effective and replaceable new research means. Accurate numerical analysis on human ear using finite element method can provide better understanding of sound transmission and can be used to assess the influence of diseases on hearing and to treat hearing loss. In this research, a three-dimensional (3D) finite element model (FEM) of the human ear of cochlea was presented to investigate the destruction of basilar membrane (BM), round window (RW) sclerosis and perilymph fistula, the key structures of the cochlea, and analyze the effects of these abnormal pathological states in the cochlea on cochlear hearing, resulting in the changes in cochlear sense structure biomechanical behavior and quantitative prediction of the degree and harm of the disorder to the decline of human hearing. Therefore, this paper can deepen reader's understanding of the cochlear biomechanical mechanism and provide a theoretical foundation for clinical otology.

Temperate grassland vegetation restoration influenced by grazing exclusion and climate change.

Grasslands are one of the most important terrestrial biomes, supporting a wide range of ecological functions and services. Grassland degradation due to overgrazing is a severe issue worldwide, especially in developing regions. However, observations from multiple sources have shown that temperate grasslands in China have significantly increased during the past two decades. It remains controversial what factors have driven the vegetation restoration in this region. In this study, we combined remote-sensing images and field survey datasets to quantify the contributions of different factors to vegetation restoration in six temperate grasslands in northern China. Across the six grasslands, the Normalized Difference Vegetation Index (NDVI) increased by 0.003-0.0319 year-1. The average contributions of grazing exclusion and climate change to the NDVI increase were 49.23 % and 50.77 %, respectively. Precipitation change was the primary climate factor driving vegetation restoration, contributing 50.76 % to the NDVI variance. By contrast, climate warming tended to slow vegetation restoration, and atmospheric CO2 concentration change contributed little to the NDVI increase in the temperate grasslands. These results emphasize the significant contributions of both climate change and human management to grassland vegetation restoration.

Study on damage of the macrostructure of the cochlea under the impact load.

Due to the tiny and delicate structure of the cochlea, the auditory system is the most sensitive to explosion impact damage. After being damaged by the explosion impact wave, it usually causes long-term deafness, tinnitus, and other symptoms. To better understand the influence of impact load on the cochlea and basilar membrane (BM), a three-dimensional (3D) fluid-solid coupling finite element model was developed. This model accurately reflects the actual spatial spiral shape of the human cochlea, as well as the lymph environment and biological materials. Based on verifying the reliability of the model, the curve of impact load-amplitude response was obtained, and damage of impact load on the cochlea and the key macrostructure-BM was analyzed. The results indicate that impact wave at middle frequency has widest influence on the cochlea. Furthermore, impact loading causes tears in the BM and destroys the cochlear frequency selectivity.

Decoding the role of gut microbiota in Alzheimer's pathogenesis and envisioning future therapeutic avenues.

Alzheimer's disease (AD) emerges as a perturbing neurodegenerative malady, with a profound comprehension of its underlying pathogenic mechanisms continuing to evade our intellectual grasp. Within the intricate tapestry of human health and affliction, the enteric microbial consortium, ensconced within the milieu of the human gastrointestinal tract, assumes a role of cardinal significance. Recent epochs have borne witness to investigations that posit marked divergences in the composition of the gut microbiota between individuals grappling with AD and those favored by robust health. The composite vicissitudes in the configuration of the enteric microbial assembly are posited to choreograph a participatory role in the inception and progression of AD, facilitated by the intricate conduit acknowledged as the gut-brain axis. Notwithstanding, the precise nature of this interlaced relationship remains enshrouded within the recesses of obscurity, poised for an exhaustive revelation. This review embarks upon the endeavor to focalize meticulously upon the mechanistic sway exerted by the enteric microbiota upon AD, plunging profoundly into the execution of interventions that govern the milieu of enteric microorganisms. In doing so, it bestows relevance upon the therapeutic stratagems that form the bedrock of AD's management, all whilst casting a prospective gaze into the horizon of medical advancements.

Agricultural HANPP Embodied in Consumption: Tracing Pressure on Ecosystems Based on an MRIO Analysis.

Agriculture is one of humankind's most significant sources of biomass; it also places tremendous pressure on ecosystems through its increasing demand for agricultural products. However, few studies have assessed human pressures on ecosystems from agricultural production and consumption based on a whole-supply-chain perspective. Based on the concept of human appropriation of net primary productivity (HANPP), we evaluate trends of agricultural HANPP embodied in consumption from a global perspective and trace the pressure from agriculture production that is exerted on the environment using an environmentally extended multiregional input-output (MRIO) model. The results show that agricultural HANPP embodied in consumption accounted for over two-thirds of total HANPP but brought about less than 7% of global value added. India, Brazil, and China were found to have the highest level of agricultural HANPP embodied in consumption. Agricultural net exporters were found to usually be low- and lower-income countries, while net importers are found to be high-income countries. According to the driving factor analysis, high-income and low-income countries should cooperate by adjusting consumption patterns and sharing agricultural technology to alleviate the pressure from agricultural production. Our study highlights the importance of agrarian expertise sharing and the need to develop sustainable and green agricultural production.

Effects of basilar-membrane lesions on dynamic responses of the middle ear.

BACKGROUND: Numerical simulations can reflect the changes in physiological properties caused by various factors in the cochlea. AIMS/OBJECTIVE: To analyze the influence of lesions of the basilar membrane (BM) on the dynamic response of the middle ear. METHOD: Based on healthy human ear CT scan images, use PATRAN software to build a three-dimensional finite element model of the human ear, then apply NASTRAN software to conduct analysis of solid-fluid coupled frequency response. The influence of lesions in the BM on the dynamic response of the middle ear is simulated through the method of numerical simulation. RESULT: Through comparing experimental data and the frequency-response curve of displacement of BM and stapes, the validity of the model in this paper was verified. CONCLUSION: Regarding sclerosis in BM, the most obvious decline of displacement and velocity exists in the range of 800-10,000Hz and 800-2000Hz frequency, respectively. The higher degree of sclerosis, the more obvious decline becomes. The maximal decline of hearing can reach from 6.2 dB to 9.1 dB. Regarding added mass in BM, the most obvious decline of displacement exists in the range of 600-1000Hz frequency, and the maximal decline of hearing can reach 4.0 dB. There is no obvious decline in velocity.

Measurement and Coupling Coordination of High-Quality Development in Guangdong Province of China: A Spatiotemporal Analysis.

Regional high-quality coordination plays a crucial role in promoting high-quality national development. Guangdong province is a trailblazer in China's reform and opening-up policies and high-quality development. This study analyzes the high-quality development of the economic, social, and ecological environments from 2010 to 2019 in Guangdong with the entropy weight TOPSIS model. Meanwhile, the coupling coordination degree model is used to investigate the spatial-temporal pattern of the coupling and coordinated development of the three-dimensional system in 21 prefecture-level cities. The results show that the high-quality development index of Guangdong increased from 0.32 to 0.39, a 21.9% increase during 2010-2019. The Pearl River Delta had the highest value of the high-quality development index, whereas Western Guangdong had the lowest level in 2019. Guangzhou, Shenzhen, Zhuhai, and Dongguan are the core cities in the high-quality development of Guangdong, with the index decreasing from the Pearl River Delta estuary cities to the province's edge. We also found that the coupling degree and coupling coordination of high-quality development of the three-dimensional system grew slowly during the study period. Half of the cities in Guangdong entered the stage of benign coupling. Except for Zhaoqing, all cities in the Pearl River Delta have a high coupling coordination degree of high-quality development of the three-dimensional system. This study provides valuable references for the high-quality, coordinated development of Guangdong province and some policy suggestions for other regions.

Behavioral characteristics in sensing mechanism of the Corti.

Some experiments can't be realized because the cochlea's Corti is the most delicate and complex sensory organ. In this paper, some typical and special behavioral characteristics in the process of sensation were found in medical clinic. Based on the interdisciplinary principles of medicine, physics and biology, a real numerical simulation model of Corti is established. On the basis of verifying the correctness of the model, the mechanism corresponding to these typical and special behavior characteristics in the process of sensation is explored through simulation calculation and analysis. This study provides theoretical and applied basis for people to better understand the sound sensing mechanism, and provides a numerical simulation platform for further analyzing Corti's sensing mechanism and good clinical application.

Development of an Assessment Model for the Effect of the Replacement of Minimal Artificial Ossicles on Hearing in the Inner Ear.

Due to ethical issues and the nature of the ear, it is difficult to directly perform experimental measurements on living body elements of the human ear. Therefore, a numerical model has been developed to effectively assess the effect of the replacement of artificial ossicles on hearing in the inner ear. A healthy volunteer's right ear was scanned to obtain CT data, which were digitalized through the use of a self-compiling program and coalescent Patran-Nastran software to establish a 3D numerical model of the whole ear, and a frequency response of a healthy human ear was analyzed. The vibration characteristics of the basilar membrane (BM) after total ossicular replacement prosthesis (TORP) implantation were then analyzed. The results show that although the sound conduction function of the middle ear was restored after replacement of the TORP, the sensory sound function of the inner ear was affected. In the low frequency and medium frequency range, hearing loss was 5.2~10.7%. Meanwhile, in the middle-high frequency range, the replacement of a middle ear TORP in response to high sound pressure produced a high acoustic stimulation effect in the inner ear, making the inner ear structures susceptible to fatigue and more prone to fatigue damage compared to the structures in healthy individuals. This developed model is able to assess the effects of surgical operation on the entire hearing system.

Study of fatigue damage to the cochlea.

In order to explore the hearing loss resulting from exposure to continuous or intermittent loud noise. A three-dimensional liquid-solid coupling finite element model of spiral cochlea was established. The reliability of the model was verified, and the stress and amplitude of the basilar membrane of the pivotal structure in cochlea were analyzed. The results show that under the action of the same high-pressure sound, the preferential fatigue area of the cochlear high-frequency area mainly causes fatigue in the cochlear. The safer area is a sound pressure level below 70 dB, while one above 90 dB accelerates damage to the ear.

Modified oropharyngeal muscle training and scientific vocalization are effective in treating mild-to-moderate obstructive sleep apnea hypoventilation syndrome in adults.

BACKGROUND: Obstructive Sleep Apnea-hypopnea Syndrome (OSAHS) has become a major public health challenge globally. Most patients have a concomitant voice disorder. The existing treatment methods have problems.Aims/Objectives: This study investigates the therapeutic effect of adding scientific vocalization to oropharyngeal muscle training on OSAHS patients. MATERIAL AND METHODS: A total of 30 patients were selected from September 2020 to October 2022. They underwent overnight polysomnography (PSG) and were identified as having mild to moderate obstructive sleep apnea hypoventilation syndrome. They were then chosen for a three-month period of modified oropharyngeal muscle training combined with scientific vocalization. RESULTS: Out of the 30 selected patients, 26 patients completed the training. Results showed a significant changes in multiple sleep-related indicators. he clinical outcomes were as follows: 7 cases were cured, 13 cases were effective, and 6 cases were ineffective. The overall effective rate was 76.92%. CONCLUSIONS AND SIGNIFICANCE: The combination of oropharyngeal muscle training and scientific vocalization for the treatment of mild to moderate OSAHS in adults significantly improves several measures used in the treatment of the condition. The method is easy to learn, effective, safe to use, and affordable. It provides more options for the treatment of OSAHS.

LncRNA OIP5-AS1 Knockdown Targets miR-183-5p/GLUL Axis and Inhibits Cell Proliferation, Migration and Metastasis in Nasopharyngeal Carcinoma.

Nasopharyngeal carcinoma (NPC) is often associated with the infection of Epstein-Barr virus in nasopharynx and is mainly happened in South China and Southeast Asia. Recently, noncoding RNAs have been reported to regulate NPC carcinogenesis. LncRNA OIP5-AS1 participates in tumorigenesis and progression; however, the inherent mechanism of OIP5-AS1-mediated progression of NPC is unclear. In the current study, we aimed to explore the role of OIP5-AS1 in NPC progression. We measured the cell viability, apoptosis, migration, and invasion in NPC cells after OIP5-AS1 modulation. Moreover, we determined whether OIP5-AS1 exerts its oncogenic functions via sponging miR-183-5p in NPC. Furthermore, we determined whether glutamate ammonia ligase (GLUL) was a downstream target of miR-183-5p. We found that OIP5-AS1 downregulation inhibited the viability, migration and invasion of NPC via targeting miR-183-5p. We also identified that GLUL might be a potential downstream target of miR-183-5p in NPC cells. Mechanistically, OIP5-AS1 promotes cell motility via regulating miR-183-5p and GLUL in NPC cells. We concluded that OIP5-AS1 performed its biological functions via targeting miR-183-5p and GLUL in NPC cells.

Towards improved modeling of SOC decomposition: soil water potential beyond the wilting point.

Soils are important carbon (C) reservoirs and play a critical role in regulating the global C cycle. Soil water potential (SWP) measures the energy with which water is retained in the soil and is one of the most vital factors that constrain the decomposition of soil organic C (SOC). The measurements for soil water retention curve (SWRC), on which the estimation of SWP depends, are usually carried out above -1.5 MPa (i.e., the wilting point for many plants). However, the average moisture threshold at which soil microbial activity ceases is usually below -10 MPa in mineral soils. Beyond the measurement range, the SWP estimation has to be derived from extrapolating the SWRC, which violates the statistical principle, resulting in possibly inaccurate SWP estimations. To date, it is unclear to what extent the extrapolated SWP estimation deviates from the "true value" and how it impacts the modeling of SOC decomposition. This study combined SWRC measurements down to -43.7 MPa, a 72-day soil incubation experiment with four moisture levels, and an SOC decomposition model. In addition to the complete SWRC (SWRCall ), we fitted two more SWRCs by using measurements above -0.5 MPa (SWRC0.5 ) and -1.7 MPa (SWRC1.7 ), respectively, to quantify the deviations of extrapolated SWPs from the complete SWRC. Results showed that extrapolating the SWRC beyond its measurement range significantly underestimated the SWP. Incorporating the extrapolated SWP in the model significantly underestimated the SOC decomposition under relatively dry conditions. With the extrapolated SWP, the model predicted no SOC decomposition in the driest treatment, while the experiment observed a significant CO2 emission. The results emphasize that accurate SWP estimations beyond the wilting point are critically needed to improve the modeling of SOC decomposition.